Evidence Report/Technology Assessment

Number 70

Criteria for Determining Disability in Infants and 

Children: Low Birth Weight

Volume 1. Evidence Report and Appendixes

Prepared for: 

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services

2101 East Jefferson Street

Rockville, MD 20852

www.ahrq.gov

Contract No. 290-97-0019

Prepared by:

Tufts New England Medical Center EPC, Boston, MA

Principal Investigator

Cynthia Cole, MD, MPH

Investigators

Geoffrey Binney, MD, MPH

Patricia Casey, RNC, MS, NNP

John Fiascone, MD

James Hagadorn, MD

Chiwan Kim, MD

EPC Staff

Joseph Lau, MD, Director

Chenchen Wang, MD, MSc., Project Leader

Deirdre DeVine, M Litt, Project Manager

Kimberly Miller, BA, Research Assistant

AHRQ Publication No. 03-E010

December 2002
This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the 

quality of health care, reduce its cost, address patient safety and medical errors, and broaden access 

to essential services. AHRQ sponsors and conducts research that provides evidence-based 

information on health care outcomes; quality; and cost, use, and access. The information helps 

health care decisionmakers—patients and clinicians, health system leaders, and policymakers—

make more informed decisions and improve the quality of health care services.
ii

This document is in the public domain and may be used and reprinted without permission except 

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Suggested Citation:

Cole C, Hagadorn J, Kim C, et al. Criteria for Determining Disability in Infants and Children: 

Low Birth Weight. Evidence Report/Technology Assessment No. 70 (Prepared by Tufts New 

England Medical Center Evidence-based Practice Center under Contract No. 290-97-0019). 

AHRQ Publication No. 03-E010. Rockville, MD: Agency for Healthcare Research and Quality. 

December 2002.
iii

Preface

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, 

Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 

6010 Executive Blvd., Suite 300, Rockville, MD 20852.

Carolyn M. Clancy, M.D.

Acting Director

Agency for Healthcare Research and Quality

Robert Graham, M.D.

Director, Center for Practice and 

 Technology Assessment 

Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report 

should not be construed as endorsement by the Agency for Healthcare Research and 

Quality or the U.S. Department of Health and Human Services of a particular drug, 

device, test, treatment, or other clinical service.
iv

Acknowledgments

The authors are grateful to the following individuals for their diverse contributions throughout 

the course of this project: Catherine Cella, Janet Connelly, Kyle Fahrbach, Kimberly James, 

Michael Rozinsky, members of the Technical Expert Panel, peer reviewers, representatives from 

the Social Security Administration, and representatives from the Agency for Healthcare Research 

and Quality.
v

Structured Abstract

Objective. The Social Security Administration (SSA) of the Department of Health and Human 

Services requested that the Agency for Healthcare Research and Quality (AHRQ), through its 

Evidence-based Practice Center (EPC) program, produce an evidence report to determine 

whether specific factors or combination of factors alone or in addition to birth weight predict 

significant developmental disability in former premature infants and whether premature infants 

with such factors have long-term deve lopmental disabilities.

Search Strategy. Studies with original data used in this evidence report were identified through 

MEDLINE® searches of the English language literature published between 1966 and January 

2002. Additional studies were identified from supplemental searches in ERIC, PsycInfo, 

HealthStar and Embase and from reference lists, review and primary articles, and from domain 

experts.

Selection Criteria. We reviewed retrospective and prospective studies reporting impairments in 

infants or children who weighed 2,000 grams or less, whose gestational age was 35 week or less, 

or whose birth weight or gestational age were below these thresholds. Preferences were given to 

recent studies and studies with a minimum of 6 months of follow-up.

Data Collection and Analysis. We incorporated 178 English language articles in the evidence 

report. Relevant data from each article were abstracted into evidence tables. Information from 

the evidence tables was synthesized into summary tables describing the findings of each study. 

Studies were graded according to the methodological quality and applicability.

Main Results. We looked for evidence of association of very low birth weight (VLBW defined 

as <1500 grams) with six outcome conditions. The evidence of the literature overwhelmingly 

supports that the risk of cerebral palsy (CP) and major neurologic disability is increased among 

VLBW infants compared to full-term infants. The literature is consistent in demonstrating that 

risk of CP, major neurosensory and/or neurologic disability is inversely proportional to the 

degree of immaturity whether measured by gestational age or by birth weight.

The evidence demonstrates that children who were born VLBW have significantly higher rates 

of cognitive abnormality in early childhood and a several-fold increased prevalence of IQ <70 as 

adults compared with children or adults who were born normal birth weight at term. There is 

evidence that even children who were apparently “well” VLBW infants during their neonatal 

course are also at significantly greater risk for both moderate and severe delay compared to 

larger birth weight groups.

VLBW infants are at high risk for developing cognitive, neuromotor, and neurosensory 

disabilities including blindness and hearing loss. These disabilities in turn may lead to other 

disabilities in speech and language, behavior problems and learning disabilities affecting school 

performance. All of the above problems have been identified in disproportionate numbers in the 

VLBW infants.

The studies provided strong evidence of increased incidence of speech and language delays 

in VLBW and extremely premature infants, and identified clinical factors associated with the 

increased incidence. Across all measures of short-term memory and language outcomes, 
vi

preschool children who were born preterm performed at a lower level than children who were 

full-term counterparts. These deficits were independent of the general IQ.

The evidence identified by this review clearly demonstrates that children born as VLBW 

infants, with or without retinopathy of prematurity (ROP), are at significantly increased risk of 

visual impairments and disability compared to children born full term. The risk of visual 

disability in VLBW infants varies inversely with gestational age.

The studies reviewed indicate that VLBW infants with bronchopulmonary dysplasia (BPD) 

are at increased risk for long-term pulmonary disability. The greater the severity of BPD, the 

greater is the association with long-term pulmonary impairment and need for re-hospitalization. 

VLBW infants, with or without other conditions, are at high risk for poor growth during the 

first years of life due to acute neonatal illnesses, developmental delays, and chronic illnesses.

Conclusions. Surviving premature infants often sustain multi-organ system complications that 

may persist beyond the first few years of life and frequently result in permanent impairments. 

Complications of even a single organ system may have a profound impact upon other organ 

systems. Biomedical determinants of disability in premature infants are often compounded by 

adverse determinants of social and psychological adaptation of these vulnerable children and 

their families.
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Contents

Summary...................................................................................................................................... 1

Evidence Report

Chapter 1. Introduction................................................................................................................ 15

Definition of Disability.......................................................................................................... 15

Definition of Prematurity....................................................................................................... 15

The Problem of Prematurity.................................................................................................. 16

Factors Associated with Disability in VLBW Infants........................................................... 17

Chapter 2. Methods.................................................................................................................... 21

Key Questions Addressed by the Evidence Report............................................................... 21

Literature Search Strategies................................................................................................... 22

Search Results.................................................................................................................. 22

Limitations of the Literature Search................................................................................ 23

Study Selection...................................................................................................................... 23

Results from Abstract Screening..................................................................................... 23

Revised Study Selection Criteria..................................................................................... 24

Outcomes and Predictors Considered in this Evidence Report............................................. 24

Data Abstraction Process................................................................................................. 26

Reporting the Evidence......................................................................................................... 27

Evidence Tables............................................................................................................... 27

Summarizing the Evidence of Individual Studies................................................................. 28

 Methodological Quality................................................................................................... 28

Applicability.................................................................................................................... 29

Results............................................................................................................................. 30

Chapter 3. Results....................................................................................................................... 31

 Evidence that VLBW With or Without Other Conditions is Associated With 

 Cerebral Palsy (CP) and Neurologic Disability................................................................ 31

 Definition of CP, Neurologic Vulnerability of Immature Brain, and 

 Detection Of Brain Injury...................................................................................... 32

 Evidence that VLBW Infants have Increased Risk of CP and Neurologic 

 Disability................................................................................................................ 32

 Evidence that VLBW Plus Other Factors are Associated with CP and 

 Neurologic Abnormalities...................................................................................... 42

 Evidence that VLBW With or Without Other Conditions is Associated with 

 Abnormal Cognitive Development and MR..................................................................... 54

 Definitions and Assessment of Cognitive Development........................................ 55

 Evidence that VLBW Infants are at Increased Risk of MR and Estimates 

 of Prevalence.......................................................................................................... 56

 Evidence that Specific Risk Factors are Independently Associated with MR in 

 VLBW Infants........................................................................................................ 60
viii

Evidence that VLBW is Associated with Disabilities of Speech/language Delay,

 Hearing Loss, Behavioral Disorders, and Learning Disabilities....................................... 77

 Speech, Language, and Communication Disorder Outcomes................................ 78

 Audiology Outcomes.............................................................................................. 83

 Behavioral/Social Outcomes.................................................................................. 89

 Learning Disability/School Performance Outcomes.............................................. 93

 Evidence that VLBW With or Without Other Conditions is Associated with Visual

 Disability.......................................................................................................................... 96

 Evidence that VLBW Infants have Increased Visual Disability............................ 97

Evidence that VLBW Infants with Retinopathy of Prematurity (ROP) have 

Visual Disability..................................................................................................... 102

Evidence that VLBW Infants with CNS Abnormality have Visual 

Disability (with No or Mild ROP) ......................................................................... 109

Evidence that VLBW and/or ROP and/or CNS Injury are Positively 

Associated With Refractive Error (Myopia) and Ocular Motility 

(Strabismus)............................................................................................................ 111

 Evidence that VLBW Plus Bronchopulmonary Dysplasia (BPD) and 

Systemic Glucocorticosteroid Therapy for Bronchopulmonary Dysplasia 

are Associated with Visual Disability.................................................................... 114

 Evidence that VLBW Infants have Increased Incidence of Ophthalmic 

 Interventions Due to Visual Disability................................................................... 115

 Evidence that VLBW With or Without Other Conditions is Associated with 

 Pulmonary Disability........................................................................................................ 116

Bronchopulmonary Dysplasia (BPD): Definition, Background, and 

Significance................................................................................. 116

 Pulmonary Outcome Measures............................................................................... 117

 Evidence that VLBW with BPD is Associated with Long-term Pulmonary 

 Morbidity and Disability by Duration of Follow-up.............................................. 118

 Pulmonary Function Testing and Exercise Tolerance............................................ 124

 Evidence that VLBW is Associated with Asthma or Hyper-reactive 

Airway Disease....................................................................................................... 125

 Evidence that VLBW Infants have Increased Rehospitalization for 

Respiratory Illness.................................................................................................. 126

Evidence that VLBW with or without Other Conditions is Associated with 

 Growth Impairment.......................................................................................................... 128

 Evidence that VLBW is Associated with Growth Impairment.............................. 129

 Evidence that VLBW plus BPD is Associated with Growth Impairment............. 132

Evidence that VLBW plus Antenatal Glucocorticoid Exposure is Associated 

with Growth Impairment........................................................................................ 133

 Evidence that VLBW Plus Necrotizing Enterocolitis is Associated with 

Growth Impairment................................................................................................ 133

 Evidence Linking VLBW Plus Postnatal Nutrition with Growth 

Impairment............................................................................................................. 134

Chapter 4. Conclusions............................................................................................................. 137
ix

Overall............................................................................................................................... 137

 Neurodevelopmental Disabilities..................................................................................... 137

 Speech and Language....................................................................................................... 139

 Visual Disability............................................................................................................... 139

 Pulmonary Disability........................................................................................................ 140

 Poor Growth..................................................................................................................... 141

Chapter 5. Future Research........................................................................................................ 143

Evaluation of the Application Process of SSA VLBW Disability Criteria....................... 143

 Determine the Appropriateness of the New VLBW Disability Criteria Proposed by 

SSA Based on the Evidence of this Report....................................................................... 143

 Proposal to Improve the Evidence of Predictors and Predictive Models.......................... 144

 Improve Definitions of Predictors........................................................................... 144

 Identify New Predictors........................................................................................... 144

Feasibility of Future Research Proposals......................................................................... 145

References/Bibliography............................................................................................................ 147

Appendixes

Appendix A. Search Strategies........................................................................................ 161

Appendix B. Data Abstraction Form............................................................................... 169

Appendix C. Acronyms and Abbreviations..................................................................... 179

Appendix D. Acknowledgements.................................................................................... 181

Tables 

Table A. Live birth distribution organized by birth weight and gestation in the United 

States in the year 2000........................................................................................... 16

Table B. Mortality and Morbidity of Premature Infants by Birth Weight Born in NICHD 

Neonatal Research Network Between January 1, 1993 and December 31, 1994 17

Table C. Inclusion/exclusion Criteria................................................................................... 24

Table D. List of Predictors and Outcomes............................................................................ 25

Table E. Evidence Tables Created in this Report................................................................. 27

Table 1.1a Association of Cerebral Palsy with VLBW/Prematurity (Prevalence of CP in 

observational studies) ........................................................................................... 32

Table 1.1b Association of Cerebral Palsy with LBW/Prematurity (Prevalence of CP in 

Clinical Trials) ...................................................................................................... 38

Table 1.2a Association of Cerebral Palsy with LBW/Prematurity.......................................... 40

Table 1.3a Association of CP and Neurologic Abnormalities to VLBW plus CNS Injury 42

Table 1.3b Association of CP and Neurologic Abnormalities with Antenatal Factors in 

VLBW Infants........................................................................................................ 47

Table 1.3c Association of CP and Neurologic Abnormalities to VLBW plus BPD and 

Postnatal Systemic Glucocorticoid Therapy.......................................................... 51
x

Table 1.3d Association of CP and Neurologic Abnormalities to Parenting/Psychological 

Factors in VLBW Infants....................................................................................... 53

Table 1.3e Association of CP and Neurologic Abnormalities to VLBW Plus Other 

Factors (Gender Size of GA)............................................................. 53

Table 2.1 Representative Ability Test Scores Defining Significantly Delayed or Deficient

Cognitive Development/Mental Retardation........................................................ 55

Table 2.2 Incidence of Mental Retardation in VLBW/ELBW Infants.................................. 56

Table 2.3 Changes in Incidence of MR with Time............................................................... 59

Table 2.4 Association of Mental Retardation/Disability to Independent Risk Factors in 

LBW Infants......................................................................................................... 60

Table 2.5 Association of Mental Retardation/Disability with Other Risk Factors in LBW 

Infants................................................................................................................... 76

Table 3.1 Association of LBW to Speech and Language Disorders..................................... 79

Table 3.2 Association of VLBW with Hearing Loss............................................................ 84

Table 3.3 Association of LBW to Behavior Outcomes......................................................... 89

Table 3.4 Association of LBW to Learning Disability and School Performance.................. 94

Table 4.1 Association of VLBW/Prematurity with Ophthalmology Outcomes.................... 97

Table 4.2a Visual Disability Related to Increasing Severity of ROP in VLBW 

Infants.................................................................................................................... 103

Table 4.2b Proportion (%) of Eyes with Unfavorable Visual Function.................................. 104

Table 4.3 Unfavorable Functional Outcome (%) in Eyes with Threshold ROP by 

Randomized Treatment Assignment (Cryotherapy vs. No Cryotherapy) 

during 1, 3.5, 5.5 and 10-year Follow-up.............................................................. 105

Table 4.4 Visual Disability Related to Severe (Threshold) ROP.......................................... 107

Table 4.5 Evidence that VLBW Infants with CNS Abnormality Have Visual Disability 

(with no or mild ROP) .......................................................................................... 109

Table 4.6 VLBW and/or ROP and/or CNS Injury are Positively Associated with 

 Refractive Error (Myopia) and Ocular Motility (Strabismus) ............................. 111

Table 4.7 Abnormal Visual Function Due to Fixation Instability (Nystagmus and 

 Strabismus) in VLBW Infants.............................................................................. 113

Table 4.8 Association Between VLBW Plus Bronchopulmonary Dysplasia (BPD) and 

Systemic Glucocorticosteroid Therapy for Bronchopulmonary Dysplasia

 with Visual Disability........................................................................................... 115

Table 5.1 Percent of Infants with BPD in Relation to Birth Weight in the Vermont Oxford 

Neonatal Network.................................................................................................. 117

Table 5.2a VLBW with BPD is Associated with Long-term Pulmonary Morbidity and 

Disability by 1-2 Year of Follow-up...................................................................... 118

Table 5.2b VLBW with BPD is Associated with Long-term Pulmonary Disability by 3 

year of Follow-up.............................................................. .................................... 121

Table 5.2c VLBW with BPD is Associated with Long-term Pulmonary Disability by 6-12 

 year of Follow-up............................................................. .................................... 122

Table 5.2d VLBW with BPD is Associated with Long-term Pulmonary Disability by 12-16

 years of Follow-up.............................................................. ................................. 123

Table 5.3 Association of VLBW/Prematurity with Asthma or Hyper-reactive Airway 

 Disease.................................................................................................................. 125
xi

Table 5.4 Association of VLBW/Prematurity with Rehospitalization for Respiratory 

 Illness: Pulmonary Outcomes............................................................................... 127

Table 6.1 Association of VLBW/Prematurity with Growth Impairment.............................. 129

Table 6.2 Association of VLBW plus BPD with Growth Impairment.................................. 132

Table 6.3 Association of VLBW plus Antenatal Glucocorticoid Exposure with Growth 

Impairment........................................................................................ .................... 133

Table 6.4 Association of VLBW plus Necrotizing Entercolitis Exposure with Growth 

Impairment............................................................................................................. 133

Table 6.5 Association of VLBW plus Postnatal Nutrition with Growth Impairment........... 134

Table 6.6 Association of LBW/Prematurity to Growth Delay.............................................. 136
Overview

The Social Security Administration (SSA) of the

Department of Health and Human Services

requested that the Agency for Healthcare Research

and Quality (AHRQ), through its Evidence-based

Practice Center (EPC) program, produce an

evidence report to determine whether specific

factors or a combination of factors alone or in

addition to birth weight predict significant

developmental disability in former premature

infants and whether premature infants with such

factors have long-term developmental disabilities.

This evidence report is prepared to assist the SSA

in updating its Listing of Impairments, and revising

its disability policy, as may be appropriate. This

report does not provide or suggest a new listing of

impairments.

This report examines the evidence that Very

Low Birth Weight (VLBW) in infants (birth

weight <1,500 grams) with or without other

conditions is associated with long-term disabling

outcomes. The primary outcomes of interest

included in this report are cerebral palsy (CP),

mental retardation (MR), hearing/speech/

language/behavioral impairments, visual

impairments, adverse pulmonary function, and

disrupted growth.

The category of VLBW infants was chosen

because it is well recognized to represent a

population of infants, primarily premature infants,

at increased risk for acute and chronic

impairments related to their immaturity. VLBW is

often divided into subcategories of lower birth

weights, such as less than 1,250, less than 1,000,

and less than 750 grams, to facilitate analyses of

infants within different birth weight strata.

Extremely Low Birth Weight (ELBW) infants are

often defined as infants with birth weight less than

1000 grams, although this definition may vary

among studies by as much as 250 grams in either

direction. In general, the lower the birth weight,

the greater the degree of immaturity, and the

greater the risk for serious complications. 

Birth weight, however, is not a perfect measure

of immaturity since some infants may have birth

weights that are disproportionately large or small

for their gestational age. Many studies

appropriately and preferably use gestational age as

the marker of prematurity. Similar to birth weight,

gestational age categories of premature infants

often include groupings of premature infants less

than 32 weeks gestation, less than 30 weeks

gestation, less than 28 weeks gestation; or less than

26 weeks gestation. Less than 32 weeks gestational

age is considered by some authorities as “very

premature” and less than 28 weeks gestational age

as “extremely premature.”

Premature birth is an important public health

problem due to the number of premature births

each year, the serious acute complications of

prematurity, and the long-term sequelae directly

related to the vulnerability of VLBW infants.

Among the four million births in the United

States during the year 2000, about 58,000 (1.4%)

were VLBW (<1,500 grams). Although VLBW is

a relatively small proportion of total births in the

USA, this category of infants accounts for the

highest neonatal mortality and greatest morbidity

among newborns. The long-term complications

result in significantly increased tangible and

intangible lifelong costs to the family and society

for medical care as well as for ongoing ancillary

health and educational services.

Advances in neonatal/perinatal medicine have

improved the survival and the quality of survival

Evidence Report/Technology Assessment

Number 70

Criteria for Determining Disability in Infants and

Children: Low Birth Weight

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
of premature infants. Despite advances in medical care, infants

born prematurely experience a disruption in the normal process

of growth and development. The degree of disruption in the

growth and development of each organ system is a reflection of

the degree of immaturity and physiologic derangement.

Survival is inversely proportional to the degree of prematurity.

Recent evidence indicates that approximately 95 percent of

infants with birth weights between 1,251 and 1,500 grams

survive in contrast to approximately 75 percent of infants with

birth weight less than 1,250 grams. For any adverse sequela

associated with premature birth, the incidence as well as the

severity of the complication is inversely proportional to the

gestational age. For instance, 12 percent of infants with birth

weight between 1,251 and 1,500 grams survived with at least

one major morbidity in contrast to 53 percent with birth

weight 501 to 1,250 grams.

Surviving premature infants often sustain multi-organ system

complications that may persist beyond the first few years of life

and frequently result in permanent impairments. Examples

include major neurodevelopmental impairments, such as CP,

MR, deafness and disorders of speech/language/

communication; perception, attention, behavior and learning

disorders; blindness or other visual impairments; chronic lung

disease; and growth retardation. Complications of even a single

organ system may have a profound impact upon other organ

systems. Biomedical determinants of disability in premature

infants are often compounded by adverse determinants of social

and psychological adaptation of these vulnerable children and

their families.

Reporting the Evidence

Key questions of interest

This review addresses the following key questions of interest

to SSA.

For infants with birth weight <1,200 grams and for infants

with birth weights between 1,200 grams and 1,500 grams:

1. What factors or combination of factors alone or in

addition to birth weight will predict significant

developmental impairment in former premature infants? 

2. Are such infants developmentally impaired at 1 year, 2

years, or beyond?

In order to identify the functional or physical outcomes

related to disability and the elements that predicted them, we

sought evidence that a specific factor was significantly

associated with a specific disability (e.g., very low birth weight

infants with bronchopulmonary dysplasia [BPD] have lower

receptive language scores; or the degree of immaturity

influences the risk of CP and neurodevelopmental disability in

VLBW infants). We looked for evidence of association of

VLBW with six outcome conditions: 

• CP and neurological impairments

• Abnormal cognitive development and MR

• Speech/language delay, hearing loss, behavioral disorders,

and learning disabilities

• Visual impairment (with or without other conditions)

• Pulmonary impairment (with or without other

conditions)

• Growth impairment

Methods

A systematic literature search was performed for journal

articles with original data. English language studies were

identified primarily through MEDLINE® searches conducted

between October 2000 and February 2001. We performed an

updated search in September 2001 and again in January 2002.

Supplemental searches were also performed in ERIC,

PsychINFO, HealthSTAR and E<BASE. Additional studies

were identified from reference lists, review and primary articles,

and from domain experts and reviewers.

Disability is not a specific medical condition that can be

readily searched for. Thus we had to look at many studies with

related concepts (i.e., medically definable impairments that are

related to disability) to identify potentially relevant studies.

Therefore, we developed a comprehensive list of predictors and

outcomes by organ system and those that are associated with

VLBW infants. The predictor and outcomes then formed the

basis of literature search terms.

We focused the literature review primarily on premature

infants born weighing less than 1,500 grams, including all

subcategories of birth weights (e.g., less than 1,250 grams, less

than 1,000 grams, and less than 750 grams). We also

incorporated literature that included infants with birth weight

less than 1,500 grams within a larger premature cohort and

literature on infants whose prematurity was defined by

gestational age, since many studies use gestational age and not

birth weight criteria.

We reviewed retrospective and prospective studies reporting

impairments in infants or children who weighed 2,000 grams

or less, whose gestational age was 35 weeks or less, or whose

birth weight or gestational age were below these thresholds.

Longitudinal data for a minimum of 6 months was preferred.

We identified and screened 16,614 abstracts from the

literature searches. These abstracts covered 13 categories: central

nervous system (2,930 abstracts), opthalmology (398),

audiology (80), pulmonary (1,833), nutrition and growth

(2,533), medication (dexamethasone) (183), perinatal factors

(875), illness acuity (56), infectious diseases (2,378),

gastrointestinal (477), bone/osteomalacia (10), health care

(466), and immune disorder (921). Approximately 1,693

potentially relevant articles were retrieved after screening the

abstracts.

2
The very large number of articles precluded all of them from

being incorporated into the evidence report. We used the

following method to reduce the articles to a feasible number

and include the most relevant. We screened in articles that met

the minimum inclusion criteria for LBW, reported one or more

relevant clinical outcomes, had a followup duration greater than

or equal to 6 months, a study size greater than 10, and enrolled

patients born after 1980. We then established a hierarchy of

studies based on study size and birth year of the infants. Studies

with birth years from 1990 onward were given preference,

followed by studies with birth years between 1985 and 1989,

and then studies before 1985. Within each birth year cohort,

studies with more than 100 infants were selected first, followed

by studies with 50 to 100 infants and less than 50 infants.

Using this classification hierarchy, we worked through the most

relevant (recent) and strongest (largest study size) studies in

succession before older and smaller studies, until a complement

of 178 articles were reviewed.

We report the evidence organized by the six outcome

conditions listed under the key questions. We summarized the

evidence in three complementary forms. The evidence tables

provide detailed information about the features of study design

and results of all the studies reviewed. A narrative and a tabular

summary of the strength and quality of the evidence of each

study are provided for each outcome condition. The summary

tables describe the strength of the evidence according to four

dimensions: study size, applicability of the study population,

association of the factor of interest with impairments, and the

methodological quality of the study.

Findings

Evidence that VLBW With or Without Other

Conditions is Associated With Cerebral Palsy

(CP) and Neurologic Disability

The literature overwhelmingly supports evidence that the

risk of CP and major neurologic disability is increased among

VLBW infants compared to full-term infants. The literature is

consistent in demonstrating that risk of CP, major neurosensory

and/or neurologic disability is inversely proportional to the

degree of immaturity whether measured by gestational age or

by birth weight. The recently reported incidence of CP is

currently stable compared to the 1980s (7-10 percent VLBW

infants; 7-17 percent ELBW infants) or modestly decreased

despite improved survival of extremely immature infants. This

suggests that recent advances in neonatal care have had either

no or modest effect on further reduction in the incidence of

CP. Several studies demonstrated that the risk of major

neurosensory or neurologic disability may range from 12-50

percent among VLBW and ELBW infants. Despite the stable

risk of CP, the risk of disability, due primarily to visual

disabilities, has increased since the 1980s. Differences among

studies regarding the incidence of CP, neurologic, and

neurosensory disability may be accounted for by differences in

the criteria for neurologic/neurosensory disability, the era of

study, the degree of immaturity, and other characteristics or risk

factors of the patient population, neonatal care practices, as well

as length and completeness of followup.

Several articles in this review provide compelling evidence

that cerebral white matter damage (WMD), as manifested by

periventricular leukomalacia (PVL) (such as echodensities and

echolucencies), ventriculomegaly, posthemorrhagic cerebral

infarct, and severe intracranial hemorrhage are among the

strongest predictors of CP and other neurologic disabilities in

VLBW infants. Visual and ocular abnormalities are often

associated with neurodevelopmental abnormalities in VLBW

infants with cerebral white matter damage. The degree of visual

impairment correlates with the degree of neurodevelopmental

impairment. 

Increasing evidence indicates that antenatal events contribute

to the etiology and sequence of events leading to neurologic

impairment and CP in VLBW infants. Antenatal

inflammation, chorioamnionitis, subclinical infection, fetal

hypoxia/acidosis, and premature rupture of membranes (which

may be related to antenatal inflammation and infection) and

abruption appear to play an important role via stimulating a

fetal inflammatory response that injures the immature cerebral

white matter. 

Several studies documented that prolonged mechanical

ventilation and BPD are associated with increased adverse

neurodevelopmental outcome in premature infants compared

to infants without BPD or prolonged mechanical ventilation.

In addition, there is increasing evidence that the use of

postnatal systemic glucocorticoid therapy (specifically,

dexamethasone) for the prevention or treatment of neonatal

chronic lung disease may have an adverse effect on long-term

neurologic development and increase the risk of CP. The

evidence supports that BPD and systemic dexamethasone each

may be separate factors influencing the risk of CP and

neurologic impairment in VLBW infants. 

Studies also illustrate that VLBW infants with parenting,

social, and environmental risk factors are at increased risk for

neurodevelopmental disabilities. The relationship between

biological-medical risk factors and parenting-psychosocial risk

factors on subsequent neurodevelopmental outcome is

complex. The interaction of these factors may have synergistic

effects on an infant’s outcome. 

Evidence that VLBW With or Without Other

Conditions is Associated With Abnormal

Cognitive Development and Mental

Retardation (MR)

The evidence demonstrates that children who were born

VLBW have significantly higher rates of cognitive abnormality

in early childhood and a several-fold increased prevalence of IQ

<70 as adults compared with children or adults who were born

normal birth weight at term. Given current rates of birth and

3
VLBW in the USA, these results suggest that there may be

more than 3,500 new cases of MR in the United States each

year in former VLBW infants. There is evidence that even

children who were apparently “well” VLBW infants during

their neonatal course are also at significantly greater risk for

both moderate and severe delay compared to larger-birthweight groups.

Among children born as ELBW infants, the prevalence of

MR is even higher than in VLBW infants, who are larger than

ELBW infants. Approximately 40 percent of ELBW survivors

have Bayley Mental Development Index (MDI) <70, half of

ELBW survivors have at least one significant

neurodevelopmental impairment, and 20-35 percent of ELBW

survivors have two or more impairments. Evidence suggests

that the incidence of MR in ELBW infants is not changing

with time, despite recent increases in survival rates in this birth

weight category. Our search methods identified evidence that

birth weight is a useful factor in identifying VLBW infants at

especially high risk for MR. However, once the range of birth

weight and gestational age are narrowed to the most immature

infants, and stronger predictors of neurodevelopmental

outcome are taken into consideration, the evidence that birth

weight or gestational age is useful in identifying VLBW infants

at high risk for MR was mixed. 

Intraventricular hemorrhage (IVH), particularly severe (i.e.,

grade III or IV) IVH, PVL, and ventriculomegaly are also

among the strongest independent predictors of cognitive

impairment and MR in VLBW and ELBW infants. Infants

with a combined outcome IVH ≥ grade III or PVL are more

than twice as likely to have Bayley MDI <70 as those without

these findings, after adjusting for the effect of other clinical

factors. 

Recent studies strongly document a significant independent

relationship between BPD and abnormal neurodevelopment in

both VLBW and ELBW infants. This effect of BPD on long

term outcome is independent from the many co-morbid

conditions commonly seen concurrently in VLBW infants,

such as intraventricular hemorrhage, posthemorrhagic

hydrocephalus and periventicular leukomalacia. Evidence

strongly indicates that postnatal systemic steroid therapy

(dexamethasone) for the amelioration or prevention of BPD is

an independent determinant of abnormal cognitive

development in ELBW infants after adjusting for clinical

factors and associated with almost two-fold increased risk of

Bayley MDI <70. 

Our search methods identified many strong studies

documenting a significant independent association between

parenting-pychosocial risk factors and cognitive development in

VLBW infants even after accounting for the effects of

intraventricular hemorrhage and chronic lung disease. Methods

used to measure social risk are numerous, however, and the

identified evidence in the literature is not always sufficient to

distinguish the independent effects of various commonly

examined elements of social risk, such as race, economic status,

or level of maternal education. The quality of parent-infant

interactions may play an important role in cognitive

development of VLBW infants. The variability among studies

with respect to the association of parenting-pyschosocial risk

and cognitive outcome may be accounted for by differences

among studies with respect to population characteristics,

sample size, age of assessment, ascertainment of other potential

confounding factors, accuracy of methods/measures used to

determine social risk, parenting risk, and other socioeconomic

markers.

The identified evidence suggests that race may be an

independent predictor of cognitive development in VLBW

infants with black race among the social risk factors associated

with an approximately 50 percent increased risk of subnormal

Bayley MDI. 

The level of maternal education was identified as a

significant independent predictor of abnormal cognitive

development in VLBW and ELBW infants. One

methodologically strong study found that maternal education

less than high school graduate level increased risk of Bayley

MDI <70 almost two-fold. 

The identified evidence suggests that gender may be a

significant independent predictor of MR among ELBW

infants, but this relationship may be less significant in larger

birth weight categories. 

Evidence suggests that illness severity scoring systems may be

useful in identifying infants at risk for MR. Durations of

various therapies such as mechanical ventilation, intravenous

nutrition, etc. are markers of illness severity and may be tested

as independent predictors of outcome. 

The evidence identified by our search methods was equivocal

regarding the utility of antepartum and intrapartum factors as

independent predictors of MR. Strong studies suggested that

specific antepartum factors (e.g., use of antenatal steroids,

maternal hypertension, route of delivery, or inborn versus

outborn) do not provide a useful contribution to prediction of

MR in ELBW infants after accounting for other clinical factors. 

The identified evidence regarding intrauterine growth

retardation/small for gestational age (IUGR/SGA) as an

independent risk factor for MR was equivocal. One study

documented worse cognitive development in children who

were SGA VLBW infants compared with appropriate

gestational age (AGA) VLBW infants. Other studies that found

that SGA ELBW infants were not at increased risk for cognitive

delay compared with their AGA peers after adjusting for other

clinical factors. 

Our methods located no studies examining the relationship

between necrotizing enterocolitis (NEC) and subsequent

cognitive development in VLBW infants.

4
Our search methods identified studies that examined the

relationship between sepsis or meningitis and subsequent

cognitive development in VLBW infants. Two studies found

that neither sepsis nor meningitis was associated with cognitive

outcome in ELBW infants after adjusting for other clinical

factors. 

Evidence that VLBW is Associated With

Speech/Language Delay, Hearing Loss,

Behavioral Disorders, and Learning

Disabilities

VLBW infants are at high risk for developing cognitive,

neuromotor, and neurosensory disabilities including blindness

and hearing loss. These disabilities in turn may lead to other

disabilities in speech and language, behavior problems, and

learning disabilities affecting school performance. All of the

above problems have been identified in disproportionate

numbers in the VLBW infants.

The studies provided strong evidence of increased incidence

of speech and language delays in VLBW and extremely

premature infants, and identified clinical factors associated with

the increased incidence. One study emphasized higher

prevalence of functional limitations in most language domains

with children who were born ELBW. Children who were

ELBW have a higher utilization rate of speech therapists and

require more educational and health care services. Across all

measures of short-term memory and language outcomes,

preschool children who were born preterm performed at a

lower level than children who were full-term counterparts.

These deficits were independent of the general IQ. 

In overall communication skills, children who had BPD as

preterm neonates scored significantly lower than the other

comparison non-BPD groups. Even after controlling for lower

IQ, children who were VLBW infants with BPD have lower

receptive language scores. 

Data on the incidence of hearing loss in ELBW infants is

conflicting. Four excellent, recent studies report higher

incidence ranging from 9 to 14 percent and nine studies report

rates (~1-2 percent) similar to their full-term controls. This

variability may be due to differences in testing methods. 

There is good evidence that VLBW infants have increased

attention problems and more passive temperament. Intracranial

lesions, CP, impaired cognition, and urban socioeconomic

setting was associated with the increased incidence.

Available evidence suggests that VLBW and ELBW infants

are at higher risk for developing learning disabilities and have

difficulty in school. Studies of school learning problems at 6

years may be too early and may miss children with less grossly

obvious difficulties. 

One study provided evidence that even seemingly “healthy”

premature infants may have later sequelae needing special

assistance. The well-preterm group, compared to full-term

controls, had significantly higher than expected incidence of

minimal brain dysfunction including attention deficit disorder,

learning disabilities, language impairment, mild neurologic

impairment, and general school concerns. In fact, only 25

percent had no concerns by grade 5 compared to 57 percent in

term controls. The mother’s perception of their infants’

competence was a sensitive marker for disabilities. 

Evidence that VLBW With or Without Other

Conditions is Associated With Visual Disability

The evidence identified by this review clearly demonstrates

that children born as VLBW, with or without retinopathy of

prematurity (ROP), are at significantly increased risk of visual

impairments and disability compared to children born full

term. The risk of visual disability in VLBW infants varies

inversely with gestational age. The risk of having any

ophthalmic morbidity (e.g., significant reduction in visual

acuity tests or presence of strabismus, myopia, color vision

defect, or visual field defect) is two-fold greater in children born

VLBW infants and five-fold greater in children born ELBW

compared to children born at term. Ophthalmic morbidity

(i.e., greatest reduction in visual acuity or incidence of

strabismus, myopia, etc.) is highest in eyes with severe (Stage 3

or 4) ROP. No or regressed mild ROP, by itself, has no major

important long-term effect on visual acuity, although children

born prematurely with no or regressed mild ROP may have

statistically significantly reduced visual acuities compared with

full-term controls. 

The risk of blindness is higher in ELBW infants compared

to normal birth weight controls and is inversely related to birth

weight or gestational age. The reported incidence of blindness

in ELBW infants, the population at greatest risk for visual

disability, ranges from 1 to 4 percent in most studies identified

in this review. 

Retinal ablation with cryotherapy or laser therapy for severe

(i.e., threshold) ROP significantly reduces the incidence of

blindness and unfavorable outcome, especially in Zone 2

threshold eyes. Despite this benefit, infants successfully treated

with cryotherapy still had an unacceptably high risk of

unfavorable functional outcome (44.4 percent of treated eyes).

Unfavorable outcome was particularly true in eyes with Zone 1

(posterior pole) threshold ROP regardless of whether or not the

eye received cryotherapy (i.e., poor outcome in 75 percent of

Zone 1 treated eyes and 92 percent of not treated eyes).

Unfavorable outcome of successfully treated eyes is most likely

a reflection of the severity of the underlying retinal injury and

of the disruption in normal growth and development of the

retina. Retinal ablative therapy (cryotherapy or laser therapy)

for threshold ROP is cost effective therapy that can improve the

quality of life. Laser therapy can reduce the risk and/or severity

of myopia, which is a major complication of premature infants,

especially in premature infants with severe ROP. Any reduction

in myopia is important in terms of long-term visual benefit.

5
A 10-year followup of premature infants with threshold

ROP revealed that the rate of retinal detachment among

control (no cryotherapy) threshold eyes increased at 5.5 years

(38.6 percent) and again at 10 years of age (41.4 percent), after

having been “stable” during the first 3 years of followup. The

rate of retinal detachment remained stable in treated eyes (22.0

percent). Eyes with severe ROP and not treated, have smaller

visual fields compared to eyes that never had ROP. Eyes treated

with cryotherapy had a further reduction in the visual fields. At

the 10-year outcome, treated and control threshold eyes are

equally likely to have 20/40 visual acuity, but this is the

minority of threshold eyes.

VLBW infants are also at increased risk for non-retinal

ophthalmic diseases. Cortical visual impairment is visual

impairment due to central nervous system (CNS) damage.

Causes of cortical visual impairment in VLBW infants include

hypoxic-ischemic-hemorrhagic and /or inflammatory injury

(antenatal, perinatal, or postnatal) which may be manifested in

the neonatal period as periventricular leukomalacia,

ventriculomegaly, intracranial hemorrhage, and

posthemorrhagic hydrocephalus. Neuroimaging of VLBW

infants via cranial ultrasonography, cranial tomography, and

magnetic resonance imaging (MRI) techniques has provided

strong evidence that central nervous system injury, especially

periventricular leukomalacia, is associated with visual disability

and other neurodevelopmental abnormalities, including motor

and perceptual abnormalities. The strong association of visual

impairment with the extent of MRI evidence of cerebral white

matter damage and the concomitant occurrence of

neurodevelopmental disability in premature infants is well

documented. 

One study demonstrated that even healthy preterm children

with no detectable neurodevelopmental problems on screening

examinations, have evidence of visual-motor disabilities when

these functions are specifically tested.

There is long-standing evidence that the risk and degree of

myopia increases with the degree of prematurity, degree of ROP

severity, and with central nervous system injury. Myopia is the

most common ophthalmic sequela of premature infants and

requires optical correction. Other adverse ophthalmic

outcomes, such as astigmatism and anisometropia, were highly

correlated with severe myopia. Studies clearly illustrate the

significant and independent contributions of prematurity, ROP,

and central nervous system injury in the development of visual

disability in terms of myopia and strabismus.

There is a strong positive association between the occurrence

of strabismus and the degree of prematurity, the severity of

ROP, abnormal cranial ultrasounds, and neurodevelopmental

abnormality, especially CP. The presence of strabismus and

nystagmus implies a central nervous system component or

insult, which may or may not be independent of ROP. The

ocular misalignments may result from CNS injury and/or as a

direct result of retinal disease (e.g., ROP) and its treatment.

Strabismus may continue to increase in frequency through

second year. Among children with Grade III or IV IVH, 100

percent had strabismus (esotropia).

Ophthalmic examinations revealed that premature infants

with BPD and no detectable severe neonatal neurological

abnormalities and no ROP > Stage 2 had greater incidence of

strabismus and high refractive error and poorer recognition

acuity compared to premature infants with hyaline membrane

disease but no BPD and healthy preterm infants. Extremely

premature infants treated with systemic dexamethasone therapy

for BPD had significantly higher rates of blindness in addition

to significantly higher rates of CP and lower intelligence

quotients. Extreme prematurity, brain injury, ROP, BPD, and

glucocorticoid therapy individually and/or collectively have an

impact on visual disability.

Children who had ROP are at even greater risk for longterm ophthalmic sequelae in terms of anatomic and functional

problems, and thus need close ophthalmic evaluation and

interventions. The frequency of procedures to correct visual

disability increases with severity of ROP. Long-term costs of

both extreme prematurity and ROP include not only the initial

ablative therapy for ROP and individual/family/societal loss

due to vision impairment and blindness, but ongoing costs of

caring for eye problems in children who were VLBW. Expenses

include doctor’s office visits, time lost from work, eyeglasses,

surgery, and special education.

Evidence that VLBW With or Without Other

Conditions is Associated With Pulmonary

Disability

The studies reviewed indicate that VLBW infants with

bronchopulmonary dysplasia (BPD) are at increased risk for

long-term pulmonary disability. The greater the severity of

BPD, the greater the association with long-term pulmonary

impairment and need for re-hospitalization. Children who were

VLBW infants who had no BPD have comparable pulmonary

outcome to children who were born full term. Children who

were VLBW with more severe BPD may have persistent lung

disease during young childhood and continuing through to

their adolescent, and young adult years. Findings in five studies

indicate that BPD at 36 weeks corrected gestational age is

predictive of longer-term pulmonary disability through at least

1-2 years of age.

Preterm children with BPD have an increase in multiple

measures of pulmonary disability. The most frequently

described consequences of pulmonary disability are increased

respiratory symptoms and respiratory illnesses, the need for

respiratory medications, and re-admission to the hospital for

other medical and surgical reasons. Respiratory illnesses

frequently documented in children who had BPD include

chronic lung disease, recurrent bronchitis and pneumonia,

increased airway responsiveness and asthma. Asthma or

6
bronchial responsiveness actually appears to be increased in

VLBW premature children who did or did not have BDP. 

Rehospitalization of former VLBW infants is unfortunately a

common event especially during the first 2 years of life and is

even higher among VLBW infants with BPD. Most

hospitalizations are for respiratory conditions or failure to

thrive. 

Evidence that VLBW With or Without Other

Conditions is Associated With Growth

Impairment

VLBW infants, with or without other conditions, are at high

risk for poor growth during the first years of life due to acute

neonatal illnesses, developmental delays, and chronic illnesses

(e.g., BPD, gastroesophageal reflux, short-gut syndrome).

Understandably, the degree of prematurity and severity of the

illness/hospital course have great impact and influence growth.

Attaining appropriate growth and nutrition in VLBW infants

continues to be a challenge during the initial hospitalization

and after discharge from the neonatal unit. Long-term studies

demonstrated definitive problems with postnatal growth. There

is evidence that the weight and height of VLBW infants is

significantly behind that of normal birth weight infants

through 14 years of age, although the differences become less

over time.

It is well documented that VLBW infants with BPD are

smaller and have difficulty gaining weight while in the neonatal

intensive care unit. Recurrent illness and pulmonary

exacerbations of BPD, increased metabolic needs and

inadequate nutrient intakes all contribute to compromise

growth in VLBW infants with BPD. BPD infants with home

oxygen therapy had a three-fold increase in rehospitalization for

failure to thrive. The primary reasons for failure to thrive in the

BPD patients were related to poor feeding and gastroesophageal

reflux.

Future Research

We propose two prospective health service research

opportunities. The first proposal, “Evaluation of the

Application Process of SSA VLBW Disability Criteria,” involves

documentation of baseline risk factor data on all VLBW infants

born within participating regions, following surviving VLBW

infants over pre-specified time with respect to pre-specified

disabilities, documenting the proportion of VLBW who come

to the attention of SSA, relative to the entire regional cohort of

VLBW infants, and identifying barriers to referring infants to

SSA. This research proposal would help SSA assess the

application of SSA VLBW Disability Criteria. This would, in

turn, provide greater insight into reasons for successful

programmatic implementation and impediments of applying

the criteria. It would provide insight regarding the effectiveness

of identifying high-risk VLBW infants.

The second proposal, “Determining the Appropriateness of

the New VLBW Disability Criteria” proposed by SSA based on

the evidence of this report, is a natural next step linked to the

first research concept. The combination of these two concepts

affords the SSA the ability to know if the process and the

criteria are achieving the objectives established by the SSA. 

Refinement of predictors of disability or identification of

new predictors, and development of a robust, well-designed,

and carefully validated predictive models to be used at the time

of hospital discharge could create a “profile” of a VLBW infant

at risk for specific disabilities. A series of models predictive of

longer-term outcome could be developed and validated to

incorporate new factors and information noted during specified

times of followup. Refinement of risk factors invites a

systematic, collaborative effort to develop a series of predictive

models using large regional cohorts of VLBW infants, followed

by validation of the model in an independent group.

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by Tufts New England Medical Center

Evidence-base Practice Center (EPC), Boston, MA, under

Contract No. 290-97-0019. It is expected to be available in

the winter 2003. At that time, printed copies maybe obtained

free of charge from the AHRQ Publications Clearinghouse by

calling 800-358-9295. Requesters should ask for Evidence

Report/Technology Assessment No. 70, Criteria for

Determining Disability in Infants and Children: Low Birth

Weight. In addition, Internet users will be able to access the

report and this summary online through AHRQ’s Web site at

www.ahrq.gov.

7
www.ahrq.gov

AHRQ Pub. No. 03-E008

December 2002

ISSN 1530-440X
Evidence Report
15

Chapter 1. Introduction

The Social Security Administration (SSA) of the Department of Health and Human Services 

requested that the Agency for Healthcare Research and Quality (AHRQ), through its Evidencebased Practice Center (EPC) program, produce an evidence report to determine whether specific 

factors or combination of factors alone or in addition to birth weight predict significant 

developmental disability in former premature infants and whether premature infants with such 

factors have long-term developmental disabilities. This is one of three reports requested by SSA 

in the broader topic of “Criteria for Determining Disability in Infants and Children.” The 

evidence reports are prepared to assist the SSA in updating its Listing of Impairments, and 

revising its disability policy, as may be appropriate. 

Definition of Disability

The definition of disability in children used for the purposes of this report came from the 

SSA and was based on a definition passed by Congress in 1996. Under Title XVI, a child under 

age 18 years will be considered disabled if he or she has a medically determinable physical or 

mental impairment or combination of impairments that causes marked and severe functional 

limitations, and that can be expected to cause death or that has lasted or can be expected to last 

for a continuous period of not less than 12 months.

Specific areas of functioning include: 1) acquiring and using information, 2) attending and 

completing tasks, 3) interacting and relating with others, 4) moving about and manipulating 

objects, 5) caring for yourself, 6) health and physical well-being. Disability is based on the 

degree to which the above functions are interfered with. Disability is established, if there are 

marked limitations in at least two areas or there is an extreme limitation in one area of 

functioning. Where standardized tests of function exist, the regulations define a “marked” degree 

of functional limitation as more than two but less than three standard deviations below the mean 

and an “extreme” limitation as three or more standard deviations below the mean. This definition 

is an administrative definition and is not always applicable to evidence available in the literature 

since disability as strictly and narrowly defined by US Congress and interpreted by the SSA is 

not the intent of the studies available in the literature. Although there is no single, standardized 

definition of disability, the literature provides overwhelming relevant evidence of functional 

impairments, disabilities, and limitations of VLBW. 

Definition of Prematurity

Prematurity is defined both by gestational age and by birth weight criteria. The World Health 

Organization (WHO) defines prematurity as less than 37 weeks gestation. Birth weight has been 

and continues to be used as a surrogate definition of prematurity because birth weight and 

gestational age are closely correlated and birth weight data are readily available. Also, there is 

variable reliability of gestational age assessment in specific datasets. Defining specific 

gestational age or birth weight ranges often further refines the degree of prematurity. 
16

The lower the gestational age, the more immature is an infant. Generally, the lower the birth 

weight, the more immature is an infant. However, birth weight is not a perfect measure of 

immaturity since infants may have birth weights that are disproportionate with their gestational 

age. For instance, some infants may be small or large for their gestational age.

Studies frequently focus on specific birth weight or gestational age groups. VLBW infants 

(birth weight less than 1500 grams) belong to one common birth weight category that targets 

infants at increased risk for problems associated with prematurity. This category of VLBW is 

often divided into subcategories of lower birth weights (less than 1250, less than 1000, less than 

750 grams) to facilitate analyses of infants within different birth weight strata.

Similarly, gestational age categories of premature infants often include groupings of 

premature infants less than 28 weeks gestation, 28 to 32 weeks gestation, 32 to 36 weeks 

gestation, or less than 36 weeks gestation. Gestational age criteria, less than 32 weeks gestational 

age is considered by some authorities as “very premature” and less than 28 weeks gestational age 

as “extremely premature.”

The Problem of Prematurity

Premature birth is an important public health problem due to the number of births in this 

category each year, the serious complications of prematurity, and the life-long tangible and 

intangible costs of caring for these infants. Among the 4,058,814 births in the USA in 2000, 

58,124 (1.43%) were VLBW (less than or equal to 1500 grams) and 467,201 (11.6%) were born 

preterm as defined as less than 37 weeks gestational age (Table A).

Table A. Live birth distribution organized by birth weight and gestation in the United States in 

the year 2000 (National Vital Statistics Reports, 2000).

Birth weight grams Number Percent Gestation

weeks

Number Percent

Total live births 4,058,814 100 Total live births 4,058,814 100

< 500 gm 5,952 0.15 <23 wk 9,243 0.2

500 – 750 gm 11,032 0.27 24-28 wk 19,652 0.5

751-1000 gm 11,878 0.29 28-31 wk 48,624 1.2

1001-1250 gm 13,291 0.33 32-35 218,928 5.5

1251-1500 gm 15,971 0.39 36-37 497,220 12.4

>1501 gm 3,995,849 98.57 38-47 wk 3,221,809 80.2

Not stated 4,841 Unknown 43,338

Although VLBW is a relatively small proportion (1.4%) of total births in the US, this 

category of infants accounts for the highest neonatal mortality and morbidity among newborns, 

as well as significant tangible and intangible lifelong costs to the family and society for medical 

care, and ancillary health and educational services. 
17

Advances in neonatal/perinatal medicine have improved the survival and the quality of 

survival of premature infants. Ninety-six percent of infants with birth weights between 1251 and 

1500 grams survive in contrast to 77% of infants with birth weight less than 1250 grams 

(Stevenson, Wright, Lemons, et al., 1998). Despite these advances, infants born prematurely 

experience a disruption in the normal process of growth and development. The degree of 

disruption in the growth and development of each organ system, and the subsequent disabilities, 

are inversely proportional to gestational age at birth. For any adverse sequelae associated with 

premature birth, the incidence and the severity of the complication is inversely proportional to 

the gestational age [Table B]. For instance, 12% of infants with birth weight between 1251 

grams and 1500 grams survived with at least one major, acute morbidity in contrast 53% with 

birth weight 501-1250 grams (Stevenson, Wright, Lemons, et al., 1998).

Table B: Mortality and morbidity of premature infants by birth weight born in NICHD Neonatal 

Research Network between January 1, 1993 and December 31, 1994 (Stevenson, Wright, Lemons, 

et al., 1998).

Complication Birth Weight

501-1250 grams

Birth Weight

1251-1500 grams

N 3176 1417

Mortality (%) 23 4

Severe ICH* (Grade 3-4) (%) 16 3

Periventricular leukomalacia (%) 7 4

NCLD** at 36 wk PMA*** 24 8

Necrotizing enterocolitis 9 3

* ICH = intracranial hemorrhage

** NCLD = neonatal chronic lung disease

*** PMA = postmenstrual age (gestational age + chronological age in weeks = adjusted gestational age)

Factors Associated with Disability in VLBW Infants

Surviving premature infants often sustain multi-organ system complications that may persist 

beyond the first few years of life and frequently result in permanent disabilities. Examples 

include major neurodevelopmental impairments, such as cerebral palsy (CP), mental retardation 

(MR), deafness and disorders of speech/language/communication, perception, attention, behavior 

and learning disorders, blindness or other visual disabilities, chronic lung disease, and growth 

retardation. 

Complications of even a single organ system may have a profound impact upon other organ 

systems. A classic example of this is BPD, a neonatal chronic lung disease, which still occurs in 

50% of extremely low birth weight (ELBW is defined as birth weight less than 1 kg) survivors 

(Stevenson, Wright, Lemons, et al., 1998). In addition to pulmonary disability, BPD predisposes 

infants to cardiovascular and neurodevelopmental disabilities, abnormal growth (height and 

weight), increased unfavorable ophthalmic risk, and more frequent infections (Farrell and 

Fiascone, 1997; Bancalari, 1997). Other determinants of disability of prematurity are 

summarized below. As previously noted, biomedical determinants of disability in premature 

infants are often compounded by determinants of social and psychological adaptation of these 

vulnerable children and their families.
18

CNS complications of prematurity, such as cerebral white matter damage, intraventricular 

hemorrhage, hypoxic-ischemic encephalopathy, and infection (e.g. meningoencephalitis), are 

related to both the degree of prematurity and illness acuity. CNS complications of prematurity 

are associated with life-long neurodevelopmental disabilities that may adversely impact an 

infant's cognitive, motor, visual, auditory, and psychosocial-behavioral development. Visual and 

audiologic compromises are individually important factors and have enormous impact on the 

overall cognitive, motor, and psychosocial development of premature babies (Hack and Fanaroff, 

1999; Piesuch, Leonard, Cooper, et al., 1997; Kuban, Sanocka, Leviton, et al., 1999; Perlman, 

1998; Stewart, Reynolds, Hope, et al., 1987; Stewart, Reynolds, Hope, et al., 1993). CNS 

complications of prematurity are associated with mental retardation and CP in premature infants.

ROP is an abnormal retinal vascular development. Severe ROP remains a leading cause of 

permanent vision compromise and blindness in premature infants (Murphy and Good, 1997; 

Oxford Registry of Vision Impairment, 1995). Although current retinal ablative therapy has 

helped reduce the incidence of retinal detachment and blindness, fewer than 20% of 51⁄2-year-old 

children who developed threshold (severe) ROP and were treated achieved 20/40 vision 

(Cryotherapy for Retinopathy of Prematurity Group, 1996).

BPD is a chronic disease of the lung that affects almost exclusively premature infants. BPD 

is associated with increased mortality and morbidity both short-term and long-term. The multisystem morbidity of BPD may be associated with compromised cardiopulmonary function, 

growth, and neurosensory development.

Gastrointestinal complications (e.g. necrotizing enterocolitis and short-gut syndrome) (Stoll 

and Kliegman, 1994) and nutritional complications of prematurity (e.g. inadequate nutritional 

and nutrient intake related to prematurity, chronic hepatic injury secondary to prolonged total 

parenteral nutrition, and osteomalacia which compromises bone growth) may adversely impact 

life-long growth potential, and nutritional tolerance (Hay, Lucas, Heird, et al., 1999). Intrauterine 

circumstances and postnatal nutrition may program premature infants for life-long disorders 

(Lucas, 1990; Seckl, 1998). 

The immune system of premature infants is also disrupted in its normal growth and 

development (Yoder and Polin, 1997). Premature infants are at increased risk for serious 

infections well beyond the neonatal hospitalization. The immune response to immunizations of 

infants who were born prematurely is less than that of infants who were born full term. The 

morbidity and mortality related to increased risk of infection among infants born prematurely 

may persist for years (Read, Clemens, and Klebanoff, 1994).

Inadequate growth in terms of both length and weight is a well-recognized, frequent, and 

persistent long-term complication of prematurity (Ehrenkranz, 2000; Doyle, 2000; Hack, 1996). 

Compromised growth among former premature infants may be due to multiple biomedical 

determinants including pulmonary, gastrointestinal, endocrine, neurological, and nutritional 

complications. Often the medical reasons for compromised growth in children born prematurely 

are compounded by familial, psychosocial, and socioeconomic factors, which independently 

compromise normal growth and development.

Educational achievement, self-esteem, psychosocial development, and effective integration 

into society are of particular concern as greater numbers of very premature infants are surviving 

in a society where resources for effective educational and psychosocial intervention are 

increasingly scarce and difficult to access. Former premature infants have increased incidence of 

learning disabilities and increased need for special education (Hack, Taylor, Klein, et al., 1994, 

Msall and Tremont, 2000). Obviously educational, emotional, and social successes, or the lack 
19

thereof, for former premature infants have a major impact on how these individuals ultimately 

function as adults and upon the fabric of our society as a whole (Park and Hogan, 2000; Lester 

and Miller-Loncar, 2000; Saigal, 2000).

Thus numerous biomedical as well as familial, socioeconomic, and psychosocial factors 

related to prematurity predict disability in former premature infants. Unfortunately, many 

premature infants, especially the most immature infants, often experience a combination of 

factors, which further compound the magnitude and complexity of their life-long disabilities. 

Acute and long-term complications of premature infants, coupled with a family’s ability to 

provide and advocate for their premature infants, have a substantial impact on the individual 

patient, their family, and society beyond the utilization of health care resources.

A systematic review of the incidence, types, and severity of factors, and the combination of 

factors, which predict long-term disabilities of premature infants, is worthwhile considering the 

societal impact of increasing number of surviving former premature infants. Review of recent 

literature may shed insights on whether factors related to premature birth predict future 

disability.

This review will summarize evidence on VLBW infants (i.e. prematurity) with or without 

other conditions to determine whether VLBW is associated with long-term disabling outcomes. 

The primary outcomes of interest included in this review are cerebral palsy, mental retardation, 

hearing/speech/language/and behavioral disability, visual disability, adverse pulmonary function, 

and disrupted growth.
21

Chapter 2. Methods

This evidence report is based on a systematic review of the literature. Our EPC formed an 

Evidence Review Team consisting of pediatricians and EPC methodological staff to review the 

literature and perform data abstraction and analysis. The Evidence Review Team held several 

meetings and teleconferences with external technical experts representing the Social Security 

Administration (SSA), the American Academy of Pediatrics, and the Disability Law Center to 

refine key questions proposed by the SSA, and identify issues central to this report. A 

comprehensive search of the medical literature was conducted to identify the evidence available 

to address the questions. For this evidence report, we compiled evidence tables of study features 

and results, appraised the methodological quality and applicability of the studies, assessed the 

correlations of the predictors and outcomes, and summarized the results.

From the outset, the external technical experts and members of the Evidence Review Team 

found it necessary to distinguish between two definitions of disability, one used by the SSA for 

administrative decision-making and the other found in the medical literature. 

SSA’s statutory definition of disability in children includes specific “medically determinable 

impairments” which result in “marked and severe functional limitations”, coupled with a 

temporal dimension: the impairment and functional limitations can be expected to result in death, 

or have lasted or can be expected to last for a continuous period of not less that 12 months (SSA, 

1999). The medical literature, however, defines impairment and disability more broadly. 

Moreover, very few studies have examined the association between VLBW and SSA-defined 

disability, per se. As a result, this report will use the terms disability and impairment as defined 

by study authors. The definitions reflect those endorsed by the World Health Organization 

(WHO). Impairment is any loss or abnormality of psychological, physiological or anatomical 

structure or function; disability is any restriction or lack of ability to perform an activity in a 

manner or within the range considered normal for a human being. This evidence report also uses 

the assessments of functional limitations as defined by study authors.

Key Questions Addressed by the Evidence Report

For infants with birth weight < 1200 grams and for infants with birth weights between 1200 

grams and 1500 grams:

1. What factors or combination of factors alone or in addition to birth weight will predict 

significant developmental disability in former premature infants?

2. Are such infants developmentally disability at 1 year, 2 years, or beyond?

To identify the functional or physical outcomes related to disability and the elements 

believed to predict them, we sought evidence that a specific factor(s) was significantly associated 

with (i.e. demonstrates a relationship with) a specific disability. For example, very low birth 

weight infants with bronchopulmonary dysplasia have lower receptive language scores; the 

degree of immaturity influences the risk of CP and neurodevelopmental disability in VLBW 

infants. The EPC Evidence Review Team looked for evidence of association of VLBW with six 

outcome conditions: cerebral palsy (CP) and neurological impairments; abnormal cognitive 
22

development and mental retardation; speech/language delay, hearing loss, behavioral disorders, 

and learning disabilities; visual impairment (with or without other conditions); pulmonary 

impairment (with or without other conditions); and growth impairment.

Literature Search Strategies

Disability is not a specific medical condition that can be readily searched for. Thus we had to 

look at many studies with related concepts (i.e., medically definable impairments that are related 

to disability) to identify potentially relevant studies. The Evidence Review Team identified a 

comprehensive list of predictors and outcomes by organ system vulnerable to VLBW (Table 4). 

The predictors and outcomes formed the basis of MESH search terms.

A systematic literature search was performed for full journal articles of original data. We did 

not include review articles, editorials, letters or abstracts. English language studies were 

identified primarily through Medline searches conducted between October 2000 and February 

2001. We performed an updated search in September 2001 and again in January 2002. 

Supplemental searches were also performed in ERIC, PsycInfo, HealthStar and Embase. 

Additional studies were identified from reference lists, review and primary articles, and from 

domain experts and reviewers.

The Medline literature searches were conducted to identify clinical studies published from 

1966 through the search dates. Development of the search strategies was an iterative process that 

included input from domain experts. Each search strategy was designed to yield approximately 

10,000 titles and the preliminary searches yielded multiple tens of thousands of titles. Samples of 

these searches were screened and keywords from potentially relevant articles were then used to 

refine future searches. All searches were limited to studies of humans that were published in 

English and included children (age < 18 years). Details of the literature searches are presented in 

Table 4 in Appendix A.

Search Results

The initial search for the literature review consisted of: 1) Medline search from 1966 through 

November 2001 (2,885 abstracts), 2) HealthStar search from 1975 to October 2000 (26 

abstracts), 3) PsycInfo search from 1984 to September 2000 (333 abstracts), 4) ERIC search 

from 1966 to August 2000 (140). The total number of abstracts in the primary search was 3,384.

 These initial search strategies used the text words “low birth weight”, “preterm infant or 

newborn”, “disability”, “limitation”, “handicap”, “impairment”, “follow-up studies”, 

“longitudinal studies”, “cohort studies”, “case-control”, “randomized controlled trials”, “research 

design”, etc. The search strategies were updated in January 2001, using as MESH terms the list 

of predictors and outcomes by organ system vulnerable to VLBW. A secondary search in 

January 2002 for the year cohort 1985 through 2001, used MESH headings “Population: infant, 

premature” or “infant, low birth weight”; Study design: “follow-up” or “cohort”; Disease: 

predictor and outcome terms such as cerebral palsy, retinopathy of prematurity, etc.

Using such a very broad search strategy, the EPC identified 13,130 articles. The study 

designs included were cohort studies, case-control studies, and randomized controlled trials, 

which compared VLBW outcomes to normal birth weight outcomes. 
23

Limitations of the Literature Search 

The literature search protocols and study inclusion criteria were both designed to identify all 

possible correlations available in the literature. However, while literature searches were intended 

to be comprehensive, they may not have been exhaustive. As noted above, search strategies were 

limited to focus on studies likely to be relevant. Searches were limited to English language 

publications. Hand searches of journal were not performed, and review articles and textbook 

chapters were not systematically searched. Nonetheless, important studies known to the domain 

experts and studies found in reference lists were included in the review.

Study Selection

Results from Abstract Screening

By the second literature search in January of 2001, a total of 16,614 abstracts had been 

identified from four databases. We screened 16,164 abstracts that covered 13 categories: central 

nervous system (2,930); ophthalmology (398); audiology (80), pulmonary (1,833); nutrition and 

growth (2,533); medication (dexamethasome) (183); perinatal factors (875); illness acuity (56); 

infectious diseases (2,378); gastrointestinal (477); bone/osteomalacia (10); health care (466); and 

immune disorder (921). Approximately 1,693 articles were retrieved after screening of the 

abstracts.

Because we used search strategies with high sensitivity but low specificity to avoid missing 

potential relevant articles for this evidence report, the result was a large number of abstracts 

requiring review. Physician members of the Evidence Review Team screened each article against 

the inclusion criteria. 

We focused the literature review primarily on premature infants born weighing less than 

1,500 grams, including all subcategories of birth weights (e.g. less than 1,250 grams, less than 

1,000 grams, and less than 750 grams). We also incorporated literature that included infants with 

birth weight less than 1,500 grams within a larger premature cohort and literature on infants 

whose prematurity was defined by gestational age, since many studies use gestational age and 

not birth weight criteria.

The Evidence Review Team reviewed all studies (retrospective or prospective) reporting 

impairments in infants or children who weighed 2000 grams or less, whose gestational age was 

35 week or less, or whose birth weight or gestational age were below these thresholds. 

Longitudinal data for minimum of 6 months was preferred. Table C lists the inclusion and 

exclusion criteria.
24

Table C. Inclusion/exclusion criteria

Include

Randomized controlled trials, 

case control studies, prospective 

cohort or retrospective cohort 

studies

• Only abstract data from primary studies

• English language

• Population (BW <= 2000gm and GA < 35 wk)

• At least 10 subjects

• At least one of the listed predictors (See Table 4)

• At least one of the listed outcomes (See Table 4)

Exclude • Articles if infants born before 1980

• Articles published before 1985

Revised Study Selection Criteria 

The EPC categorized by sample size and birth year the articles that met the minimum 

inclusion criteria for LBW: articles with one or more relevant clinical outcomes; follow-up 

duration greater than of equal to 6 months; enrolled patients born after 1980, and study size 

greater than 10.

We then established a hierarchy of studies based on study size and birth year of the infants. 

Studies with birth years from 1990 onward were given preference, followed by studies with birth 

years between 1985 to 1989 and then studies before 1985. Within each birth year cohort, studies 

with more than 100 infants were selected first, followed by studies with 50 to 100 infants and 

less than 50 infants. Using this classification hierarchy, we worked through the most relevant 

(recent) and strongest (largest study size) studies in succession before older and smaller studies, 

until a complement of 178 articles was achieved.

Outcomes and Predictors Considered in this Evidence 

Report

The Evidence Review Team identified a list of predictors and outcomes (Table D). The 

universe of outcomes included those, which SSA recognizes as medically determinable physical 

or mental impairments that result from anatomical, physiological, or psychological abnormalities 

(SSA, 1999).
25

Table D. List of predictors and outcomes

PREDICTORS OUTCOMES

Various BW categories (such as...

< 1500 gm

< 1250 gm

< 1 kg

< 750 gm

All outcomes listed below:

Neurodevelopmental/behavioral outcomes, 

Vision, Hearing, Pulmonary, Growth, etc.

Various Gestational Age categories (such as

< 35 weeks

<32 weeks

<30 weeks

<28 weeks

<26 weeks

All outcomes listed below: 

Neurodevelopmental/behavioral outcomes, 

Vision, Hearing, Pulmonary, Growth, etc.

Central Nervous System – CNS

Intracranial /intraventricular hemorrhage Motor delay/ Cerebral palsy

Periventricular leukomalacia Cognitive delay Mental retardation 

Seizures Behavioral

Hypoxic-Ischemic encephalopathy (HIE) School performance

Ventriculomegaly/ ventricular dilatation Learning disabilities

Primary Outcomes feeding / swallowing 

Prolonged apnea Hearing disorders /Deafness

Intrauterine substance abuse (opiates, cocaine, ethanol) Visual impairment/Blindness

Low Apgar Score Speech / Language / Communication disorder

Feeding / Swallowing disorders

Post hemorrhagic hydrocephalus (PHH)

Ventricular peritoneal (VP) shunt & other 

disabilities

Neurodevelopmental Impression: Normal, 

Abnormal, Suspect

Neurological examination: Normal, Abnormal, 

Suspect

Ophthalmology

ROP (retinopathy of prematurity) Visual outcome

HIE 

Audiology

Aminoglycosides Hearing outcomes

Furosemide 

Hearing Screen Failure 

Cardiovascular diseases

Cor pulmonale

Pulmonary

Chronic Lung Disease Asthma

Bronchopulmonary dysplasia Pulmonary function

Tracheostomy

Upper airway

Chronic Lung Disease

Reactive airway

Exercise tolerance
26

PREDICTORS OUTCOMES

Gastrointestinal

Short gut Short gut

Necrotizing “enterocolitis” – NEC Cholestasis / Cirrhosis

Total parenteral nutrition – TPN Gastrostomies / GERD / Fundoplication

Cholestasis

Nutrition / Growth

Weight

Height

Bone

Osteomalacia Osteomalacia

Infectious Diseases

RSV

Meningitis

Sepsis

Congenital/Acquired Immune Disorders

Hospital / Health Care Resource Utilization

Rehospitalization (for any reason)

Costs

Physical/occupational therapy

Orthopedic

Illness Acuity

SNAP

CRIB

Medications

Dexamethasone

Perinatal 

factors

Drug hx

Antenatal steroid use

Chorioamnionitis

Chorionic villous sampling

Diabetes

Pre-eclampsia

Data Abstraction Process

EPC staff developed draft data abstraction forms, which were refined through an iterative 

process with the methodologic and domain expert members of the Evidence Review Team 

(Appendix B). Information abstracted for assessment included the study population 

characteristics (i.e. such information as age, height, weight and gestational age), inclusion and 

exclusion information, study design, study funding source, the results and conclusions of the 
27

study. In addition, data for quality assessment of individual studies were systematically 

abstracted, including data for rating the internal validity and applicability of the study.

Pediatrician domain experts performed all the data abstraction. The EPC staff trained 

abstractors. As part of the training each Team Member abstracted three studies in duplicate with 

the Team Leader and meetings were held to discuss discrepancies. After training, all remaining 

studies were abstracted by one pediatrician. Abstracted data were verified by a member of the 

EPC staff when the data was transferred to evidence and summary tables. 

Reporting the Evidence

We summarized the evidence we found for the LBW condition in two complementary forms. 

The evidence tables contain detailed information about the study characteristics, population and 

disease characteristics, patient demographics, treatment comparisons, and outcome measures. 

We used this information to derive an evidence-grade to provide an indication of “quality” for 

each of the studies used to address the key questions. This evidence-grading scheme captures 

dimensions of a study that are important for the proper interpretation of the evidence: internal 

validity, applicability, magnitude of treatment effect (for treatment studies), and the size of the 

study. This evidence-grading scheme is used as part of the reporting of the results.

A narrative and a tabular summary of the strength and quality of the evidence of each study 

are provided for each outcome condition. For some conditions, studies are grouped first by study 

sample disease type. For some conditions, studies are ordered first by methodological quality 

(best to worst), then by study size (largest to smallest). For other conditions, studies are grouped 

first by methodological quality, then by applicability of study sample.

Evidence Tables

EPC staff constructed evidence tables for each the outcomes within the six conditions of 

interest. These tables are presented in Chapter 7 of this evidence report:

Table E. Evidence tables created in this report

Table number Table name

Evidence Table 1 Studies evaluating association of LBW and multiple outcomes: CNS, Eye, 

Lung, Growth, etc

Evidence Table 2 Randomized Control Trials for LBW infants and multiple outcomes: CNS, 

Eye, Lung, Growth, etc

Evidence Table 3 Studies evaluating association of LBW and cerebral palsy and neurological 

outcomes

Evidence Table 4 Studies evaluating treatment effects of LBW and cerebral palsy and 

neurological outcomes
28

Table number Table name

Evidence Table 5A, B Studies evaluating association of LBW with speech/language and hearing 

loss

Evidence Table 6A, B Studies evaluating association of LBW with behavioral disorders and school 

performance 

Evidence Table 7 Studies of association of LBW to ophthalmic outcomes

Evidence Table 8 Studies of treatment effects for LBW infants with retinopathy of prematurity 

(ROP)

Evidence Table 9 Studies evaluating association of LBW and pulmonary outcomes

Evidence Table 10 Studies evaluating association of LBW and bone and growth outcomes

Evidence Table 11 Randomized Controlled Trials in LBW Neonates for growth outcomes

Evidence Table 12 Studies evaluating association of LBW and nutritional outcomes 

Evidence Table 13 Studies evaluating association of LBW and other outcomes

Summarizing the Evidence of Individual Studies

Grading of evidence can be useful in appreciating the overall “quality” of a group of studies 

addressing a question. Over two-dozen scales have been proposed to evaluate the quality of 

randomized controlled trials (Moher, Jadad, Nichol, et al., 1995). While it may be desirable to 

have a simple evidence grading system using a single quantity, the “quality” of evidence is 

multi-dimensional and a single metric cannot fully capture information needed to interpret a 

clinical study (Ioannidis and Lau, 1998). A recent empirical study applied 25 quality scales to 

one meta-analysis and found that different quality scales could result in different conclusions 

hence quality scales are inconsistent among themselves (Juni, Witschi, Bloch, et al., 1999). 

Another empirical study demonstrated the greater usefulness of assessing studies according to 

specific study design features (Lijmer, Mol, Heisterkamp, et al., 1999).

Methodological Quality

Methodological quality, often referred to as internal validity, addresses the design, conduct, 

and reporting of the clinical trial. Some of the items belonging to this entity have been widely 

used in various “quality” scales and usually include items such as concealment of random 

allocation, treatment blinding, and handling of dropouts. In this evidence report, we define a 

three category internal validity scale: A (least bias), B (susceptible to some bias), C (likely to 

have large bias). 
29

Study Quality

A Least bias. Prospective study that is clearly reported, uses explicit and 

appropriate eligibility criteria, uses appropriate definitions of predictors and 

outcomes that are properly measured or estimated, uses appropriate statistical and 

analytical methods, and is free of obvious bias. Retrospective studies, irrespective 

of other aspects of quality, cannot be in category A. Study size should not be a 

factor for quality.

B Susceptible to some bias. Prospective or retrospective study that does not meet 

qualifications of category A but deficienc ies are unlikely to cause major bias.

C Likely to have a large bias. Major deficiencies that cannot exclude possibility of 

significant bias. Insufficiently reported information.

Applicability

Applicability, also known as generalizability or external validity, addresses the issue of 

whether the evidence from the study population is sufficiently broad as to be able to generalize to 

the population at large. Individual studies are often unable to achieve broad applicability due to 

restricted study population characteristics and a small number of study subjects (Lau, Ioannidis, 

Schmid, 1997). 

For questions where all studies within a given table evaluate children with the same (or 

similar) diseases, a designation for applicability was assigned to each article, according to the 

following three-level scale:

ÇÇÇ Sample is representative of the whole population of babies with prematurity and 

low birth weight condition relevant to the topic question (eg, whole population of 

preterm babies and infants with BW 1200-2000g). This implies a reasonable 

sample size, a diverse group of infants with the condition, and inclusion/exclusion 

criteria that will capture the whole group. 

ÇÇ A relevant sub-group or subgroups of very low birth weight and prematurity, 

(only those with a specific, though common, condition eg: BW 1200-1500 

grams). 

 Ç A very narrow group of subjects who are a limited sample of very low birth 

weight and prematurity (only those with a relatively rare condition, or a nonrepresentative demographic group e.g. crack babies).
30

Study Size

The study (sample) size is used as a measure of the weight of the evidence. In general, large 

studies provide more precise estimates of prevalence and associations. In addition, large studies 

are more likely to have wide applicability, depending on eligibility criteria. However, large study 

size does not guarantee applicability. 

Results

The type of results available is determined by each study’s design, the purpose of the study, 

and the question(s) being asked. Therefore, the results presented vary across summary tables. 

Summary tables for some question present either association or percentage of subjects with 

impairment. Other questions include separate columns for the strength of the association of the 

predictors with the outcome of interest. For appropriate topics, associations are described with 

the following arrows:

Statistically significant positive association found between the predictor and the outcome. 

Significantly increased the risk of MR/CP/Growth/BPD/POP (any disability) associated 

with VLBW or GA.

Statistically significant negative association found. Significantly decreased the risk of 

 MR/CP/Growth/BPD/POP (any disability) associated with VLBW or GA. 

No association. 
31

Chapter 3. Results 

We reviewed 1,693 full articles; 178 are used in this evidence report. The results of our 

research are presented in six major sections in this chapter. The first section reports the evidence 

on the association of VLBW with cerebral palsy (CP) and neurologic disabilities. The second 

section provides evidence that VLBW infants are at high risk for abnormal cognitive 

development and MR. The third section reports the evidence on the association of VLBW with 

disabilities of speech/language delay, hearing loss, behavioral disorders, and learning disabilities. 

The fourth section presents the evidence that VLBW (with or without other conditions) is 

associated with visual disability. The fifth section reports evidence on the association of VLBW 

(with or without other conditions) with pulmonary disability. The last section summarizes the 

evidence on the associations of VLBW with growth.

Evidence That VLBW With Or Without Other Conditions Is 

Associated With Cerebral Palsy (CP) And Neurologic 

Disability (Evidence Tables 1- 4)

This summary reports the evidence that VLBW infants, with or without other conditions or 

clinical risk factors, are at increased risk for disability due to CP and other neurologic/ 

neuromotor abnormalities. The evidence that VLBW is associated with MR is addressed in a 

separate section. The narrative regarding VLBW and CP/neurologic outcome is organized as 

follows:

1) Definition of CP, neurologic vulnerability of immature brain, and detection of brain 

injury

2) Evidence that VLBW infants have increased risk of CP/neurologic disability: estimates of 

prevalence and influence of degree of immaturity on risk of neurodevelopmental outcome

3) Evidence that VLBW plus other factors are associated with CP and neurologic 

abnormalities

A. CNS injury (intracranial hemorrhage, cerebral white matter damage: periventricular 

leukomalacia, ventriculomegaly 

B. Antenatal risk factors

C. Bronchopulmonary dysplasia (BPD) and postnatal systemic glucocorticoid therapy 

(Dexamethasone)

D. Parenting/psychosocial factors

E. Other postnatal factors
32

Definition of CP, Neurologic Vulnerability of Immature Brain, And 

Detection of Brain Injury.

CP is a neuromuscular disorder secondary to central nervous system injury, lesions or 

anomalies of the brain arising in the early stages of its development. The increased risk of 

VLBW infants for central nervous system injuries is due to increased vulnerability of the 

immature brain to cytotoxic, hypoxic-ischemic, and inflammatory injuries, impaired 

cerebrovascular autoregulation, and hemorrhage (Kuban and Leviton, 1994; Volpe, 2001).

CP manifests as a symptom complex of non-progressive, but often changing, neuromotor 

impairment syndromes (Kuban and Leviton, 1994; Mutch, Alberman, Hagberg, et al., 1992). 

The diagnosis of cerebral palsy is made in the presence of abnormal muscle tone, persistent or 

exaggerated primitive reflexes, and major delay in motor development. Classification of cerebral 

palsy is based on the extremities involved (monoplegia, hemiplegia, diplegia, and quadriplegia) 

and the characteristics of the neurologic dysfunction (spastic, hypotonic, dystonic, athetotic, or a 

combination (Kuban and Leviton, 1994; Mutch, Alberman, Hagberg, et al., 1992; Scrutton, 

1992).

The availability of and refinement in neuroimaging technology, such as cranial ultrasound 

and magnetic resonance imaging (MRI), has improved our detection of brain injury of premature 

infants. The injuries detected via cranial ultrasound or magnetic resonance imaging include 

cerebral white matter damage (WMD) such as periventricular leukomalacia (PVL) and/or 

ventriculomegaly (VM), or intracranial hemorrhage (ICH). Detection of central nervous system 

injury, in turn has facilitated our understanding of risk factors associated with brain injury and 

has improved out ability to predict outcome of infants with evidence of brain injury. 

Evidence That VLBW Infants have Increased Risk of CP And 

Neurologic Disability: Estimates of Prevalence And Influence of 

Degree of Immaturity on Risk of Neurodevelopmental Outcome 

Prevalence of CP in Observational Studies 

Thirty observational studies reported the prevalence of CP in VLBW and ELBW infant 

population (N= from 17 to 1187; BW= from 500 to1500g). Each patient’s CP condition was 

defined from clinical signs and symptoms along with Bayley Scales. The percentage of CP 

reported from these studies varied from 6 to 97 (Table 1.1a).

Table 1.1a. Association of Cerebral Palsy with VLBW/Prematurity (Percentage of CP in 

observational studies)

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Definition of CP % of CP Applicability Quality

Hack, 2000

20358826 221 BW: <1000GA: 26.4

Clinical 15% mmm A
33

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Definition of CP % of CP Applicability Quality

Hack, 1996

97066997 249 BW : 500-759

GA: 24

Clinical

1982-88: 10%

1990-92:

10%

mm A

51

BW: 1153

GA: 29 (25-34) 18%

16

BW < 1000 g GA: 

ND 34%

Valkama, 

2000

20233239

14 ND

According to 

Hasberg et al.

14%

mm A

1151 BW: 401-1000 g 17% Vohr, 2000

20295211 15 BW: 401-500 g

ND

29%

mm A

Victorian 

Infant 

Collaborative 

study Group, 

1997

453

BW: 500-999 g GA: 

ND

Clinical

and

Bayley Scales

6.6%

(1985-87)

9.3%

(1991-92)

mm B

Victorian 

Infant 

Collaborative 

study Group, 

1997

35 GA: 23-27 wk

Clinical

and

Bayley Scales

19.1%

(1985-87)

12.5%

(1991-92)

mm B

Victorian 

Infant 

Collaborative 

study Group, 

1997

97466059

989

BW: 500-999 g GA: 

ND

Clinical

and

Bayley Scales

0%

(1985-87)

12.5%

(1991-92)

mm B

O’Shea, 

1997

98049056

2076 BW: 681( 501-800)

GA: 25 Clinical

19%

(1984-89)

7%

(1989-94)

mmm B

Piecuch, 

1997

98012134

446 BW 500-999

GA: 24-25

Clinical 

and

Bayley Scales

9% mm B

Sethi, 

1996

96334245 92

BW <1501 g

GA: ND Clinical 8.7% mmm B

Wood,

2001

20373840

283 GA ≤ 25 wks

Clinical 

and

Bayley Scales

10% mmm B
34

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Definition of CP % of CP Applicability Quality

Palta, 2000

20096107 425 GA: 29BW: 1003

Clinical (Physician 

dx at parent 

interview and 

confirmed by clinic 

record abstraction 

as well as blindness 

and use of 

corrective lenses)

13% mm B

Pierrat, 2001 

27221167

39

39

GA: 29

BW: 1003

Criteria of Hagberg 

et al.

76%

97%

mm B

Ambalavanan

2000

21031370

218 BW: 830G g

GA: 26

Clinical

Bayley Scales 28% mm B

Robertson, 

1994

94181384

163

BW: 500-1500

GA: ND Bax’s definition 6.7% mmm B

143 GA: 26.7

BW: 820 19%

81 GA: 26-35

BW: 570-3200 9%

66 BW <1501 g

GA: ND 20%

Salokorpi, 

1999

99353226

Shepherd, 

1999

99165413

Sethi, 1996

96334245

Vohr, 1999

99332101

101

BW: 965

GA: 28

Clinical

Clinical

Clinical 

Presence of 

hypertonicity, 

hyperreflexia, and 

dystonic or spastic 

movement quality in 

the affected limbs

9%

mm

mm

mmm

mm

B

B

B

B

Cooke, 1999

99257637 1187 ND

Data from Regional 

Cerebral Palsy 

Register

11%

(1986-89)

7.3%

(1990-93)

mmm C

Emsley, 1998

98238139 64

BW: 753

GA: 23-25 Clinical

21%

(1984-89)

18%

(1990-94)

mm C

Battin, 1998

99002694 44 GA: 23-25BW: ND Clinical 20% m

C
35

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Definition of CP % of CP Applicability Quality

Blitz, 1997

97154301 100 BW: 776

GA: 27

Clinical 

BSID, MDI, PDI, 

CLAM 24% mm C

Chen, 1995

96009403

Cooke, 1999

993806719

Dammann, 

2001

21221175

17

1187

324

BW: 1197 (625-

1500)GA: 30 (27-

36)

ND

BW: ND

GA: ND

Spastic CP, 

diagnosed by 

“complete neuro 

exams”

Data from Regional 

Cerebral Palsy Rgst

ND

41%

10%

10%

mm

mmm

mm

C

C

C

Spinillo, 1997

98021316 & 

97277958

Spinillo, 

1998

98237382

345 GA: 30

BW: 1371

Spastic diplegia, 

Hemiplegia, 

Tetraplegia, 

w/ moderate to 

severe interference 

with function or w 

mental retardation: 

MDI < 71

12% m C

Thompson,

1993

93234177

143 BW <1250

GA 32.0

Clinical

(Neurological exam

Greffther scale )

 6% m C

The evidence of the literature by the methods of this review overwhelmingly supports that 

the risk of CP and major neurologic disability is increased among VLBW infants, especially 

extremely low birth weight (ELBW) infants, compared to full-term infants. Due to the improved 

survival of VLBW and ELBW infants, concerns remain that the incidence of 

neurodevelopmentally disabled children has increased and will increase. However, recent studies 

from developed nations that evaluated the change in prevalence of CP over time suggest that the 

incidence of CP is stable or modestly decreased compared to the 1980s, despite improved 

survival of extremely immature infants (Cooke, 1999; Emsley, Wardle, Sims, et al., 1998; Hack, 

Friedman, and Fanaroff, 1996; Piecuch, Leonard, Cooper, et al., 1997; The Victorian Infant 

Collaborative Study Group, 1997; The Victorian Infant Collaborative Study Group, 1997; The 

Victorian Infant Collaborative Study Group, 1997). This suggests that recent advances in 

neonatal care have had either no or modest effect on reducing the incidence of cerebral palsy. 

Differences among studies regarding incidence trends may be accounted for by the period of 

time under study, characteristics and risk factors of the patient population, neonatal care 

practices, as well as length and completeness of follow-up.

A study by Hack, Wilson-Costello, Friedman, et al. (2000) provides relatively recent 

information regarding the neurodevelopmental outcome at 20-months corrected age of 221 

extremely immature infants born between 1992 to 1995. They found that 48% of the infants had 
36

neurodevelopmental impairment (neurologic abnormality, subnormal MDI, blindness or 

deafness); 20% a major neurologic abnormality, and the incidence of CP was 15%.

Hack, Friedman, and Fanaroff (1996) prospectively studied at 20 months corrected age two 

cohorts of children who were born VLBW (birth weight <1500g) in a single U.S. center. The 

first cohort was born in 1982-1988 (N=166), which was an era prior to surfactant therapy and 

prior to widespread use of dexamethasone. The second cohort was born 1990-1992 (N=114) 

during an era when surfactant therapy and dexamethasone were used in the treatment of 

premature infants. The 20-month corrected age neurodevelopmental outcomes did not change 

appreciably between two cohorts (10% of infants had CP in both periods). In first period, 49% 

had major neurosensory abnormalities and/or MDI<80, compared to 35% in second period. 

Vohr, Wright, Dusick, et al. (2000) evaluated the neurodevelopmental, neurosensory, and 

functional outcomes at 18-22 months corrected age of 1151 American, ELBW infants (401-1000 

grams) born in 1993-1994. This recent study documented the increased incidence of abnormal 

neurologic outcome, including CP, in the cohort of ELBW infants. Overall, 25% had an 

abnormal neurologic examination, 37% had a Bayley II Mental Developmental Index <70, 29% 

had a Psychomotor Developmental Index <70, 17% of the cohort developed cerebral palsy (6.4% 

quadriplegia, 1.4% hemiplegia, 8.2% diplegia, 1.0% monoplegia), and 5% had seizure disorder. 

Within this narrow range and sample size of extremely premature infants, birth weight was not a 

significant predictor of neurologic outcome although there was a trend toward more CP among 

the lower birth weight categories (400-800 grams: CP range 29%-15% vs. 801-1000 grams: CP 

15%). Factors significantly associated with increased neurodevelopmental morbidity included 

chronic lung disease, grades 3 to 4 intracranial hemorrhage, periventricular leukomalacia, 

glucocorticosteroid therapy for BPD, necrotizing enterocolitis, and male gender. This large, 

contemporary, prospective, multicenter US study emphasizes the high risk of neurologic and 

neurodevelopmental problems are noted in ELBW infants at 18-22 months age. 

The Victorian Infant Collaborative Study Group published three studies in 1997 which 

evaluated the outcome of extremely premature infants. (The Victorian Infant Collaborative Study 

Group 1997a; The Victorian Infant Collaborative Study Group 1997b; The Victorian Infant 

Collaborative Study Group 1997c). One study compared survival and outcome of ELBW infants 

by birth weight (500-999 grams) with normal birth weight controls over the course of three eras 

(1979-1980, 1985-1987; 1991-1992). The second study compared survival and outcome of 

extremely premature infants by gestational age between 23-27 weeks with normal birth weight 

controls born during 1991-1992, and compared the change in survival and outcome with 

premature infants (23-27 weeks gestational age) born during 1986-1987. The third study 

evaluated the survival and outcome of outborn ELBW infants (BW 500-999 g) among 3 eras 

(1979-1980, 1985-1987; 1991-1992). In all three studies, the survival of extremely premature 

infants improved in 1991-1992 compared to the earlier eras of neonatal care by ‘birth weight’ 

criteria (500-999 g), by ‘gestational age’ criteria (23-27 weeks), or by ‘outborn status and birth 

weight’ criteria (500-999 grams). 

In The Victorian Infant Collaborative Study Group (1997a) study that compared survival and 

outcome of extremely premature infants with birth weight 500-999 grams, survival improved in 

the 1991-1992 era to 56.2% compared to survival of 25.4% and 37.9% for 1979-1980, 1985-

1987 respectively. The proportion of children with CP in the ELBW cohort was 13.5%, 6.6%, 

9.3% for each of the three eras 1979-1980, 1985-1987, 1991-1992 respectively. The rate of CP 

was not significantly lower in 1991-1992 compared to the earlier eras. Severe sensorineural 

disability fell between the two earlier eras for infants with birth weight 500-749 grams (25% vs. 
37

11.1% vs. 12.1%), but not for infants with birth weight 750-999 grams. The rate of severe 

sensorineural disability was higher across all three eras for the most immature infants (500-749 

grams) compared to that of premature infants with birth weight 750-999 grams. ELBW children 

(500-999 grams) had significantly higher rates of sensorineural disability compared to normal 

birth weight children born ≥2499 grams in the latest era 1991-1992 (6.8% vs. 1.7%).

In The Victorian Infant Collaborative Study Group (1997b) study that compared survival and 

outcome of extremely premature infants by gestational age criteria (23-27 weeks) with normal 

controls born during 1991-1992, the rates of CP and deafness were not different compared to 

similar gestational age children born in 1985-1987, but the rate of blindness decreased. There 

was no significant difference in sensorineural disability between premature cohorts (23-27 weeks 

gestational age) born during 1986-1987 compared to 1991-1992. 

In The Victorian Infant Collaborative Study Group (1997c) study of outborn ELBW infants 

(birth weight 500-999 grams) survival improved in the 1991-1992 era to 60.7% compared to the 

two earlier eras (34.6% and 36.7% for 1979-1980, 1985-1987 respectively). The proportion of 

CP was 11.1%, 0%, 12.5% for each of the three eras 1979-1980, 1985-1987; 1991-1992 

respectively. Severe sensorineural disability fell between the two earlier eras for outborn ELBW 

infants. There was no comparison to normal birth weight controls in this study. 

O'Shea, Klinepeter, Goldstein, et al. (1997)also demonstrated that the incidence of 

neurodevelopmental disability, assessed at 1 year of age, did not increase in extremely premature 

survivors (birth weight 501 to 800 grams) over the time period of 1979 through 1994, despite a 

significant improvement in survival of extremely premature infants. The proportion of children 

who developed cerebral palsy were 13%, 19%, and 7% for time periods 1979-1984, 1984-1989, 

1989-1994, respectively. Similarly, the incidence of major neurosensory impairment did not 

increase across these same time periods (25%, 28%, and 21%). After adjusting for gestational 

age, which was inversely proportional to risk of major neurosensory impairment, major cranial 

ultrasound abnormalities were associated with an increased risk (OR 5.71, 95% CI 2.2, 14.84) 

and years of maternal education was associated with a decreased risk (OR 0.82, 95% CI 0.67, 

1.0) of major neurosensory impairment.

Piecuch, Leonard, Cooper, et al. (1997) reviewed neurodevelopmental outcomes of a large 

(446) group of ELBW (500-999 gm) infants born between 1979-1991 at a mean age of 55±33 

months of age (range 12 to >72 months). Within this narrow birth weight range of 500-999 g, 

they found that 15% of infants had abnormal neurologic/neurosensory outcome. Among the 442, 

9% specifically had a diagnosis of CP or significant impairment in neuromotor function. There 

was no change in incidence of CP or neuromotor impairment over the time periods.

Other studies within this review were not designed to compare change in incidence of 

specific neurodevelopmental outcomes over time, but they are valuable to note because they 

provide recent evidence of the increased prevalence of CP and neurosensory impairment in 

VLBW population. Similar to other reports, Sethi and Macfarlane (1996) found that 11% of 

VLBW children had a major impairment (9% cerebral palsy; 2% blind). Sethi and Macfarlane 

(1996) and Wood, Marlow, Costeloe, et al. (2000) evaluated all children born at 25 weeks or less 

in the United Kingdom and Ireland during 1995 and determined the neurologic and 

neurodevelopmental outcome at 30-months corrected age. The mean (±SD) scores on Bayley 

Mental (MDI) and Psychomotor Developmental Indexes (PDI) were 84±12 and 87±13, 

respectively (population mean 100). Ten percent had severe neuromotor disability. Among the 

children with neuromotor disability, 18 percent had CP, of which more than half (54%) was 

severe. Overall, 49% of the children had disability. 
38

Cooke (1999) retrospectively studied a cohort of VLBW infants (birth weight not specified) 

born in the United Kingdom in 1982-1993 and followed until 3 years corrected age. Data were 

obtained from Regional CP Register. The authors found that prevalence of CP decreased 

significantly in early 1990s (p=0.046) compared to 2 periods in 1980s, despite the improved 

survival of VLBW infants. They found 10.9% (45/411) infants had CP in 1982-85, 10.9% 

(42/387) in 1986-1989 and 7.3% (29/398) in 1990-1993. The authors speculated that this 

improved survival and outcome was related to increased routine use of antenatal steroids in 

mothers at risk for preterm delivery.

Emsley, Wardle, Sims, et al. (1998) demonstrated that improved survival from 1984 through 

1994 in premature infants at the limit of viability (23-25 weeks gestation) was associated with 

increase in disability. They examined prospectively 2 cohorts of premature infants born in 2 

different periods 1984-1989 (N= 24) versus 1990-1994 (N=40) at 2 sites in US. Survival 

increased from 27% to 42% and the rate of disability increased from 38% to 68%. Although the 

proportions of survivors with cerebral palsy were similar between two time cohorts (1984-1989: 

21% vs. 1990-1994: 18%), the increase in visual disabilities (blindness due to ROP, myopia, and 

squint) contributed to the overall increase in disability over time. A high illness severity score (as 

assessed by CRIB score) was strongly associated with disability. Within the second period 

(1990-1994), 38% of children had mild disability (myopia, language delay, mild hearing loss, 

hyperactivity or clumsiness), 13% had moderate disability (spastic diplegia, moderate learning 

disability), and 18% had severe disability (spastic quadriplegia, blindness, deafness, uncontrolled 

epilepsy or severe learning disabilities and multiple disabilities. Study sample numbers were 

small and there is no information on when the assessments of these infants were carried out or 

whether evaluators were blinded. 

Battin, Ling, Whitfield, et al. (1998) compared the outcome of extremely low gestational age 

infants born between 23-25 weeks during 1991-1993 vs. similar gestational age infants born in 

1983-1989. Major neurologic impairments were found in 36% of 44 infants born 1991-1993 and 

in 36% of infants born 1983-1989.

Prevalence of CP in Clinical Trials

Additional 5 studies (Table 1.1b), which were conducted to evaluate various interventions, 

confirmed similar increased incidences of CP in VLBW infants. Gerdes, Gerdes, Beaumont, et 

al. (1995) evaluated the 1-year outcome of infants with birth weight 700-1100 grams treated with 

either 1 or 3 doses of surfactant found no difference in outcomes between the two surfactant 

groups. Forty to 60% of these infants had some impairment (20-27% were severe impairments). 

CP was present in 12-16% (moderate to severe cerebral palsy in 6-9%).

Table 1.1b. Association of Cerebral Palsy with LBW / Prematurity (Percentage of CP in clinical 

trials)

Author, Year Population N Mean BW, g; 

 GA, week

Baseline (Range)

Definition

of CP

% of CP Applicability Quality

Gerdes, 1995

95264241

BW 700-1100 g

Treated with 

2 surfactant 

508 BW: 907

GA: 27

Clinical 12-16% mmm A
39

Author, Year Population N Mean BW, g; 

 GA, week

Baseline (Range)

Definition

of CP

% of CP Applicability Quality

regimens

Ment, 1996

97040638

BW 600-1250 g

Indocin IVH 

prevention trial

431 ? 

343 at 

36 mos

BW 600-1250 g Clinical 7% in both groups mmm A

Ment, 2000

20164956 Premature 

infants with IVH 343

BW:

Sample 1: 988 

Sample 2: 945

GA: 28

Clinical 1% mmm A

Tin, 2001

21143595 GA <28 wks 249 GA: 23-27 Clinical 15.4-16.9% mm B

The Northern 

Nursing 

Initiative Trial 

Group 1996

96304894

GA <32 weeks 776

GA : 29

BW:1253 Clinical 11.2-14.1% mmm B

Roth, 2001

21262686 GA <33 wk 782

BW:

Sample 1: 1350 

Sample 2: 1324 

GA: 29

Clinical

Impaired 

Neurodevelopment 

28% and 36%

Disabling 

12-14%

mmm C

 Ment, Vohr, Oh, et al. (1996) found no difference in incidence of cerebral palsy between 

study groups of VLBW survivors (defined as 600-1250 grams) participating in the Multicenter 

Randomized Indomethacin IVH Prevention Trial (indocin 7% vs. 7% placebo) evaluated at 54 

months’ corrected age. In a study designed to evaluate whether differing oxygen saturation 

policies among nurseries in Northern England were associated with differences in incidence of 

retinopathy of prematurity (ROP) and cerebral palsy, Tin, Milligan, Pennefather, et al. (2001) 

found that the incidence of cerebral palsy (diagnosed at one year age) in premature infants born 

<28 weeks gestation during 1990-1994 ranged between 15.4% and 16.9% among the 

participating nurseries. There was no difference in incidence of CP in infants treated with oxygen 

saturation range 70-90% and 88-98% (15% vs. 17%, respectively).

The Northern Neonatal Nursing Initiative Trial Group (1996) conducted a trial in 1990-1992 

to study the effect of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm 

babies born <32 weeks gestation on long-term outcome at 2 years age. They found no difference 

in sensorineural, neuromotor, or neurologic outcomes among the three groups (median or mean 

gestational ages not provided). Specifically, the incidence of severe disability was 11.3%, 11.2%, 

and 14.1% in the prophylactic early fresh-frozen plasma or gelatin-based plasma substitute or 

maintenance glucose infusion groups, respectively. 

Roth, Amess, Kirkbride, et al. (2001) conducted a study designed to compare two methods of 

cranial ultrasound scanning (linear-array versus mechanical-sector) regarding accuracy of 

prediction of neurodevelopmental outcome. They enrolled all surviving premature infants born 

<33 weeks gestational age born between 1979 and 1988 (n=854). Of these, 92% were evaluated 

between ages 7 years and 2 months and 10 years and 6 months. In addition to showing there was 

no significant difference between the two methods, they found neurodevelopmental impairments 

in 28% and 36% of the two groups (linear-array versus mechanical-sector) and disabling 
40

impairment was found in 12% and 14% of the two groups (linear-array versus mechanicalsector). 

Evidence That Immaturity And The Degree of Immaturity (GA and/or BW) 

Influence The Risk of CP And Neurodevelopmental Disability In VLBW Infants

 Five studies (Table 1.2a) support the increased risk of CP and neurologic disability in 

premature and extremely premature infants in the current era of neonatal care.

Table 1.2a. Association of Cerebral Palsy by Degree of Immaturity 

 

Author, Year N

Mean BW, g; GA, 

week

Baseline (Range)

Definition of CP % of CP Applicability Quality

Victorian Infant 

Collaborative 

study Group, 

1997

453

BW: 500-999 g 

GA: ND

Clinical

and

Bayley Scale

BW 500-999g: 

6.8%

BW>2499: 1.7%

mm B

Victorian Infant 

Collaborative 

study Group, 

1997

97466059

989 BW: 500-999 g 

GA: ND

Clinical

and

Bayley Scale

0%

(85-87)

12.5%

(91-92)

mm B

Murphy, 1997

97192793 293 BW: NDGA: 29 (24-32) Clinical 32% mmm

B

Saigal, 2001

11483807

154 BW: 835, GA: 27 Clinical

ELBW group: 

17%

FT group: 0.8%

mm B

Finnström, 

1998

99041345

362 GA: = 23

BW: 798 Clinical

Entire cohort: 7%

23-24 wk: 14%

25-26 wk: 9%

≥27 wk: 3%

mmm C

The Victorian Infant Collaborative Study Group (1997) documented that ELBW children 

(500-999 grams) had significantly higher rates of sensorineural disability compared to normal 

birth weight children born ≥2499 g in the era 1991-1992 (6.8% vs. 1.7%), and that the rate of 

severe sensorineural disability was higher across all three eras for the most immature infants 

(500-749 grams) compared to that of premature infants with birth weight 750-999 g. 

Another study by The Victorian Infant Collaborative Study Group (1997) compared survival 

and outcome of extremely premature infants by gestational age criteria (23-27 weeks) with 

normal birth weight controls born during 1991-1992. As expected, the investigators found the 

rate of sensorineural disability was higher in the premature cohort than the normal birth weight 

controls born in 1991-1992. None of the normal birth weight controls born had CP, blindness, or 
41

deafness. In contrast, among the extremely premature infants followed through 2 years age, CP 

was diagnosed in 11% (half with quadriplegia, 20% hemiplegia, 20% with diplegia, and 

remainder mixed CP); 2.3% were blind; and 0.9% required hearing aids for sensorineural hearing 

deafness. The rates of cerebral palsy and deafness were not different compared to similar 

gestational age children born in 1985-1987, but the rate of blindness decreased. Compared with 

controls born in 1991-1992, the overall rate of sensorineural disability was higher in the 

premature cohort (p<0.0001). 

Murphy, Hope, and Johnson (1997) conducted a case-control study to identified neonatal risk 

factors for cerebral palsy in very preterm babies (<32 weeks gestation) born between 1984 and 

1990 independent of coexisting, previously identified antenatal and intrapartum factors. The 

incidence of CP among survivors increased with decreasing gestational age (p<0.0001).

Saigal, Stoskopf, Streiner, et al. (2001) compared the long-term outcome at 12 to 16 years of 

age between adolescents who were born ELBW vs. full-term controls, and evaluated changes 

over time. Their study confirmed that ELBW adolescents compared to full-term control 

adolescents had significantly higher proportion with neurosensory impairments (28% vs. 2%) 

including a greater prevalence of cerebral palsy (17% vs. 0.8%); greater current prevalence of 

seizures (7% v. 1%, p=0.03); higher proportion with multiple (≥ 3) health problems (35% vs. 

7%, p<0.001); greater proportion with any functional limitation (81% vs. 42%, p<0.0001); 

greater utilization of health care resources in the proportion of adolescents who were seen by 

pediatricians, ophthalmologists, otolaryngologists, speech parthologists, occupational therapists; 

and greater proportion of parents with out-of-pocket expenses (10% vs. 1%, p<0.001).

Finnstrom, Otterblad Olausson, Sedin, et al. (1998) evaluated neurosensory outcome at 3 

years age in extremely low birth weight infants (<1000 grams birth weight and ≥23 weeks 

gestation) born during 1990-1992 and enrolled in the national Swedish prospective study. 

Ninety-eight percent of surviving ELBW (mean birth weight 798±144 g) were assessed at 

median age of 3 years. The incidence of cerebral palsy for the entire cohort was 7%, which is 50 

times higher than that reported in term infants in Sweden. The incidence of cerebral palsy for 

children born at 23-24, 25-26, ≥27 weeks gestation was 14%, 10%, and 3%, respectively. The 

overall incidence of major handicap in ELBW cohort was 7%. At least one handicap was noted 

in 14%, 9%, and 3% of each of the three gestational age groups, respectively. Severe intracranial 

hemorrhage (≥ grade 3), periventricular leukomalacia, and retinopathy of prematurity ≥ Stage 3 

were significantly predictive of increased risk of handicap after adjusting for gestational age. 

This study illustrates that this cohort of ELBW children are at increased risk for adverse 

neurosensory outcome, and the risk increases with decreasing gestational age. 

The evidence of the studies within this review clearly supports the increased risk of cerebral 

palsy and neurologic disability in premature infants in the current era of neonatal care, and that 

the risk for CP and adverse neurodevelopmental outcome is further increased in extremely 

premature infants. 
42

Evidence That VLBW Plus Other Factors Are Associated With CP and 

Neurologic Abnormalities

CNS Injury (Intracranial Hemorrhage, Cerebral White Matter Damage: 

Periventricular Leukomalacia, Ventriculomegaly)

Numerous studies provide evidence that cerebral white matter damage (WMD), as 

manifested by periventricular leukomalacia (PVL) (such as echodensities and echolucencies), 

ventriculomegaly (VM), and posthemorrhagic infarct, as well as severe intracranial hemorrhage 

(ICH) are among the strongest predictors of cerebral palsy and other neurologic disabilities in 

VLBW infants (Ekert, Keenan, Whyte, et al., 1997; Holling and Leviton, 1999; Levene, 1990; 

Ment, Vohr, Allan, et al., 1999; Pasman, Rotteveel, Maassen, et al., 1998; Rademaker, 

Groenendaal, Jansen, et al., 1994). There are additional studies supporting this association that 

proceeded the time period of this literature review. Although the diagnosis of cerebral WMD is 

understandably made postnatally, WMD may originate antenatally and may also occur or 

continue to occur postnatally. The etiology of WMD appears to be related to the immature and 

incomplete development of the vascular supply to the cerebral white matter, the immaturity of 

cerebral blood flow regulation and increase risk for ischemic injury, and the vulnerability of the 

oligodendroglial precursor cell to cytotoxic injury (Volpe, 2001).

Fourteen studies (Table 1.3a) abstracted according the search criteria for this review are 

noted below: 

Table 1.3a. Association of CP and neurologic abnormalities in VLBW with CNS injury

Associations

Author, Year N

Mean BW, g;

GA, wk

Baseline

Risk Factors

Univariate Multivariate

Applicability Quality

PVL ↑* ↑*

Allan, 1997

97336492

Ment, 1996

97040638

337

Indomethacin grp:

BW: 945

GA: 28

Placebo grp:

BW: 988

GA: 28

VM ↑* ↑*

mm A

Piecuch, 1997 

98012134 86

BW: 

Sample 1: 668

Sample 2: 790

Sample 3: 842

GA: 24-26

c-PVL and/or 

grade III or IV 

ICH

↑ ↑ mmm A

PVL ↑ ↑

Piecuch, 1997

97456215 445

BW: 

Sample 1: 668

Sample 2: 790

Sample 3: 842

 Sample 4: 850

 Sample 5: 942

 GA:26-27

ICH Gr 3 or 4 ↑ ↑

mmm A
43

Associations

Author, Year N

Mean BW, g;

GA, wk

Baseline

Risk Factors

Univariate Multivariate

Applicability Quality

Hack, 2000

20358826 221 BW: 813GA: 26

c-PVL and/or 

grade III or IV 

ICH

↑* ↑* mmm A

Valkama, 2000

20233239

51 BW: 1153

GA: 29 (25-34)

Parenchymal 

lesions a ↑ ↑ mmm A

Lefebvre, 1998

98387703 121

BW: 961

GA: 27 NBRS c ↑ ↑ mm A

Pierrat, 2001

27221167

60 BW: 1003

GA: 29

Grade II or III cPVL ↑ ↑ mm B

Salokorpi, 1999

99353226

143 BW: 820

GA: 27

Grade III or IV 

ICH, PVL ↑* ↑ mm B

Cioni, 2000

20150341 29 BW: NDGA: 31

WM damage; WM 

loss ↑* ↑ mm B

Pennefather, 

2000

20217908

558 BW: ND

GA: < 32

Ocular 

abnormalities b

↑* ↑ mmm B

Wilkinson, 1996

97087405

10 BW: 1144

GA: 27 Severe c-PVL ↑ ↑ m B

Rogers, 1998

98438124

41 BW: 1125

GA: 28 c-PVL ↑ ↑ m B

Krageloh-Mann, 

1999

99431017

29

BW: 1461 (690-

2655)

GA: 30 (27-34)

Abnormal brain 

MRI findings x ↑ ↑ mm C

a Parenchymal lesions was defined as hemorrhage, PVL, infarctions, and reduction in cerebral white matter on MRI findings

b Ocular abnormalities: cicatricial ROP, cortical visual impairment, and strabismus

c Neurobiologic Risk Score (NBRS) represents the summation of the occurrence or degree of the following variables: duration of 

ventilation, acidosis, seizures, presence and degree of ICH and PVL

A randomized, placebo-controlled clinical trial of indomethacin prophylaxis for 

intraventricular hemorrhage was conducted. Four hundred and thirty-one VLBW infants (BW 

600-1250 g) were followed up at 36 months corrected age (Allan, Vohr, Makuch, et al., 1997). 

and 54 months corrected age (Ment et al, 1996; Ment et al, 2000, described in 3.B). They

evaluated the determinants of CP and the relationships of these determinants to CP. Cerebral 

palsy was found in 9.5% of the VLBW infants at 36 months corrected age. The authors found 

that sonographic evidence of cerebral periventricular leukomalacia (PVL) and ventriculomegaly 

(VM) were associated with the highest detection rates for CP: 37% for PVL, 30% for VM, and 

22% for grade 3 or 4 intracranial hemorrhage. Chorioamnionitis (Detection Rate = 28, 95% CI 

16, 40, p=0.02) and surfactant therapy (p=0.005) were significantly associated with cerebral 

palsy in the univariate analyses, but were not independent predictors of cerebral palsy in the 
44

multivariate analysis once indicators of cerebral WMD (PVL and VM), severe intracranial 

hemorrhage, and bronhopulmonary dysplasia (BPD) were included in the prediction model. 

Possible explanations for the difference in univariate and multivariate findings are the notable 

association of chorioamnionitis with parenchymal brain injury and sonographic evidence of 

WMD, and the fact that surfactant use is closely related to BPD. Cystic PVL had the strongest 

association with CP among the other cranial ultrasound findings (cystic PVL OR =16;. Grade III 

or IV IVH OR= 14; VM OR= 9). Cranial sonographic findings can be helpful in predicting CP as 

early as 3 days of age. The 40-week adjusted gestational age cranial ultrasound had the highest 

odds ratio for predicting CP at 3 years corrected age (OR 52%, 95% CI 26, 65). The three classic 

forms of CP (spastic diplegia, hemiplegia, and tetraplegia) were distributed equally among the 

children with CP (Allan, Vohr, Makuch, et al., 1997).

 Piecuch, Leonard, Cooper, et al. (1997) reviewed neurodevelopmental outcomes of 446 

ELBW (500-999 grams) infants born between 1979-1991. At a mean age of 55±33 months of 

age (range 12 to >72 months, they found that 15% of infants had abnormal neurologic/ 

neurosensory outcome. Among 442 infants, 9% specifically had a diagnosis of CP or significant 

impairment in neuromotor function. There was no change in incidence of CP or neuromotor 

impairment over the time period. Within this narrow range of extreme prematurity, there was a 

significant association between abnormal neurologic outcome and gestational age (i.e. the more 

immature the gestational age, the greater the risk of abnormal neurologic outcome). 

Approximately half the infants (46%) who had complicated ICH and or cystic PVL had 

abnormal neurologic outcome. The proportion of children with cerebral palsy or neuromotor 

impairment increased as the grade of intracranial hemorrhage increased as evidence by the strong 

association between abnormal outcome and cystic periventricular leukomalacia and/or grade III 

and IV intracranial hemorrhage. Mild to moderate neurologic delays were also associated with 

BPD. 

Piecuch, Leonard, Cooper, et al. (1997) also evaluated outcome at a mean age of 32 ±17 

months in extremely premature infants born at 24 to 26 weeks gestation between 1990-1994. The 

incidence of cerebral palsy was 11%, 20%, 11% across all three gestational ages (24,25,26 

weeks) (p=ns). Abnormal neurologic outcome was documented in 33% of infants born at 24 

weeks, 27% born at 25 weeks, and 11% born at 26 weeks gestation, but the difference was not 

statistically significant in this group of patients. Abnormal neurologic outcome was significantly 

associated with medical risk factors of cerebral injury (periventricular leukomalacia and severe 

intracranial hemorrhage (grade III or IV). 

A study by Hack, Wilson-Costello, Friedman, et al. (2000) provides relatively recent

information regarding the neurodevelopmental outcome at 20-months corrected age of 221 

extremely immature infants born between 1992 to 1995. They found that 48% of the infants had 

neurodevelopmental impairment (neurologic abnormality, subnormal MDI, blindness or

deafness); 20% a major neurologic abnormality, and the incidence of CP was 15%. Predictors of 

abnormal neurologic outcome included severe abnormal cranial ultrasound (OR, 8,09; 95% CI 

3.69-17.71) and bronchopulmonary dysplasia. Rates of neurodevelopmental disability for

children with Grade III or IV intracranial hemorrhage, periventricular leukomalacia, and

ventriculomegaly were 69%, 75%, and 71% respectively. There was no difference in outcomes 

of ELBW infants who were AGA vs. SGA (birth weight <-2 SD).

With increased use of magnetic resonance imaging, it is becoming clear that cranial 

ultrasound under-diagnoses milder or diffuse lesions of cerebral white matter damage (de Vries, 

Eken, Groenendaal, et al., 1993; Levene, 1990). Valkama, Paakko, Vainionpaa, et al. (2000) 
45

compared the value of neonatal brain magnetic resonance imaging (MRI) with cranial 

sonographic findings at full-term equivalent age for predicting neuromotor outcome in VLBW 

infants. Fifty-one infants (birth weight <1500 grams and gestational age <34 weeks at) had MRI 

and cranial ultrasound at 40 weeks equivalent gestational age, and were followed until 18 months 

corrected age. CP was diagnosed in 23%. All infants with cerebral palsy were <29 weeks 

gestation at birth. Parenchymal lesions (defined as hemorrhage, PVL, infarctions, and reduction 

in cerebral white matter) on MRI predicted cerebral palsy with 82% sensitivity and 97% 

specificity (OR 171, 95% CI 13.9, 2100). Parenchymal lesions on cranial ultrasound predicted 

cerebral palsy with 58% sensitivity and 100% specificity. Chen, Shen, Wang, et al. (1995) 

demonstrated that MRI at 1 year of age confirmed changes of PVL and that these findings 

correlated with cerebral palsy.

Lefebvre, Gregoire, Dubois, et al. (1998) demonstrated that the Neurobiologic Risk Score 

(NBRS) is useful in predicting 18-month outcome of very premature infants (mean birth weight 

961±179 grams, gestation 27.0±1.2 weeks, born during 1987-1992). The NBRS represents the 

summation of the occurrence or degree of the following variables during the entire neonatal 

admission period: duration of ventilation, acidosis, seizures, presence and degree of intracranial 

hemorrhage and periventricular leukomalacia, infection, and hypoglycemia in premature infants. 

NBRS scores of low (0-4), moderate (5-7), or high (≥8) correlated with the prevalence of CP 

(4% vs. 19% vs. 41%), severe disability (0 vs. 24% vs. 50%), and of any disability (16% vs. 30% 

vs. 71%), respectively. The NBRS also correlated with mean developmental quotient and 

prevalence of developmental quotients <90.

Consistent evidence in 6 studies has showed strong association between severe abnormal 

cranial ultrasound findings (c-PVL and grade III or IV ICH) and CP or neurologic abnormalities.

Evidence that cystic PVL is one of the strongest predictors of CP is noted in a study by Pierrat, 

Duquennoy, van Haastert, et al. (2001). These investigators compared the ultrasound evolution 

and neurodevelopmental outcome of infants with localized (grade II) and extensive (grade III) 

cystic periventricular leukomalacia (c-PVL). Between 1990 and 1998, all preterm infants ≤32 

weeks gestational age admitted to the Level III neonatal units of Lille and Utrecht were enrolled 

in the prospective cranial ultrasound study. Cystic PVL was diagnosed in 96/3451 (2.8%). The 

mean gestational ages were the same (29±1.8 weeks) for both groups of c-PVL. CP was 

diagnosed in 22 of 29 survivors (74%) with grade II c-PVL and in 26 of 27 survivors (96%) with 

grade III c-PVL. In this cohort of infants with c-PVL, ventriculomegaly was another excellent 

predictor of CP as 29 of 30 infants with ventriculomegaly developed cerebral palsy. Also, the 

severity of CP was worse in grade III c-PVL than grade II c-PVL. All infants with grade III cPVL had severe handicap. Nine of 39 (23%) infants with grade II c-PVL were free of motor 

sequelae through 24 months follow-up compared to only 1 of 39 (3%) with grade III c-PVL. 

Eighty-eight percent of grade III c-PVL/CP could not walk independently in contrast to 24% 

with grade II c-PVL/CP.

Salokorpi, Rajantie, Viitala, et al. (1999) also demonstrated a significant, positive association 

between abnormal cranial ultrasound (Grade III and IV hemorrhage, PVL) and subsequent 

diagnosis of cerebral palsy in children who were born ELBW (<1000 grams) between 1991 and 

1994 (OR 7.94, 95% CI 2.75, 22.95). The overall prevalence of cerebral palsy was 17% in the 

survivors of this ELBW cohort. 

Cioni, Bertuccelli, Boldrini, et al. (2000) evaluated infants at one year of age who were born 

preterm (mean 31 ± 2.8 weeks gestational age) during 1989-1991, had periventricular 

leukomalacia and abnormal neurological examination at full-term equivalent age. The purpose of 
46

the study was to evaluate whether visual function abnormalities at one-year age were associated 

with neurodevelopmental outcome and findings on magnetic resonance imaging at the same time 

in this high-risk cohort. This study found a high incidence of CP (76%) and abnormal visual 

function in this cohort of infants. Seventy-nine percent had at least one abnormal visual function 

test and >50% had multiple abnormal visual function tests: 28% abnormal fixation; 66% 

strabismus; and 45% abnormal grating acuity, 31% reduced visua l field, and 59% had abnormal 

horizontal optokinetic nystagmus. The degree of visual impairment correlated with MRI 

findings: size of later ventricles (p<0.000), white matter damage (p=0.01), white matter loss 

(p=0.003), abnormal corpus callosum (p=0.03), and abnormal optic radiation (p<0.000). The 

degree of visual impairment correlated with the degree of neurodevelopmental impairment 

(p=0.000). Visual impairment was the most important variable in determining the 

neurodevelopmental scores of infants with leukomalacia, and was more important than motor 

disability and the extent of lesions on MRI. 

Visual and ocular abnormalities are often associated with neurodevelopmental abnormalities 

in VLBW infants with cerebral white matter damage. Pennefather and Tin (2000) investigated 

the incidence of ocular abnormalities associated with cerebral palsy after preterm birth. They 

found preterm children with CP had more ocular abnormalites than preterm children without 

cerebral palsy: cicatricial ROP (14.8% vs. 1.6%, p<0.0001); cortical visual impairment (11.1% 

vs. 0.2%, p<0.0001), and strabismus (51.9% vs. 8.4%, p<0.0001). This study emphasizes the 

importance of ocular assessment of children with cerebral palsy. 

In studying the relationship between growth failure in preterm infants with cystic 

periventricular leukomalacia, Rogers, Andrus, Msall, et al. (1998) found that 39 of 41 preterm 

infants (all <33 weeks gestation, born 1988 to 1993, and followed through 59 months age) 

developed cerebral palsy. Growth failure in children with cystic PVL was attributed solely to 

oral feeding impairment.

Within this review, there is very strong evidence that central nervous system injuries, such as 

cerebral white matter damage (periventricular leukomalacia and ventriculomegaly) and severe 

intracranial hemorrhage, are highly predictive of subsequent CP and abnormal neurological 

outcome noted in VLBW infants. 

Similarly, Krageloh-Mann, Toft, Lunding, et al. (1999) prospectively compared high-risk 

preterm infants with term-born children at 5.5-7.5 years of age during a case-control study in 

terms of neurological, neuropsychological, and magnetic resonance imaging (MRI) results. The 

proportion of preterm infants with history of maternal pre-eclampsia p=0.03), mechanical 

ventilation >7 days (0.03), and cerebral blood flow < 2ml O2/100g/min (p=0.03) were 

significantly different between infants who had normal MRI versus abnormal MRI. The authors 

demonstrated specific morphological correlation of abnormal MRI results with major central 

nervous system disabilities, including CP (involvement of the motor tracts), mental retardation 

(bilateral extensive white matter reduction or cerebellar atrophy), and severe visual impairment 

(severe optic radiation involvement). 

Antenatal Risk Factors

Increasing evidence indicates that antenatal events contribute to the etiology and sequence of 

events leading to neurologic impairment and CP in VLBW infants. Antenatal inflammation, 

chorioamnionitis, subclinical infection, and fetal hypoxia/acidosis may play an important role via 

stimulating a fetal inflammatory response that injures the immature cerebral white matter (Allan, 
47

Vohr, Makuch, et al., 1997; Gaudet and Smith, 2001; Kato, Yamada, Matsumoto, et al., 1996; 

Murphy, Hope, and Johnson, 1997; O'Shea, Klinepeter, and Dillard, 1998; O'Shea, Klinepeter, 

Goldstein, et al., 1997; O'Shea, Preisser, Klinepeter, et al., 1998; Volpe, 2001). Other antenatal 

events such as premature rupture of membranes (which may be related to antenatal inflammation 

and infection) and abruption have been evaluated for their contribution to risk of cerebral palsy 

and/or neurodevelopmental disability in premature infants. (O'Shea, Klinepeter, and Dillard, 

1998; O'Shea, Klinepeter, Goldstein, et al., 1997; O'Shea, Preisser, Klinepeter, et al., 1998). The 

degree of prematurity and central nervous system injury, as discussed above, plus other neonatal 

factors may influence the development of CP. 

Ten studies identified by the criteria of this review report the association of CP and 

neurologic abnormalities with antenatal factors in VLBW infants (Table 1.3b).

Table 1.3 b. Association of CP and neurologic abnormalities with antenatal risk factors in VLBW 

infants 

Associations

Author, Year N

Mean BW, g;

GA, wk

Baseline

Risk Factors

Univariate Multivariate

Applicability Quality

Murphy, 1997

97192793 293 BW: NDGA: 29 (24-32)

Antenatal factors 

a

n.d. ↑* mmm B

Redline, 1998

99086405 119 BW: 995GA: 27

Fetal placental 

vascular lesions b

↑* -? mm B

O’Shea, 1998

98167528

98190123

723 BW 500-1500

GA: 25

Antenatal factors 

c ↑ - mmm B

Spinillo, 1994

94257064 231 BW: 1750GA: 33

Moderate to 

severe abruptio 

placenta

↑ -? mm B

Kurkinen-Raty, 

1998

98197235

156

BW: 1205

GA: 

PROM grp: 28.2 

Vs 

Contorl grp: 28.3

Very early (17-30 

wk) PROM ↔ . ↔ mmm B

Kurkinen-Raty, 

2000

20284814

206

BW : 1294

 GA: 24-33 wk 

Delivery for 

maternal or fetal 

indications

↔ ↔ mm B

Ambalavanan

2000

21031370

218 BW: 829

GA: 26

IVH, PVL, BPD, 

lower mat edu - - mm B

Spinillo, 1997

98237382 345 BW: 1371GA: 30

Increased risk of 

infection d

↑ ↑ m C

Burguet, 1999

99126269 167 BW: 8%>2000GA: 25-32

Antenatal factors 

e

n.d. ↑* mmm C

Kato, 1996

97182916 228 BW: 1031GA: 28 Antenatal factors f ↑* . - mmm C

a

Including chorioamnionitis and neonatal sepsis, maternal infection, cerebral parenchymal damage, ventriculomegaly, patent 

ductus arteriosus, hypotension, blood transfusion, prolonged ventilation, pneumothorax, sepsis, hyponatremia, parenteral 

nutrition and seizure.

b

Including chorionic plate thrombi, chorioamnionitis, and severe villous edema

c

Including multiple gestation, chorioamnionitis, materanl antibiotics, and antepartum vaginal bleeding.

d Prolonged rupture of membranes and meconuim stained fluid
48

e Premature rupture of membranes (PROM) ≥ 48 hrs, monochorionic twin pacentation, and RDS

f Malpresentation, tocolytic agents (beta 2 stimulant plus magnesium sulfate)

A case-control study by Murphy, Hope, and Johnson (1997) demonstrated that antenatal, 

intrapartum, and postnatal factors are independently and interactively associated with 

development of cerebral palsy. Murphy et al identified new neonatal risk factors for cerebral 

palsy in very preterm babies (<32 weeks gestation, born between 1984 and 1990) independent of 

coexisting, previously identified antenatal and intrapartum factors. The factors were as follows 

(expressed as OR; 95% CI): chorioamnionitis and neonatal sepsis (7.1;1.2,40.6); any maternal 

infection and neonatal sepsis (4.2; 1.6,11.2); cerebral parenchymal damage on sonography (OR 

32, 12.4, 84.4); ventriculomegaly (5.4; 3.0, 9.8); patent ductus arteriosus (2.3; 1.2, 4.5); 

hypotension (2.3, 1.3,4.7), blood transfusion (4.8; 2.5, 9.3); prolonged ventilation (4.8; 2.5,9.0), 

pneumothorax (3.5, 1.6, 7.6), sepsis (3.6;1.8,7.4); hyponatremia (7.9, 2.1, 29.6), and total 

parenteral nutrition (5.5; 2.8,10.5), and seizures (10.0; 4.1, 24.7). Cranial ultrasound 

abnormalities were more predictive of CP than cardiovascular disturbances. Murphy’s study 

demonstrates that antenatal factors such as intrauterine inflammation, infection, and conditions 

that predispose to hypoxic-ischemic injury were significantly associated with development of 

CP. Both antenatal factors and postnatal factors were influenced by the degree of prematurity.

Redline, Wilson-Costello, Borawski, et al. (1998) examined the link between placenta 

pathology and neurologic outcome in VLBW infants. They analyzed placentas from mothers of 

children who were born VLBW and had subsequent neurologic impairments (CP and other 

neurologic abnormalities) vs. placentas from mothers of control children (matched for gestational 

age, birth weight, gender, race) to assess antenatal processes that might be associated with 

subsequent cerebral palsy and neurologic impairment in VLBW infants (born 1983-1991). They 

found that the presence of chorionic plate thrombi, seen only with chorioamnionitis, and severe 

villous edema were statistically associated with neurologic impairment, including CP, at 20 

months corrected age. This study demonstrates an association between fetal placental vascular 

lesions associated with chorioamnionitis and subsequent neurologic impairment of VLBW 

infants. 

O'Shea, Klinepeter, and Dillard (1998) conducted a case-control study to analyze 

associations between antenatal factors and CP in a geographically-based cohort of premature 

infants (birth weights 500-1500 grams) born between 1978 and 1989 and followed for 1 year. 

The prevalence of cerebral palsy was 9% among premature children returning for 1-year followup. As in other studies, gestational age was associated with risk of CP (OR per week increase in 

gestational age = 0.79 (95% CI 0.66, 0.93). Antenatal factors independently and strongly 

associated with cerebral palsy were multiple gestation, chorioamnionitis, maternal antibiotics, 

antepartum vaginal bleeding, and labor lasting less than 4 hours. Pre-eclampsia and delivery 

without labor were associated with decreased risk of CP. Although the focus of this study was on 

antenatal factors associated with CP, O’Shea et al also found that a majority of infants with CP 

had an antecedent major cranial ultrasound abnormality, most often intraparenchymal 

echodensity (70% of infants with diplegia; 52% with quadriplegia, 32% with diplegia vs. 2% of 

controls). Forty-seven percent of the cases had no major ultrasound abnormality. 

Spinillo, Fazzi, Stronati, et al. (1994) compared early morbidity and neurodevelopmental

outcome in low birth weight infants (<2500 grams) delivered after third trimester bleeding with 

consecutive controls of similar gestational age with no maternal history of third trimester 

bleeding. The period of study was between 1983-1989. This study demonstrated that moderate to 
49

severe abruptio placenta is associated with increased risk of poor outcome (death or cerebral 

palsy) in low birth weight infants compared to controls (OR 3.9, 95% CI 1.2, 12.1). 

Kurkinen-Raty, Koivisto, and Jouppila (1998) conducted two studies, which evaluated the 

long-term impact of very early preterm (17-30 weeks gestation) premature rupture of membranes 

(PROM) and of maternal or fetal indications for delivery. In the first study evaluating very early 

preterm PROM, the investigators demonstrated late, long-term pulmonary problems of preterm 

infants born to mothers with very early PROM, but the results of this study did not reveal any 

effect of very early PROM on neurologic outcome in this cohort. The infants followed in this 

study were compared to infants delivered from mothers with spontaneous preterm delivery 

without very early PROM during the same time period of 1990-1996. The mean gestational age 

at birth was similar between the PROM and Control groups (PROM 28.2 vs. Control 28.3 

weeks). The incidence of cerebral palsy was high, but not different, in both preterm groups (18% 

vs. 16%, OR 1.2, 95% CI 0.4, 3.1) at one year of age. 

In Kurkinen-Raty’s second study, premature infants delivered between 24 and 33 weeks 

gestational age for either maternal or fetal indications were compared to premature infants of 

similar gestational age born to mothers who had spontaneous preterm delivery. There was no 

difference between the two groups with respect to neurologic outcome at one year of age. The 

mean gestational age at birth was similar between the two groups (Indicated Delivery 30.5 vs. 

Spontaneous Preterm Delivery 30.4 weeks). The incidence of cerebral palsy was similar to that 

reported by others and not different between the preterm groups (Indicated Delivery 6% vs. 11%, 

OR 0.6, 95% CI 0.2, 1.6) at one year of age. The incidence of delayed motor development was 

similar between groups (Indicated Delivery 10% vs. Spontaneous Preterm Delivery 9%, OR 1.2, 

95% CI 0.5,3.0) (Kurkinen-Raty, Koivisto, and Jouppila, 2000).

Ambalavanan, Nelson, Alexander, et al. (2000) conducted a retrospective cohort study of a 

regional Level III NICU database to identify major determinants of adverse neurodevelopmental 

outcome in ELBW (<1000 grams birth weight) infants born 1990-1994. The determinants for 

major handicap included intraventricular hemorrhage, necrotizing enterocolitis ≥ Stage 2, black 

race, and no chorioamnionitis. Determinants of low psychomotor developmental index (PDI) 

included intraventricular hemorrhage, periventricular leukomalacia, BPD, lower maternal 

education, and no chorioamnionitis. These determinants accounted for <20% of the variance in 

neurodevelopmental outcomes. The study has limitations of being retrospective, small sample 

size, and short follow-up period. The determinants of neurodevelopmental outcome identified in 

this study are similar to other studies except one notable exception-‘no chorioamnionitis’. 

Ambalavanan et al. found that infants with chorioamnionitis had higher MDI, and PDI and 

incidence of major handicap was similar between infants exposed to chorioamnionitis vs. no 

chorioamnionitis. Chorioamnionitis has been identified in numerous studies, as noted above, as 

an independent risk factor for cerebral white matter damage. The authors offered no clear 

explanation for these findings.

Spinillo, Capuzzo, Orcesi, et al. (1997) also evaluated effects of antenatal risks on neonatal 

death and CP in a cohort of preterm infants (24-33 weeks) delivered between 1987-1992. Among 

310 infants assessed at 2 years, 12.5% had CP. Among children with cerebral palsy, 34% of CP 

was diagnosed in infants born between 23-33 weeks gestational age. Prolonged rupture of 

membranes (>48 hours) was associated with increased risk of CP in univariate analysis. 

Gestational age and meconium stained fluid were independent predictors of CP in the 

multivariate analysis. Both prolonged rupture of membranes and meconium stained fluid are 

associated with increased risk of infection. Thus, it is possible that these factors are co-variates 
50

of subclinical antenatal infection that predisposes to brain injury and leads to cerebral palsy 

(Spinillo, Capuzzo, Orcesi, et al., 1997; Spinillo, Fazzi, Capuzzo, et al., 1997). Increasing 

gestational age was associated with decrease in odds of cerebral palsy.

Burguet, Monnet, Pauchard, et al. (1999) conducted a prospective, geographically-defined 

(France), collaborative study in 1990-1992 to identify antenatal risk factors of 

neurodevelopmental disabilities in very premature (GA<33 weeks), singleton or twin, nonmalformed infants (n-203). The study was conducted prior to routine use of antenatal steroids. 

Among 171 survivors, 167 (98%) were evaluated at 2 years of age: 22 (13%) had CP; Significant 

risk factors for neurologic disabilities by a multivariate approach included premature rupture of 

membranes ≥48 h (OR 4.3, 95% CI 1.6-11.8); monochorionic twin placentation (OR 6.0, 95% CI 

1.7-21.3), and respiratory distress syndrome (OR 2.8, 95% CI 1.1-7.1). Incidence of CP was 7% 

in infants without PROM, 20% in infants with PROM <48 hrs, 30% in PROM 48 hrs to 7 days, 

11% in PROM >7 days, chi-square trend: p=0.004. 

Kato, Yamada, Matsumoto, et al. (1996) noted additional antenatal factors are significantly 

related to increased risk of CP and neurologic impairment. These factors include 

malpresentation, tocolytic agents (beta 2 stimulant plus magnesium sulfate).

Bronchopulmonary Dysplasia (BPD) And Postnatal Systemic Glucocorticoid 

Therapy (Dexamethasone) 

Numerous studies have documented that mechanical ventilation (especially prolonged 

mechanical ventilation), and bronchopulmonary dysplasia (BPD), or neonatal chronic lung 

disease, are associated with adverse neurodevelopmental outcome in premature infants (Cheung, 

Barrington, Finer, et al., 1999; Kim, Namgung, Chang, et al., 1999; Murphy, Hope, and Johnson, 

1997; Palta, Sadek-Badawi, Evans, et al., 2000; Pasman, Rotteveel, Maassen, et al., 1998; 

Salokorpi, Rajantie, Viitala, et al., 1999; Thompson, Buccimazza, Webster, et al., 1993). In 

addition, there is increasing evidence that the use of postnatal systemic glucocorticoid therapy, 

specifically dexamethasone, for the prevention or treatment of neonatal chronic lung disease may 

have an adverse effect on long-term neurologic development and increase the risk of CP 

(Barrington, 2001; Shinwell, Karplus, Reich, et al., 2000).

Eight studies (Table 1.3c) identified in this review provide evidence that BPD and systemic 

dexamethasone may be factors influencing the risk of CP and neurologic impairment in VLBW 

infants.
51

Table 1.3 c. Association of CP and neurologic abnormalities in VLBW with BPD and BPD and 

postnatal systemic glucocorticoid therapy 

Associations

Author, Year N

Mean BW, g;

GA, wk

Baseline

Risk Factors Univariate Multivariate

Applicability Quality

Allan, 1997

97336492

33

7

BW: 600-1250

GA: 28 BPD ↑ ND mm A

O’Shea, 1999

99318938 95

Dexamethasone grp:

BW: 747 (420-1362)

GA: 25 (23-29)

Placebo grp:

GA: 26 (23-31)

BW: 775 (495-1324)

BPD and 

Dexamethasone 

↑ - mmm A

Hack, 2000

20358826 221 BW: 813GA: 26

BPD and 

postnatal 

steroid

↑ - mmm A

DeReginer, 1997

98041177

17

4

GA: 27

BW: 1014 BPD ↑* - mmm B

Gregoire, 1998

98232532 217 BW: 1039GA: 24-28

BPD oxygen 

dependency a ↔ « mm B

Palta, 2000

20096107 425 GA: 29BW: 1003 BPD; IVH ↑* - mm B

Victorian Infant 

Collaborative 

study Group, 

2000

20307288

346

Corticosteroids & No 

corticosteroids:

BW: <1000

GA: <28

Postnatal 

steroid Rx ↑* ↑* mm B

Cheung, 1999

99146391 164 BW: 961GA: 27

Predischarge 

apnea b

duration of 

ventilation 

and IVH

↑* ↑* mm B

a Oxygen dependency: requiring oxygen at 28 days but not at 36 weeks CGA, requiring oxygen at 36 weeks CGA; and, not 

oxygen dependent

b Frequency and degree of oximetry desaturation: duration of ventilation and IVH

In Allan’s study of the determinants of cerebral palsy in a cohort of VLBW (600-1250 g) 

infants enrolled in a randomized, placebo-controlled clinical trial of indomethacin prophylaxis 

for intraventricular hemorrhage, 15% of 177 infants with BPD and 4% of 203 infants without 

BPD had CP at 36 months corrected age (p<0.001) (Allan, Vohr, Makuch, et al., 1997).

O'Shea, Kothadia, Klinepeter, et al. (1999) demonstrated that a 42-day tapering course of 

dexamethasone in VLBW infants, with severe, evolving neonatal chronic lung disease, was 

associated with an increased risk of cerebral palsy (25% dex vs. 7% placebo, OR 5.3, 95% CI 

1.3, 21.4) and abnormal neurologic examination (45% dex vs. 16% placebo, OR 3.6, 95% CI 1.2, 

11.0). More dexamethasone recipients had major intracranial sonographic abnormalities 

compared to placebo controls (21% vs. 11%). This study was not able to determine if the 

increased risk was due to an adverse effect of dexamethasone per se or to improved survival of 

infants who were already at increased risk for neurologic disability. 

Hack, Wilson-Costello, Friedman, et al. (2000) found in a former-ELBW group at 20 

months’ corrected age that chronic lung disease, or bronchopulmonary dysplasia, and postnatal 
52

steroids were predictive of subnormal MDI and abnormal neurologic outcome. The effects of 

systemic postnatal steroids independent of chronic lung disease was not evaluated. 

deRegnier, Roberts, Ramsey, et al. (1997) evaluated whether there was an association 

between severity of BPD in VLBW infants and 5-year neurodevelopmental, sensory, and growth 

outcome. In order to isolate the effect of BPD on outcome, infants were excluded if they had 

conditions known to adversely affect neurosensory status (e.g. intraparenchymal cranial 

ultrasound abnormalities or ventriculomegaly). They demonstrated that the risk of adverse 

neurodevelopmental and sensory outcome increased with decreasing gestational age and with 

increasing severity of BPD in VLBW infants: no BPD (3.6% adverse neurodevelopmental); mild 

BPD (21.4% adverse neurodevelopmental); severe BDP (31.6% adverse neurodevelopmental) 

(p<0.001). The odds of cerebral palsy was significantly increased in the BPD group (vs. no BPD 

group) (unadjusted odds 6.4, 95% CI 1.05, 139.8). 

Gregoire, Lefebvre, and Glorieux (1998) prospectively compared health and developmental 

outcomes at 18 months of three cohorts of premature infants (GA 24-28 weeks): infants requiring 

oxygen at 28 days but not at 36 weeks CGA, infants requiring oxygen at 36 weeks CGA, and 

infant who were not oxygen dependent at 28 days. No significant difference in incidence of CP 

was found between the 3 groups, but a significantly lower mean developmental quotient was 

found in infants requiring oxygen at 36 weeks CGA. 

Palta, Sadek-Badawi, Evans, et al. (2000) found that and bronchopulmonary dysplasia (odds 

ratio, 2.3; 95% confidence interval, 1.2-4.6) and intraventricular hemorrhage (odds ratio, 2.3 per 

grade; 95% confidence interval, 1.8-2.8) were independently predictive of cerebral palsy and of 

functional outcome in their study of 425 VLBW (<=1500 g) infants born 1988-1991 in one of 6 

NICUs who were followed to an average age of 5 years. The study was designed to compare 

outcomes before and after introduction of surfactant. Cerebral palsy was present in 12.6% of the 

children, and the incidence did not change after the introduction of surfactant.

Investigators of The Victorian Infant Collaborative Study Group (2000)studied the 

association between postnatal systemic glucocorticosteroid therapy and sensorineural outcome at 

5 years of age among children who were born extremely premature (<1000 gram or gestational 

age <28 weeks) during 1991-1992. Survivors treated with systemic glucocorticoid therapy 

compared to those without corticosteroid therapy had significantly higher rates of cerebral palsy 

(23% vs. 4%), blindness (4% vs. 1%), and intelligence quotient greater than 1 SD below the 

mean (54% vs. 32%), respectively. The association between adverse sensorineural outcome and 

postnatal glucocorticoid therapy remained significant after adjustments for potentially 

confounding factors. 

Cheung, Barrington, Finer, et al. (1999) prospectively evaluated the relationship between 

prehospital discharge apnea with subsequent neurodevelopment at 24 months adjusted age in 

premature infants (<1250 grams birth weight and ≤32 weeks gestational age) during 1990-1993 

(mean 961±185 grams; mean gestational age 27±2 weeks). The frequency and degree of 

oximetry desaturation during predischarge apnea correlated with mental and motor 

developmental scores, especially those with grade 3 or 4 intraventricular hemorrhage. Duration 

of ventilation and grade of intraventricular hemorrhage remained the most powerful predictors of 

mental and motor development in the total premature population.
53

Parenting/ Psychosocial Factors

One study (Table 1.3d) was identified in this review that evaluated the association of CP and 

neurologic abnormalities to parenting / psychosocial factors in VLBW infants. 

Table 1.3d. Association of CP and neurologic abnormalities in VLBW infants parenting / 

psychosocial risk factors

Associations

Author, Year Pop N

Mean BW, g;

GA, wk

Baseline

Risk 

Factors Univariate Multivariate

Applicability Quality

Leonard,1990

90204169

BW

<1250 g 129 BW: 1003GA: 29

Poor 

parenting ↔ ND ?? B

Leonard, Clyman, Piecuch, et al. (1990) (Table 1.3 D) followed a cohort of 129 premature 

infants (BW <1250 g) for more than 4.5 years to determine the independent effects of medical 

risk factors (intracranial hemorrhage and bronchopulmonary dysplasia) and a social-parenting 

risk factor (abuse or neglect) on neurodevelopmental outcome. Neurologic disability (including 

neuromotor and cerebral palsy) increased with severity of intracranial hemorrhage (ICH Grade I 

or II = 0% vs. ICH Grade III or IV = 21%). Neurologic abnormalities were higher in infants with 

a positive parenting risk factor (17% vs. 6%) but the difference was not statistically significant in 

contrast to the significant influence of parenting risk factor on cognitive outcome. Low 

socioeconomic status per se could not account for adverse effects of poor parenting (abuse or 

neglect). This and other studies illustrate the vulnerability of high-medical risk VLBW infants to 

parenting, social, and environmental risk factors. It underscores the importance of having 

constructive parenting, social, and environmental milieu for children at increased risk for 

neurodevelopmental problems related to their biomedical risk of being VLBW. 

The relationship between biological/medical risk factors and parenting/ psychosocial risk 

factors on subsequent neurodevelopmental outcome is complex. The interaction of these factors 

may have additive or synergistic positive or negative effects on an infant’s outcome. Full 

expression of disabilities is influenced in part by parenting, social, and environmental factors. 

Other Postnatal Factors

Table 1.3e. Association of CP and neurologic abnormalities in VLBW plus other factors (Gender. 

Size for GA)

Associations

Author, Year N

Mean BW, g;

GA, wk

Baseline

Risk Factors Univariate Multivariat

e

Applicability Quality

Allan, 1997

97336492

33

7

BW: 600-1250

GA: 28

Gender, AGA / 

SGA ↔ ↑ mm A
54

Associations

Dezoete, 1997

97359687+ 105 BW: 835GA: 27 AGA / SGA ↔ ND mmm B

Spinillo, 1994

94257064 231 BW: 1750GA: 33 Male sex ↑ ↑ mmm C

Spinillo, 1997

98237382 345 BW: 1371GA: 30 Male sex ↑ ↑ m C

Dammann, 

2001

21334215

324 BW: < 1500

GA: ND AGA / SGA ↔ ND mm C

The association between gender and CP varies among studies. Two of Spnillo et al. studies 

indicate that male sex was significantly associated with CP among premature infants (Spinillo, 

Capuzzo, Orcesi, et al., 1997; Spinillo, Fazzi, Stronati, et al., 1994). However, Allan, Vohr, 

Makuch, et al. (1997) found gender not to be a significant antecedent of CP. 

With respect to size for gestational age, Allan, Vohr, Makuch, et al. (1997), Dezoete, 

MacArthur, and Aftimos (1997), and Dammann, Dammann, Allred, et al. (2001) found no 

association between growth restriction (when matched for gestational age) and CP.

Evidence That VLBW With Or Without Other Conditions Is 

Associated With Abnormal Cognitive Development And MR 

(Evidence Tables 1- 4)

This portion of the VLBW Project examines the evidence linking clinical factors that alone, 

in combination, or in addition to birth weight predict significant cognitive disability in former 

very low birth weight infants. The narrative in this section is organized as follows:

1. Definitions and Assessment of Cognitive Development

2. Evidence that VLBW Infants Are At Increased Risk of MR and Estimates of 

Prevalence

A. VLBW

B. ELBW

C. Changes in incidence of MR with time

3. Evidence that Specific Risk Factors are Independently Associated with MR in VLBW 

Infants

A. Birth weight

B. Gestational age

D. Acquired intracranial lesions

i. ICH

ii. PVL

iii. IVH, Indomethacin, and MR

E. Bronchopulmonary dysplasia (BPD)

F. Surfactant therapy

G. Social Risk, Race, and Maternal Education
55

i. Social risk

ii. Race

iii. Maternal Education

H. Gender

I. Illness Severity

J. Ante-partum and intrapartum factors

i. Antenatal corticosteroid therapy

ii. Intrauterine growth retardation (IUGR) / Small for gestational age (SGA)

K. NEC

L. Sepsis and Meningitis

M. Postnatal Corticosteroid Therapy

N. Other

Definitions and Assessment Of Cognitive Development

The American Association on Mental Retardation defines mental retardation (MR) as subaverage general intellectual functioning that originates in the developmental period, manifests 

before 18 years of age, and is associated with impairment in adaptive behavior (American 

Association on Mental Retardation, 1992). MR can result from a wide variety of insults that may 

affect the developing brain, including chromosomal disorders, single gene defects, syndromes 

including primary brain malformations, toxic exposures, infections, and environmental problems. 

In addition, many acquired conditions complicating the hospital course of VLBW infants may 

increase risk for cognitive delay and MR. Moreover, epidemiological factors leading to 

premature birth may contribute to sub-optimal cognitive development subsequently.

Table 2.1. Representative ability test scores defining significantly delayed or deficient cognitive 

development/mental retardation

Score

Bayley MDI Stanford-Binet IQ WISC-R

Significantly delayed/deficient < 70 <68 <70

Representative ability test scores defining significantly delayed or deficient cognitive 

development/mental retardation. (Task Force for the Handbook of Psychiatric Measures, 2000; 

Wodrich, 1984)

In general, cognitive development in childhood is assessed with standardized tests that 

examine a broad range of abilities and yield a score. The child’s test score is related to 

chronological age-appropriate standards or percentile ranks in order to assess relative progress 

and identify those developing abnormally. In the case of premature infants, chronological age is 

usually corrected for degree of prematurity when the performance of children less than three 

years of age is compared to age-appropriate standards. Several well-validated standardized 

developmental scales are available for assessing cognitive development in early childhood (Task 

Force for the Handbook of Psychiatric Measures, 2000; Wodrich, 1984). Such tests naturally 

overlap each other with respect to areas of cognitive development examined, but differ in many 
56

aspects including specific purpose and methods, calibration, appropriate age of use, level of 

training required for administering personnel, and degree of correlation with eventual adult 

function. They differ, as well in their usefulness for making specific diagnoses; the interested 

reader should consult specific references for further information on this robust subject. The 

Bayley Scales of Infant Development Mental Development Index (Bayley MDI), Stanford-Binet 

Intelligence Scale (Stanford-Binet IQ) and Wechsler Intelligence Scale for Children-Revised 

(WISC-R) are representative tests of cognitive development that are widely used as clinical and 

research tools for assessing premature infants 

Evidence that VLBW Infants Are at Increased Risk of MR and 

Estimates of Prevalence

Eleven studies (Table 2.2) were reviewed in this section. Studies were categorized into three 

subsections: A. VLBW infants (BW< <1500 g), B. ELBW infants (BW < 1000 g); C. Changes in 

incidence of MR with time. Table 2.2 summarized Part A and Part B results. Part C results are in 

Table 2.3.

Table 2.2. Incidence of Mental Retardation in VLBW / ELBW Infants

Author, Year N

Mean BW, g; 

GA, week

Baseline

Measures

Associatio

n (% of 

MR)

Applicability Quality

Hack, 1996

97060805 249 BW: 1177GA: 30

Major 

neurosensory 

abnormality

↑

(VLBW 

10% vs. 

nl BW 0%)

mmm A

Corbet, 1995

95264244 597 BW: 933GA: 27 MDI < 69 17% mmm A

Gerdes,1995 

95264241 508

BW: 

Sample 1: 907

Sample 2: 911

GA: 27

Bayley MDI <70

1 dose 

22%

3 dose

18%

mmm A

Vohr, 2000

20295211 1056 BW: 401-1000 Bayley MDI <70 37% mmm A

Ambalavanan

2000

21031370

218 BW: 829

GA: 26 Bayley MDI <68 12% mmm A

Hack, 2000

20358826 221 BW: 813GA: 26 MDI < 70 42% mmm A

Piecuch, 1997 

(in Pediatrics)

97456215

446 BW: 500-999

GA: 24-25

Cognitive 

abnormality and/or 

other neurological 

deficits

35% mm B

Saigal, 2001

11483807 154

ELBW grp: 

BW: 835

GA: 27

Neurosensory 

impairment

↑

(28% vs. 

2%)

mm B
57

Author, Year N

Mean BW, g; 

GA, week

Baseline

Measures

Associatio

n (% of 

MR)

Applicability Quality

Learning disability

↑

(34% vs. 

10%)

DQ –3 to –2 SD 6%

Doyle, 2001

11433066

Victorian 

Infant 

Collaborative 

study Group, 

1997

97290716

225 BW: ND

GA: 23-27 IQ < -2 SD ↑ (15.4% vs. 4.1%) mm B

Casiro, 1995

95264245 89

Exosurf:

BW: 652

GA: 26

Placebo:

BW: 661

GA: 25

Bayley MDI < 69 23-31% mm B

Agustines, 

2000

20279724 36

BW: 674 (500-

750)

GA: 25 (24-29)

MDI < -2 SD 28% mm B

Battin, 1998

99002694

44 BW: < 800

GA: 23-25 MDI < -2 SD 18% mm C

↑ increased the risk of MR, compared to NBW controls

↑* significantly increased the risk of MR, compared to NBW controls

VLBW

The evidence identified by our search methods demonstrates clearly that VLBW infants have 

high rates of cognitive abnormality in early childhood compared with normal birth weight 

controls. Hack, Weissman, and Borawski-Clark (1996) found that among 249 VLBW infants 

from a 1977-1979 cohort the incidence of major neurosensory impairment at 8 years of age was 

10% versus 0% of normal birth weight controls. When the same cohort was evaluated at 20 years 

of age, the prevalence of IQ <70 was 6.7%, a 4-fold increase in risk compared with term controls 

(Hack, Flannery, Schluchter, et al., 2002). Others have found comparable rates of MR in VLBW 

infants (Corbet, Long, Schumacher, et al., 1995; Gerdes, Gerdes, Beaumont, et al., 1995). Given 

current rates of birth and VLBW in the United States (Guyer, Hoyert, Martin, et al., 1999), these 

results suggest that there may be more than 3500 new cases of MR in the United States each year 

in former VLBW infants.
58

ELBW

Among ELBW infants the prevalence of MR appears to be still higher. Vohr, Wright, 

Dusick, et al. (2000) reported for the 12-center National Institute of Child Health and Human 

Development Neonatal Research Network reported developmental outcomes of ELBW survivors 

from a cohort born 1993-1994. Of 1,056 infants assessed at 18 to 22 months-corrected age, 37% 

had Bayley MDI <70. Ambalavanan, Nelson, Alexander, et al. (2000) retrospectively studied 

218 ELBW infants and found Bayley MDI <68 in 12% at 18 months of age

Hack, Wilson-Costello, Friedman, et al. (2000) and colleagues studied determinants of 

neurodevelopmental outcome among ELBW infants born between 1992 and 1995. This study 

was noteworthy for a high rate of follow-up: Of 333 ELBW infants admitted during the study 

period, 241 survived to 20 months corrected age and 221 were studied. Among the studied 

cohort, 14% had intraventricular hemorrhage ≥ grade 3, 7% had periventricular leukomalacia, 

and 40% were dependent upon supplemental oxygen at 36 weeks-corrected age . At the time of 

20 month evaluation, 42% had Bayley MDI <70 and 26% had borderline scores (70 to 84). Forty 

eight percent had at least one significant neurodevelopmental impairment defined as subnormal 

MDI score, neurological abnormality, blindness, or deafness, while 20% had two or more 

impairments.

Piecuch, Leonard, Cooper, et al. (1997) studied cognitive development in 446 ELBW infants. 

All infants in this study were born between 1979-1991, and were followed to 55 ± 33 months of 

age. The authors found entirely normal neurological development in 61% of infants, without 

cognitive, neurosensory, or neurological deficit. Cognitive abnormality occurred alone or in 

combination with other deficits in 35%.

Saigal, Stoskopf, Streiner, et al. (2001) examined outcomes at 12-16 years of age among 154 

infants 500-1,000 g at birth compared with 125 full-term controls. The ELBW infants compared 

to full-term controls were significantly more likely to have neurosensory impairment (28% 

versus 2%) or learning disability (34% versus 10%).

Others found similarly high rates of cognitive delay among extremely premature infants in 

studies based on gestational age. In a series of population-based cohort studies, Australia's 

Victorian Infant Collaborative Study Group found that among infants 23-27 weeks gestation 

(equivalent to ELBW AGA infants) born 1991-92 and examined at two and five years of age, 

incidence of IQ > 2 SD below the mean was 15.4%, compared with 4.1% among full-term 

controls (Doyle, Casalaz, and The Victorian Infant Collaborative Study Group, 2001; The 

Victorian Infant Collaborative Study Group, 1997).

Others have found similar rates of MR in ELBW infants or subgroups. In a study of infants 

500-749 grams, Casiro, Bingham, MacMurray, et al. (1995) found an overall incidence of Bayley 

MDI <69 of 23-31%. Agustines, Lin, Rumney, et al. (2000) examined infants 500-750 grams at 

30 months corrected age. Battin, Ling, Whitfield, et al. (1998) found that 18% (8 of 44) of

ELBW infants 23-26 weeks gestation had Bayley MDI >2 standard deviations below the mean 

when examined at 18 months. Overall, 36% of this cohort had significant impairment, and 14% 

had multiple handicaps. Bayley MDI was normal in 32% of infants, and was >2 SD below the 

mean in 28%. Unfortunately, only 57% of patients were studied at follow-up, and small numbers 

(total n=36) precluded subgroup analysis.
59

Changes in incidence of MR with time

Evidence identified by our search of 4 studies suggests that the incidence of MR in ELBW 

infants may not be changing with time, despite recent increases in survival rates in this birth 

weight category. (Table 2.3). 

Table 2.3. Changes in incidence of MR with time in LBW infants

Author, Year N Year of Birth

Mean BW, g; 

GA, week

Baseline

Measures Association 

(% of MR)

Applicability Quality

166 1982-1988

BW: 687 (560-

740)

GA: 26 (22-31)

MDI < 70 26%

Hack, 1996

97066007

114 1990-1992

BW: 671 (502-

742)

GA: 26 (22-31)

MDI < 70 20%

mmm A

DQ < -3 SD 6%

212 1985-1987 BW: 500-999

GA: ND

DQ –3 to –2 SD 4%

DQ < -3 SD 6%

Victorian 

Infant 

Collaborative 

study Group, 

1997

97290716

Doyle and 

Victorian 

Infant 

Collaborative 

Study Group, 

2001

11433066

241 1991-1992 BW: 500-999

GA: ND

DQ –3 to –2 SD 5%

mm B

Sig. impairment 36% Battin, 1998

99002694 44 1991-1993 BW: < 800GA: 23-25 Multi. Handicaps 14% mm C

Hack, Friedman, and Fanaroff (1996) compared neurodevelopmental outcome for 

a cohort of infants birth weight 500-750 g born 1982-1988 to those of a similar cohort born 

1990-1992. They found no significant difference in neurodevelopmental outcomes at 20 monthscorrected age between the two eras. Overall, 26% of infants in the 1982-1988 cohort had 

subnormal cognitive function with Bayley MDI <70 compared with 20% in the 1990-1992 

cohort. 

The Victorian Infant Collaborative Study Group found no difference in outcomes among 

1991-92 infants when compared with a 1985-87 control cohort (Doyle, Casalaz, and The 

Victorian Infant Collaborative Study Group, 2001; The Victorian Infant Collaborative Study 

Group, 1997).

Battin, Ling, Whitfield, et al. (1998) found that among ELBW infants 23-26 weeks gestation 

born in 1991-1993, the rates of significant impairment (36%) and multiple handicaps (14%) were 
60

not significantly changed compared with a 1983-1989 cohort born prior to routine use of 

surfactant or antenatal steroids.

Evidence that Specific Risk Factors Are Independently Associated 

With MR in VLBW Infants

Forty-four studies were reviewed in this section. Table 2.4 summarizes results of each 

individual study in methodological quality order. 

Table 2.4. Association of Mental Retardation / Disability to Independent Risk Factors in LBW 

infants

Author, Year N

Mean BW, g; 

GA, week

Baseline

Predictors MR / Disability 

measures

Association 

(% of MR / 

Disability in 

overall 

sample)

Applicability Quality

Anderson, 

1996

96314587

Smith, 1996

9708185

Wildin, 1995

95385294

Wildin, 1997

97422739

112 BW: 1944

GA: 29 SES status Bayley’s MDI & PDI ↔ m mmm A

Corbet, 1995

95264244 597

Surfactant:

BW: 934

GA: 27

Placebo:

BW: 931

GA: 27

Synthetic 

surfactant Rx

MDI < 69, 

PDI<69, CP, 

Sensorineural 

hearing 

deafness, 

Blindness, ROP

↔ mmm A

BW 500-749 g 

vs. 750-999 g ↔

GA, IVH ≥ grade 

III, PVL, gender ↔ m

CLD/BPD ↑* m

High social risk ↑* m

Hack, 2000

20358826 221 BW: 813GA: 26

Black race

MDI < 70

↑

mmm A

Kraybil, 1995

95264242 258

Surfactant:

BW: 1022

GA: 28

Placebo:

BW: 1028

GA: 28

Surfactant Rx

MDI < 69, 

PDI<69, CP, 

Sensorineural 

hearing 

deafness, 

Blindness, ROP

↔ m A

Lefebvre, 1998 50 Low risk 12%

98387703 37

GA: 27

BW: 961 (585- Moderate risk

DQ < 80

24%

mm A
61

Author, Year N

Mean BW, g; 

GA, week

Baseline

Predictors MR / Disability 

measures

Association 

(% of MR / 

Disability in 

overall 

sample)

Applicability Quality

34 1450) High risk 71%

Ment, 1996

97040638

Ment, 2000

20164956

431 

? 

343 

at 36 

mos 

? 

337 

at 54 

mos

Indomethacin:

BW: 945

GA: 28

Placebo:

BW: 988

GA: 28

Low dose 

indomethacin 

decreased both 

incidence and 

severity of IVH

IQ < 70 ↓ mm A

Schmidt,

2001

21298249

1202

Indomethacin:

BW: 782

GA: 26

Placebo:

BW: 783

GA: 26

Indomethacin 

decreased the 

frequency of IVH 

and PVL

Survived w/o 

neurosensory 

impairment

↑ mmm A

Disability i ↑ (23%)

Wood, 2000

20373840

283 BW: ND

GA: 22-25 GA

MDI < -2 SD (19%) mmm A

IVH, BPD ↔ m (15%) Singer, 1997

98049057

Singer, 2001

21163669

206 GA: 28

BW: 1077 Minority race

MDI < 70

↑

mmm A

GA, gender ↔ m

IVH, 

parenchymal 

lesions 

enlargement

↑* m

Whitaker, 

1996

97040639

597 BW: 1481

GA: 32

Maternal social 

risk

IQ < 68 

(Stanford-Binet)

Borderline 

intelligence

↑* m

mmm A

Ambalavanan 

2000

21031370

218 BW: 829

GA: 26

IVH ≥ grade III, 

BPD MDI < 68 ↑* m (12%) mm B

Buhrer, 2000

20280896 352

GA: 29 (23-37)

BW: 1149 (430-

1495)

CRIB IQ (Griffiths) < -2 

SD ↔ m (22%) mmm B

Cheung, 1998

99059896 164 BW: 955GA: 27 (22-32) IVH ≥ grade III MDI < -3 SD ↑ (10%) m B

deReginer, 

1997

98041177

174 BW: 1014

GA: 27

Mild / Severe 

CLD a

MDI < -2 SD 5% mmm B

Dezoete, 1997

97359687 105 BW: 835GA: 27 IVH ≥ grade III

Moderate 

/Severe disability 

b

↑* mmm B
62

Author, YearN

Mean BW, g; 

GA, week

Baseline

Predictors MR / Disability 

measures

Association 

(% of MR / 

Disability in 

overall 

sample)

Applic-

ability Quality

Doyle, 2001

11433066

Victorian Infant 

Collaborative 

study Group, 

1997

97290716

225

BW: 

Sample 1: 797

Sample 2: 932

GA:

Sample 1: 26

Sample 2: 27

GA Major disability 

c

↑* (19%) mm

B

Ekert,1997

97251211 104 BW: 962GA: 27

Visual evoked 

potentials

Abnormal 

neurodevelopme

ntal outcome

↔ mm

B

Finer, 1999

99436635 10

BW: : 663 (440-

968)

GA: 25 (24-28)

ELBW requiring 

CPR

Abnormal 

neuromotor 

function

↔ m mm

B

Futagi, 1999

99450356 276

Surfactant 

cohort:

BW: 786

GA: 27

Presurfactant 

cohort:

BW: 834

GA: 27

Surfactant Rx Neurodevelopme

ntal outcomes

↔ mm

B

Katz-Salamon, 

2000

20332284 86 GW: 907

GA: 26 BPD

Lower Griffith 

developmental 

scores

↑* mmmB

Koller, 1997

97193708 203 BW: 1170GA: 31

BW, GA, health 

index, 

neurological 

status @ 1 yr, 

male gender; 

maternal educ.

Worse cognitive 

development 

pattern (Bayley 

scales)

↑* mmm

B

Pierrat, 2001

27221167 60 BW: 1003

GA: 29

Grade II or III cPVL Motor delay 

f

↑ mm

B

Piecuch, 1997

98012134 18 GA = 24

BW: 668 GA, male gender Deficient Bayley scores 

↑ mm

B

Vohr, 1999

99332101 278 BW: 965

GA: 28

Early IVH h vs. 

Late IVH Binet IQ < 70

↑* (38% vs.

19%) mm

B

Gerner, 1997

97329414 171 BW: 1047GA: 28 PVL

Worse Griffith 

mental 

development, 

performance 

subscales

↑* 

m mm

B

48 BW: 997

GA: 27 Mild BPD Gregoire, 

a

↑

1998

98232532 93 BW: 930

GA: 27 Severe BPD 

a

Total disability 

d

↑*

mm

B
63

Author, Year N

Mean BW, g; 

GA, week

Baseline

Predictors MR / Disability 

measures

Association 

(% of MR / 

Disability in 

overall 

sample)

Applicability Quality

BPD IQ < -2 SD 

(Stanford-Binet) ↔

IQ < -2 SD 

(Stanford-Binet)

↑* Leonard,1990

90204169 129 BW: 1003

GA: 29

IVH ≥ grade III, 

at risk parenting e

Neurologic 

abnormalities

↑* mmm B

100g subgroups 

Piecuch, 1997 of BW<1000 g ↔ (35%)

(in Pediatrics)

97456215

446 BW: 500-999

GA: 24-25

GA

Cognitive 

abnormality 

and/or other 

neurological 

deficits ↔

mm B

18 GA = 25

BW: 790

30 GA = 25

BW: 790

Piecuch, 1997 

98012134

38 GA = 26

BW: 842

GA,male,gender Deficient Bayley 

scores ↑ mm B

Schendel, 

1997

98033417

920

VLBW grp:

BW: 1088

GA: 28

LBW: grp:

BW: 2184

GA: 36

VLBW Greater DELAY g

(DDST-II) ↑* mmm B

23 HC < 3%tile 61%

13 HC 3-10 %tile 77% Stathis, 1999

99325758

40

GA: 28 (27-28)

BW: 860 (837-

833) HC > 10 %tile

McCarthy 

general cognitive 

index < 70 30%

mm B

Thyroxine Rx ↓

Van 

Wassenaer, 

1997

98103082

158 BW: < 1500 g

GA: 25-30 BW

Worse Bayley 

MDI ↑

mm B

100g subgroups 

of BW<1000 g ↔ m (37%)

IVH ≥ grade III, 

severe BPD a

↑* m

Surfactant 

replacement Rx ↔ m

Vohr, 2000

20295211 1151 BW: 501-1000 gGA: ND

White race

MDI < 70

↓ m

mmm B
64

Author, Year N

Mean BW, g; 

GA, week

Baseline

Predictors MR / Disability 

measures

Association 

(% of MR / 

Disability in 

overall 

sample)

Applicability Quality

Cooke RW, 

1999

99380719

87

BW: 1103 (630-

1500)

GA: 29 (24-35)

White matter 

disorder, PVL, 

Ventriculomegaly, MRI 

abnormality

IQ ↔ mmm C

Goetz, 1995

96119489 14 BW: 550-1100

GA: ND IVH, c-PVL Mild / severe cognitive delay ↑ mm C

Blitz, 1997

97154301 100 BW: 776

GA: 27

IVH ≥ grade III, 

BPD MDI < 70 ↑* m (9%) mm C

Thompson, 

1997

972683338

55

BW: 1100 (700-

1500)

GA: 28 (24-33)

Higher 

neurobiologic risk 

score (NBRS)

Worse cognitive 

performance 

(McCarthy 

Scales)

↑ mmm C

Gaillard, 2001

21221175 84

BW: 816 (520-

2710)

GA: 26 (23-34)

Antenatal 

steroids and 

postnatal 

surfactant Rx

Neurodevelopmental outcomes ↑ mm C

Kato, 1996

97182916

228 BW: 1031

GA: 28

Antenatal factors 

j MR ↑* m mmm C

a

 “Mild CLD/BPD” – requiring supplemental oxygen at 28 days but not at 36 weeks PMA; “Severe CLD/BPD” – requiring 

oxygen at 28 days and 36 weeks PMA

b

 Moderate/Severe Disability: “Severe disability” / Category I – =1 of the following: (1) Sensorineural deafness (requiring 

hearing aids). (2) Bilateral blindness. (3) Severe cerebral palsy. (4) Developmental delay (adjusted Bayley mental scores 2 or 

more SD below mean). “Moderate disability” / Category II - – =1 of the following: (1) Adjusted Bayley mental scores between 

1 and 2 SD below mean. (2) Mild-moderate CP w/o developmental cognitive delay. (3) Impaired vision requiring spectacles.

c

 Major disability was defined as blindness, deafness, CP or IQ > 2 SD below the mean for NBW controls

d

 Total disability 

e

 At risk parenting was defined as referral by a health professional for neglect or mild abuse

f

 Motor delay - 12, 18, 24 month outcome as the protocol of Amiel-Tison and Stewart, and Touwen

g

 “DELAY” defined by 9 measures of performance on Denver Developmental Screening Test II at age 15 months corrected.

h

 Early IVH: IVH occurring within the first 6 postnatal hours

i Disability was defined as need for physical assistance to perform daily activities

j Malpresentation, tocolytic agents (beta 2 stimulant plus magnesium sulfate)

m

 Multivariate association

DQ = Griffiths Development Quotient

All association is univariate, unless noted.

↑ Significantly increased the risk of MR/Disability associated with VLBW or GA; and, presence of other factors

↑* Significantly increased the risk of MR/Disability associated with VLBW or GA; and, presence of other factors

↔ No association

↓ Significantly decreased the risk of MR/Disability associated with VLBW or GA; and, presence of other factors
65

Birth Weight

Our search methods identified significant evidence that birth weight is a useful factor in 

identifying VLBW infants at especially high risk for MR. For example, Koller, Lawson, Rose, et 

al. (1997) found that birth weight was useful in differentiating longitudinal pattern of cognitive 

development. Using the Bayley MDI, Stanford-Binet IQ, and WISC-R, the investigators 

followed 203 VLBW infants until 6 years of age, obtaining four cognitive scores at yearly 

intervals. They identified five developmental patterns: average-stable (13% of the sample); 

average-declining to low average (24%); average-declining to below average (43%); very lowincreasing to low average (8%); and very low-stable (12%). Biological factors known during the 

neonatal hospitalization that allowed differentiation of these patterns included birth weight, as 

well as gestational age, level of maternal education, and a simple neonatal health index that 

incorporated length of stay adjusted for birth weight. Assessments of neurological status and 

head circumference at 1 year added significant prognostic information, with abnormal 

neurological status at 1 year showing an associa tion with a pattern of very low, stable scores.

There is evidence that risk for developmental delay may be significantly elevated even 

among apparently normal VLBW infants. Schendel, Stockbauer, Hoffman, et al. 1997 studied 

the relationship between VLBW and developmental delay in a 1989-1991 population-based 

cohort. All study subjects were asymptomatic for disabling conditions and were free of obvious 

developmental delay when examined at median 15 months corrected age. The investigators 

compared VLBW infants to LBW infants weighing 1,500-2,499 grams and to singleton controls 

with birth weight ≥2,500 grams, using the Denver Developmental Screening Test II. They found 

that apparently well VLBW children were at greater risk for both moderate and severe delay than 

were either of the larger birth weight comparison groups.

Based on the evidence identified by our search methods, birth weight appears less useful in 

identifying ELBW infants at highest risk for MR. The NICHD Neonatal Research Network 

found no association between cognitive outcome and birth weight (within the birth weight range 

of 500-1000) in 1,151 ELBW infants at 18 to 22 months corrected age (Vohr, Wright, Dusick, et 

al., 2000). The proportion of infants with Bayley MDI <70 showed no statistically significant 

trend over 100-gram subgroups of birth weight <1000 g, and birth weight (within the birth 

weight range of 500-1000) was not significantly associated with cognitive outcome in 

multivariate logistic regression after adjusting for other factors. 

Hack, Wilson-Costello, Friedman, et al. (2000) 1992-1995 ELBW cohort also showed no 

significant differences in performance on the Bayley MDI between infants born 500-749 g (38% 

with Bayley MDI <70) versus those who weighed 750-999 at birth (50%). Among 12 infants 

weighing 500-599 grams at birth, 67% had Bayley MDI <70. This rate varied from 35%-45% for 

100 gram subgroups between 600-999 grams birth weight. These differences were not 

statistically significant but the subgroups were small. The high rate of subnormal Bayley MDI 

among infants 750 to 999 grams birth weight, and the even higher rate of subnormal Bayley MDI 

among infants 500 to 599 grams birth weight, is noteworthy.

Piecuch, Leonard, Cooper, et al. (1997) studied cognitive development at 55 ± 33 months of 

age in ELBW infants born between 1979-1991. They found no association between outcome and 

birth weight in univariate analysis examining birth weight in 100-gram subgroups within the 

narrow weight range for ELBW.
66

Gestational Age

Among the studies identified by our search methods, the evidence that gestational age is 

useful in identifying VLBW infants at high risk for MR was mixed. Koller, Lawson, Rose, et al. 

(1997) found that gestational age was associated with subsequent pattern of cognitive 

development after accounting for other factors in VLBW infants followed through 6 years of 

age. However, in their study of cranial ultrasound abnormalities and cognitive outcomes at 6 

years of age in infants <2000 grams birth weight, Whitaker, Feldman, Van Rossem, et al. (1996) 

found that gestational age was not significantly associated with MR after adjusting for ultrasound 

findings, duration of mechanical ventilation, and other factors. 

Evidence supporting gestational age as a predictor of MR was also mixed for ELBW infants. 

The Victorian Infant Collaborative Study Group evaluated performance at 5 years for 225 infants 

born between 1991-1992 at 23-27 weeks gestation controls (Doyle, Casalaz, and The Victorian 

Infant Collaborative Study Group, 2001; The Victorian Infant Collaborative Study Group, 1997). 

This study found that, among infants surviving to discharge, survival with major disability at 5 

years decreased significantly from 40% at 23 weeks to 6% at 27 weeks, a near-linear decrease 

with advancing gestational age for infants <28 weeks gestation. Major disability (defined as 

blindness, deafness, cerebral palsy, or IQ score greater than two standard deviations below the 

mean for normal birth weight controls) was present in 19% of the cohort as a whole.

Wood, Marlow, Costeloe, et al. (2000) examined developmental outcomes among 283 

infants born less than 25 weeks gestation and examined at 28-40 months. Twenty-three percent 

had severe disability (defined as need for physical assistance to perform daily activities), and 

19% had Bayley indices greater than three standard deviations below the mean. Forty-nine 

percent had no disability. In this study, survival without disability increased from 0.7% at 22 

weeks' gestation to 23% at 25 weeks.

Piecuch, Leonard, Cooper, et al. (1997) studied the cognitive development of infants born 

between 1990-1994 at 24-26 weeks gestation. Measured with the Bayley MDI at 18 months 

mean corrected age, infants born at 24 weeks gestation were less likely to be normal then infants 

born at 26 weeks (28% versus 71%), and more likely to show deficient cognitive development 

(39% versus 11%).

Two methodologically strong studies found that gestational age (within the range of 23-27 

weeks) was not useful in identifying ELBW infants at risk for MR. Hack, Wilson-Costello, 

Friedman, et al. (2000) noted no decrease in rate of subnormal Bayley MDI with advancing 

gestational age among 221 infants born at 23-27 weeks gestation. Bayley MDI <70 occurred in 

38-53% of these infants at 20 months corrected age, and decreased to 17% of infants born at 28 

weeks gestation. Similarly, Piecuch, Leonard, Cooper, et al. (1997) studied determinants of 

cognitive delay in ELBW infants born between 1979-1991, and found that gestational age 

(within the range for ELBW infants) was not an independent predictor related to cognitive 

outcome.

Acquired Intracranial Lesions

Intraventricular Hemorrhage (IVH). Intraventricular hemorrhage (IVH) is one of the 

strongest independent predictors of MR for both VLBW and ELBW infants. Our search methods 
67

identified many methodologically sound studies in which IVH, particularly severe grade III or IV 

IVH, was a significant predictor in both univariate analysis and multivariate modeling.

Whitaker, Feldman, Van Rossem, et al. (1996) performed a prospective cohort study to 

examine neonatal cranial ultrasound abnormalities and cognitive outcomes at 6 years of age in 

infants <2000 g birth weight. Study subjects were a large regional cohort born in central New 

Jersey between 1984 and 1987, who received screening cranial ultrasounds according to a 

standard protocol. The investigators found MR in 6% of children with a history of isolated 

germinal matrix and/or intraventricular hemorrhage, 41.3% of infants with cerebral parenchymal 

lesions and/or ventricular enlargement, and 1.3% of infants with no ultrasound abnormality. 

After adjusting for maternal social risk and other perinatal and neonatal risk factors, isolated 

germinal matrix/intraventricular hemorrhage was associated with MR (adjusted OR for the 

combined risk factor, 4.6; 95% CI 1.2 to 18.6). The authors estimated that 5% of cases were 

attributable to germinal matrix/intraventricular hemorrhage. They did not differentiate outcome 

by grade of IVH in their analysis. The effect they estimated for parenchymal lesions and/or 

ventricular enlargement was much larger than for isolated germinal matrix/intraventricular 

hemorrhage.

Using data from Ment, Oh, Ehrenkranz, et al. (1994), a trial of early postnatal indomethacin 

for prevention of IVH, Vohr, Allan, Scott, et al. (1999) found that VLBW infants who 

experience the early onset of IVH may be at especially high risk for cognitive handicaps at 3 

years corrected age. In this study, children with IVH occurring within the first 6 postnatal hours 

were significantly more likely to have Stanford-Binet IQ scores <70 than children without early 

IVH (38% vs 19%).

The NICHD Neonatal Research Network found a significant association between cognitive 

outcome and cerebral ultrasound abnormalities in ELBW infants at 18 to 22 months corrected 

age (Vohr, Wright, Dusick, et al., 2000). In their analysis, infants with a combined outcome IVH 

≥ stage III or PVL were more than twice as likely to have Bayley MDI <70 as those without 

these findings, after adjusting for the effect of other clinical factors.

Ambalavanan, Nelson, Alexander, et al. (2000) found Bayley MDI <70 in 7% of ELBW 

subjects without IVH, 29% of those with grade III IVH, and 44% of those with grade IV IVH. In 

this study, the presence of IVH ≥ grade III was the strongest determinant of subnormal MDI after 

adjusting for the presence of NEC ≥ stage 2, bronchopulmonary dysplasia, absence of 

chorioamnionitis, low maternal education level, and multiple gestations. However, the regression 

model’s overall predictive performance was poor.

Other investigators have described increased adjusted or unadjusted risk of impaired 

cognitive development in VLBW or ELBW infants with grade III or IV IVH seen at 1 to 5 years 

of age (Blitz, Wachtel, Blackmon, et al., 1997; Cheung, Barrington, Finer, et al., 1999; Dezoete, 

MacArthur, and Aftimos, 1997; Leonard, Clyman, Piecuch, et al., 1990).

Our search methods did identify some methodologically sound studies in which IVH was not 

predictive of MR. Hack, Wilson-Costello, Friedman, et al. (2000) examined cognitive 

development prospectively among ELBW infants born 1992-1995. Among infants with IVH ≥

grade III, 53% had MDI <70. In stepwise multivariate regression analysis male sex, social risk, 

and chronic lung disease were significant predictors of Bayley MDI <70 at 20 months corrected 

age. After adjusting for these factors and birth weight, the presence of a grade III or grade IV 

IVH was not a risk factor for abnormally low MDI, although it was associated with an eight-fold

increase in odds of any neurodevelopmental abnormality (MDI<70, neurologic abnormality, or 

unilateral or bilateral blindness or deafness). Similarly, Singer, Yamashita, Lilien, et al. (1997) 
68

found that IVH was not associated with performance on the Bayley MDI in VLBW infants at 36 

months corrected age after adjusting for the effects of birth weight, race, and a neurologic risk 

score.

Periventricular leukomalacia (PVL). Periventricular leukomalacia (PVL) was found to be 

another of the strongest independent predictors of cognitive impairment in several of the studies 

identified by our search methods. Whitaker, Feldman, Van Rossem, et al. (1996) found a strong 

association between cerebral parenchymal lesions and cognitive development in their study of 

neonatal cranial ultrasound abnormalities and cognitive outcomes at 6 years of age in infants 

<2000 grams birth weight. Parenchymal lesions/ventricular enlargement were strongly associated 

with MR in multivariate regression analysis (adjusted OR for the combined risk factor 

parenchymal lesions/ventricular enlargement versus normal intelligence, 65.8; 95% CI, 19.1 to 

227.4). The authors estimated that half of the cases of MR were attributable to parenchymal 

lesions/ventricular enlargement independent of other factors. Gerner, Katz-Salamon, Hesser, et 

al. (1997), a study of development in VLBW infants at 10 months corrected age, found that 

presence of PVL showed independent adverse association with total Griffiths' Mental 

Developmental Scale and with the Performance subscale after adjusting for duration of 

mechanical ventilation. Among a selected cohort of 10 Australian infants <35 weeks gestation or 

<1500 grams birth weight with severe bilateral cystic PVL, all had severe neurodevelopmental 

abnormalities when evaluated at mean chronological age of 27.3 months (Wilkinson, Bear, 

Smith, et al., 1996).

Among the studies identified by our search, not all found an independent relationship 

between PVL and cognitive development. Hack, Wilson-Costello, Friedman, et al. (2000) found 

Bayley MDI <70 at 20 months corrected age among 63% of ELBW infants with PVL. However, 

as was the case in this study with IVH, in multivariate regression analysis PVL was not 

significantly associated with cognitive development after adjusting for the effects of gender, 

birth weight, and social risk.

Using cranial magnetic resonance scans at 15-17 years of age, Cooke and Abernethy (1999) 

examined the relationship between intracranial structural anomalies and neurodevelopment in 87 

VLBW infants with learning disorders but without cerebral palsy. Thirty-seven VLBW subjects 

had abnormalities on MRI, including 28 with PVL. The study found no significant differences in 

intelligence quotient between subjects with MRI lesions and those with normal scans. 

It is likely that not all cases of PVL are identified. Among 14 VLBW infants with 

periventricular leukomalacia, Goetz, Gretebeck, Oh, et al. (1995) found that 8 had normal studies 

in the first week of life, four had intraventricular hemorrhage, and two had periventricular 

echodensities. Cystic PVL developed between 17 and 104 days of age and occurred later in those 

infants whose initial study was normal. Tone abnormalities were found in 11 of the 12 infants 

who received developmental follow-up, and severe cognitive delays were common in the older 

infants. Similarly, Pierrat, Duquennoy, van Haastert, et al. (2001), a study of PVL in infants <32 

weeks gestation, found that localized PVL developed after the first month of life in 53% of cases, 

and disappeared by 40 weeks PMA in 34%. Mild ventriculomegaly at 40 weeks PMA followed 

localized PVL in 23.7% of cases. 

IVH, indomethacin, and MR. The identified evidence is equivocal regarding the effect of 

early indomethacin on subsequent cognitive development. Ment and colleagues demonstrated 

that early indomethacin therapy is associated with a decrease in both the incidence and severity 
69

of IVH in VLBW infants, and described cognitive outcomes to 4.5 years (Ment, Vohr, Allan, et 

al., 2000; Ment, Vohr, Oh, et al., 1996). They performed a randomized placebo-controlled trial of 

431 neonates 600-1250 g birth weight with no evidence of IVH at 6 to 11 hours of age and found 

that within the first 5 days, significantly fewer infants developed IVH in the indomethacintreated group (12% vs 18%). One indomethacin-treated infant developed grade IV IVH versus 10 

placebo-treated infants. Eighty-nine percent of survivors were examined at 36 months of age and 

88% at 54 months of age. Of note, the mean gestational age was significantly younger for the 

children seen at follow-up who received indomethacin than for those who received placebo. At 

36 months, Stanford-Binet IQ scores for children who received indomethacin were not 

significantly different from those who received placebo. However, at 54 months, the 

investigators observed significantly less mental retardation among children randomized to early 

low-dose indomethacin. For the indomethacin group, 9% had an IQ <70, 12% had an IQ of 70-

80, and 79% had an IQ >80, while for the placebo group, 17% had an IQ <70, 18% had an IQ of 

70-80, and 65% had an IQ >80.

Schmidt, Davis, Moddemann, et al. (2001) studied 1775 ELBW infants randomized to 

receive prophylactic indomethacin or placebo. Despite a reduction in frequency of severe IVH 

and PVL, the study found that prophylaxis with indomethacin does not improve the rate of 

survival without neurosensory impairment at 18 months.

It appears clear that early indomethacin reduces the incidence of severe IVH. While it is 

reasonable to hope that this promising finding will result in improved cognitive outcomes, the 

identified studies do not demonstrate this consistently. Prophylactic treatment of VLBW infants 

with early indomethacin remains the subject of further study.

Bronchopulmonary Dysplasia (BPD)

Our methods located many studies documenting a significant independent relationship 

between neonatal chronic lung disease, also known as bronchopulmonary dysplasia (BPD), and 

abnormal cognitive development in both VLBW and ELBW infants. deRegnier, Roberts, 

Ramsey, et al. (1997) studied the effect of BPD upon neurodevelopment in VLBW infants who 

survived until discharge. When compared with infants who had no supplemental oxygen 

requirement after 28 days of life, those requiring oxygen at both 28 days chronological age and 

at 36 weeks postmenstrual age were significantly more likely to have Bayley MDI >2 standard 

deviations below the mean. Gregoire, Lefebvre, and Glorieux (1998) found similar results

BPD may have a deleterious effect on cognitive development even in the absence of IVH or 

PVL. Katz-Salamon, Gerner, Jonsson, et al. (2000) compared 43 VLBW infants with BPD, but 

without IVH or PVL, and 43 VLBW without BPD, IVH, or PVL at 10 months of corrected age 

using the Griffiths developmental test. BPD was associated with significantly lower performance 

scores on each Griffiths subscale.

Not all identified studies found an independent association between BPD and cognitive 

development in VLBW infants. Leonard, Clyman, Piecuch, et al. (1990) examined the

independent effects of intracranial hemorrhage and severe BPD, together with a parenting risk 

factor (referral by a health professional for neglect or mild abuse) on neurodevelopmental 

outcome at mean 60 months in 129 infants ≤ 1250 g birth weight. The study found that for 

subjects without any intracranial hemorrhage or parenting risk factors, the presence of severe 

BPD was not related to cognitive outcome. Singer compared VLBW infants with and without 
70

BPD (defined as typical radiographic changes with supplemental oxygen requirement >28 days) 

to healthy term controls. At 36 months corrected age, 21% of VLBW infants with BPD had 

Bayley MDI <70 compared to 11% of VLBW infants without BPD and 4% of full term controls. 

Abnormal MDI was evident by 8 months of age in the majority of cases in both VLBW groups. 

In hierarchical multivariate regression analysis, however, BPD was not associated with 

performance on the Bayley MDI after adjusting for the effects of birth weight, race, and a 

neurologic risk score (Singer, Yamashita, Lilien, et al., 1997; Singer, Siegel, Lewis, et al., 2001).

Among ELBW infants, our search methods located strong studies supporting the relationship 

between BPD and MR. After controlling for male sex, social risk, and birth weight, Hack, 

Wilson-Costello, Friedman, et al. (2000) found that oxygen dependence at 36 weeks 

postconceptional age was predictive of Bayley MDI <70 among 221 ELBW infants born 1992-

1995. Supplemental oxygen requirement at 36 weeks post conceptual age more than doubled the

adjusted risk of subnormal Bayley MDI in this cohort. Of 89 infants with BPD in this study, 55% 

had MDI <70 at 20 months corrected age. The NICHD Neonatal Research Network found that 

persistent supplemental oxygen requirement at 36 weeks post-conception increased risk of 

Bayley MDI <70 at 18-22 months in ELBW infants by more than 50% after adjusting for other 

clinical factors (Vohr, Wright, Dusick, et al., 2000). Ambalavanan, Nelson, Alexander, et al. 

(2000) found increased risk of MDI <70 at 18 months corrected age among ELBW infants who 

developed BPD. BPD was associated with subnormal MDI after adjusting for severe IVH, NEC 

≥ stage 2, and absence of chorioamnionitis, presence of BPD, low maternal education level, and 

multiple gestation. Blitz, Wachtel, Blackmon, et al. (1997) found that BPD was associated with 

Bayley MDI <70 in ELBW infants at 1 year of age after adjusting for other clinical risk factors.

Surfactant Replacement Therapy

The evidence identified by our search methods strongly suggests that, while surfactant 

therapy improves survival among VLBW infants, its use is not an independent predictor of 

cognitive development. The NICHD Neonatal Research Network found that surfactant 

replacement therapy was not associated with cognitive outcome at 18-22 months in ELBW 

infants after adjusting for other clinical factors (Vohr, Wright, Dusick, et al., 2000). In separate 

studies Corbet, Long, Schumacher, et al. (1995) and Kraybill, Bose, Corbet, et al. (1995) found 

no differences in neurodevelopmental status at 1 year among infants treated with a single dose of 

surfactant compared with placebo, despite lower mortality. Futagi, Suzuki, Goto, et al. (1999) 

found similar results at 6-7.5 year follow-up. Gaillard’s suggestion that neurodevelopmental 

outcome at 3 years of age for VLBW infants who require prolonged mechanical ventilation may 

be improved by treatment with antenatal steroids and postnatal surfactant requires further study 

(Gaillard, Cooke, and Shaw, 2001).

Race, Social Risk, and Maternal Education

Our search methods identified many strong studies documenting a significant independent 

association between social risk factors and cognitive development in VLBW infants. Methods 

used to measure social risk are numerous, however, and the identified evidence is not always 

sufficient to distinguish the independent effects of various commonly examined elements of 

social risk, such as race, economic status, or level of maternal education.
71

Social Risk Measured With Scoring Systems. Hack, Wilson-Costello, Friedman, et al. 

(2000) examined the relationship of cognitive development to social risk among ELBW infants 

born 1992-1995, using a simple social risk score. The score assigned 1 point each for single 

parenthood, black race, and maternal education less than high school. High social risk, as 

assessed with this score, was significantly associated with cognitive outcome at 20-months 

corrected age, after adjusting for gender and BPD. Social risk factors increased odds of Bayley 

MDI <70 by 50%. However, using a similar risk scale, Whitaker, Feldman, Van Rossem, et al. 

(1996) did not find this association in a cohort with larger birth weights examined at a later 

chronological age. In their study of infants <2000 g birth weight seen at 6 years, maternal social 

risk was assessed with a composite risk assessment score that incorporated maternal education, 

race, public assistance income, marital status, and age. After adjusting for cerebral ultrasound 

findings, maternal social risk was associated with risk for borderline intelligence but not with 

true MR at 6 years of age.

Not all studies found an independent relationship between social risk and cognitive 

development. Wildin found that Hollingshead social status (Hollingshead, 1975) did not 

contribute to assessment of risk for cognitive delay when information from 6 and 12 month 

examinations was considered (Wildin, Anderson, Woodside, et al., 1995; Wildin, Smith, 

Anderson, et al., 1997). Data was from the longitudinal study of University of Texas Health 

Sciences Center in Houston and the University of Texas Medical Branch in Galveston. The 

quality of parent-infant interactions may play an important role in cognitive development of 

VLBW infants. Smith, Landry, Swank, et al. (1996) used home observations to assess the impact 

of maternal behaviors on infant development in VLBW infants with severe neonatal 

complications and those with milder complications compared to term controls at 6 and 12 

months. Severe complications included the presence of bronchopulmonary dysplasia, IVH ≥

grade III, and/or PVL. The investigators found that active maternal maintenance of infant interest 

was positively related to infant development for all groups. During toy play and daily activities, 

maternal attention-maintaining was most strongly related to cognitive and language skills for 

both preterm groups than for the FT infants. The impact upon cognitive development of this 

aspect of parenting deserves further investigation.

Leonard, Clyman, Piecuch, et al. (1990) examined the relationship of at-risk parenting 

(defined as referral by a health professional for neglect or mild abuse) to cognitive development 

at mean 60 months in 129 infants ≤ 1250 g birth weight. This study found that the parenting risk 

factor was strongly associated with cognitive outcome after accounting for the effects of 

intraventricular hemorrhage and chronic lung disease. The authors concluded “that infants with 

medical risk factors may have additional social risk factors, and that both of these influences 

must be considered in an examination of the long-term sequelae of neonatal complications.”

The variably among studies with respect to association of social risk/parenting risk and 

cognitive outcome may be accounted for by differences among studies with respect to population 

characteristics, sample size, age of assessment, ascertainment of other potential confounding 

factors, accuracy of methods/measures used to determine social risk, parenting risk, and other 

socioeconomic markers.

Race. The identified evidence suggests that race may be an independent predictor of 

cognitive development in VLBW infants. After adjusting for the effects of birth weight and a 

simple neurological risk score, Singer, Yamashita, Lilien, et al. (1997) found that minority race 
72

was more strongly associated with poor performance on Bayley MDI than chronic lung disease

or IVH in VLBW infants at 36 months corrected age. The NICHD Neonatal Research Network 

found that among ELBW infants at 18-22 months, whites were at about 40% lower risk for 

Bayley MDI <70 after adjusting for other clinical factors (Vohr, Wright, Dusick, et al., 2000). In 

Hack’s cohort of 1992-1995 ELBW infants examined at 20 months corrected age, black race was 

among the social risk factors associated with an approximately 50% increased risk of subnormal 

Bayley MDI (Hack, Wilson-Costello, Friedman, et al., 2000).

Level of Maternal Education. Our search methods located strong studies in which level of 

maternal education was identified as a significant independent predictor of abnormal cognitive 

development. After adjusting for biological risk with the Neurobiologic Risk Score, Thompson 

Jr., Gustafson, Oehler, et al. (1997) demonstrated that maternal education level was a significant 

determinant of VLBW infant cognitive performance at 4 years of age. Koller, Lawson, Rose, et 

al. (1997) found that level of maternal education was associated with subsequent pattern of 

cognitive development after accounting for other factors. In this study, maternal education 

appeared to be especially important among children born at the upper end of the VLBW range, 

who had fewer risk factors than those with lower birth weights. 

The relationship between level of maternal education and subsequent infant cognitive 

development appears to be important in the ELBW subgroup as well. In univariate analysis 

Piecuch, Leonard, Cooper, et al. (1997) found a strong relationship between social risk and 

cognitive development in ELBW infants born between 1979-1991. The NICHD Neonatal 

Research Network found that level of maternal education was a significant determinant of 

cognitive development in ELBW infants at 18-22 months (Vohr, Wright, Dusick, et al., 2000). In 

their multivariate regression analysis, maternal education less than high school graduate level 

increased risk of Bayley MDI <70 almost two-fold. Maternal education level was also a 

determinant of neurodevelopmental outcome in Ambalavanan’s study of ELBW infants 

(Ambalavanan, Nelson, Alexander, et al., 2000), which found that low maternal education level 

was associated with increased risk of Bayley MDI <70 after adjusting for severe IVH, NEC 

>stage 2, absence of chorioamnionitis, presence of bronchopulmonary dysplasia, and multiple 

gestation.

Gender

Our search methods identified few strong studies examining the independent relationship of 

gender and MR in VLBW infants. The identified evidence suggests that gender may be a 

significant independent predictor of MR among ELBW infants, but this relationship may be less 

significant in larger birth weight categories. Among infants <2000 g birth weight, Whitaker, 

Feldman, Van Rossem, et al. (1996) found that gender was not significantly associated with MR 

after adjusting for ultrasound findings and duration of mechanical ventilation. However, in the 

NICHD Neonatal Research Network’s study of ELBW infants at 18-22 months, males were 

twice as likely as females to have Bayley MDI <70, after adjusting for other clinical factors 

(Vohr, Wright, Dusick, et al., 2000). Hack found similar odds of MR in ELBW males compared 

to females after adjusting for social risk and the presence of chronic lung dis ease, and suggested 

that this may reflect higher illness severity among males(Hack, Wilson-Costello, Friedman, et 

al., 2000). Others found that ELBW males were at higher risk of cognitive impairment than 
73

females in unadjusted analyses (Piecuch, Leonard, Cooper, et al., 1997; Wood, Marlow, 

Costeloe, et al., 2000).

Illness Severity

Some clinical risk factors for MR (e.g. severe IVH or PVL) offer obvious mechanisms by 

which they increase risk of cognitive impairment, i.e. cerebral parenchymal damage. Other 

identified risk factors may act as proxies for the physiological disarray that accompanies severe 

illness in general. Transient but recurrent physiological disturbances such as metabolic acidosis, 

hypotension, etc., may have a cumulative effect and may increase risk for MR (Goldstein, 

Thompson, Jr., Oehler, et al., 1995). Neonatal illness severity scoring systems may capture this 

risk effectively. Our search methods identified several studies providing evidence that such 

scoring systems may be useful in identifying infants at risk for MR.

Lefebvre, Gregoire, Dubois, et al. (1998) examined the nursery Neurobiologic Risk Score as 

a predictor of cognitive development in VLBW infants. The original NBRS incorporated 

intracranial ultrasound abnormalities, need for and duration of mechanical ventilation, and the 

presence of acidosis, infection, hypoglycemia, or seizures at any time during the initial 

hospitalization (Brazy, Eckerman, Oehler, et al., 1991). Lefebvre found that infants less than 28 

weeks gestation who were at high risk as assessed with the NBRS at the time of nursery 

discharge had significantly higher rates of severe delay or any delay at 18 months corrected age 

as measured with the Griffiths Mental Development Scale. Thompson Jr., Gustafson, Oehler, et 

al. (1997) found similar results in VLBW infants at 4 years of age. Brazy, Eckerman, Oehler, et 

al. (1991) found that the NBRS measured at 2 weeks of age and at discharge was significantly 

correlated with Bayley MDI at 6, 15, and 24 months. 

After adjusting for the effects of birth weight and race, Singer, Yamashita, Lilien, et al. 

(1997) found that a simple neurological risk score was more strongly associated with 

performance on Bayley MDI than chronic lung disease or IVH in VLBW infants at 36 months 

corrected age. In this study infants were assigned a score of 1 if any of the following were 

present: minor neurological malformation, seizures, echodense craniosonographic lesions, 

porencephaly, hydrocephalus, ventriculoperitoneal shunt, meningitis, or periventricular 

leukomalacia; infants without such findings received a score of 0.

Buhrer, Grimmer, Metze, et al. (2000) examined the ability of the Clinical Risk Index for 

Babies (CRIB) to predict long-term neurodevelopmental impairment in 352 VLBW infants born 

1992-1997. The CRIB score incorporates birth weight, gestational age, the presence of 

congenital malformations, worst base excess, and maximum and minimum appropriate fraction 

of inspired oxygen (FIO2) during the first 12 hours of life. Griffiths scales of mental 

development general quotient was > 2 standard deviations below average in 22% of the studied 

infants. CRIB scores were independently associated with neurodevelopmental impairment, but 

did not significantly contribute to identification of affected infants when compared with birth 

weight alone.

Durations of various therapies such as mechanical ventilation, intravenous nutrition, etc., are 

markers of illness severity and may be tested as independent predictors of outcome; our search 

methods identified several such studies examining cognitive development. Whitaker, Feldman, 

Van Rossem, et al. (1996) found that after adjusting for ultrasound findings, the number of days 

on mechanical ventilation was strongly associated with risk for MR at 6 years of age in infants 

<2000 g birth weight. In univariate analysis, Piecuch, Leonard, Cooper, et al. (1997) found a 
74

significant association between duration of oxygen requirement and cognitive delay in ELBW 

infants.

Antepartum And Intrapartum Factors

The evidence identified by our search methods was equivocal regarding the utility of 

antepartum and intrapartum factors as independent predictors of MR. Kato, Yamada, 

Matsumoto, et al., (1996) performed a retrospective study of perinatal factors and outcome at 12 

months in 228 singleton VLBW infants without major anomaly. Regression analysis found that 

malpresentation, use of tocolytic agents and cord arterial pH <7.20 were associated with 

combined outcome of cerebral palsy (CP) and mental retardation (MR). The authors suggested 

that delivery method was not an independent risk factor for CP/MR, but that malpresentation was 

a significant risk factor regardless of route of delivery. Multiple gestation was a determinant of 

neurodevelopmental outcome at 18 months in Ambalavanan, Nelson, Alexander, et al. (2000), a 

study of ELBW infants. In this study multiple gestation was associated with increased risk of 

Bayley MDI <70 after adjusting for severe IVH, NEC >stage 2, absence of chorioamnionitis, 

presence of bronchopulmonary dysplasia, and low maternal education level.

However, our search methods identified strong studies suggesting that antepartum factors do 

not provide a useful contribution to prediction of MR in ELBW infants after accounting for other 

clinical factors. For example, after adjusting for other clinical factors in multivariate regression 

analysis, the NICHD Neonatal Research Network found no association between cognitive 

outcome and use of antenatal steroids, maternal hypertension, route of delivery, or inborn versus 

outborn birth in 1151 ELBW infants at 18 to 22 months corrected age (Vohr, Wright, Dusick, et 

al., 2000). Similarly, after controlling for male sex, social risk, and birth weight, Hack, WilsonCostello, Friedman, et al. (2000) found no association between subnormal Bayley MDI and 

multiple birth, cesarean section delivery, antenatal steroid therapy, or history of 

chorioamnionitis. Interestingly, Ambalavanan, Nelson, Alexander, et al. (2000) found that the 

presence of chorioamnionitis was associated with a lower adjusted risk of MR in ELBW infants 

at 12-18 months corrected age.

Antenatal Corticosteroid Therapy. The NICHD Neonatal Research Network found that 

antenatal steroid therapy was not associated with cognitive outcome at 18-22 months in ELBW 

infants after adjusting for other clinical factors (Vohr, Wright, Dusick, et al., 2000). Gaillard, 

Cooke, and Shaw, (2001) suggest that neurodevelopmental outcome at 3 years of age for VLBW 

infants who require prolonged mechanical ventilation may be improved by treatment with 

antenatal steroids and postnatal surfactant; this warrants further study.

Intrauterine Growth Retardation (IUGR)/Small for Gestational Age (SGA). The 

identified evidence regarding IUGR/SGA as an independent risk factor for MR was equivocal. 

Korkman, Liikanen, and Fellman (1996) documented worse cognitive development at 5-9 years 

among VLBW infants who were SGA compared with VLBW infants who were AGA. However, 

the NICHHD Neonatal Research Network found that SGA ELBW infants were not at increased 

risk for cognitive delay compared with their AGA peers after adjusting for other clinical factors 

(Vohr, Wright, Dusick, et al., 2000). Others observed no difference between AGA and SGA 
75

ELBW infants in univariate or multivariate analyses (Hack, Wilson-Costello, Friedman, et al., 

2000; Piecuch, Leonard, Cooper, et al., 1997).

NEC

Our methods located no studies examining the relationship between NEC and subsequent 

cognitive development in VLBW infants. Among ELBW infants, the identified evidence was 

equivocal. Ambalavanan, Nelson, Alexander, et al. (2000) found increased risk of MDI <70 

among ELBW infants who developed NEC ≥ stage 2. In this study NEC was associated with 

subnormal MDI after adjusting for severe IVH, absence of chorioamnionitis, presence of 

bronchopulmonary dysplasia, low maternal education level, and multiple gestation. However, 

other strong studies do not support an independent association of NEC and MR in ELBW 

infants. Hack, Wilson-Costello, Friedman, et al. (2000) found Bayley MDI <70 at 20 months 

corrected age among 64% of ELBW infants with NEC. However, in multivariate regression 

analysis, NEC was not significantly associated with cognitive development after adjusting for the 

effects of gender, birth weight, and social risk. Similarly, The NICHD Neonatal Research 

Network found no association between cognitive outcome and NEC ≥ stage 2 in ELBW infants 

at 18 to 22 months corrected age (Vohr, Wright, Dusick, et al., 2000) after adjusting for the 

effect of other clinical factors in multivariate regression analysis.

Sepsis and Meningitis

Our search methods did not identify studies that examined the relationship between sepsis or 

meningitis and subsequent cognitive development in VLBW infants. Among ELBW infants,

The evidence suggests that the occurrence of sepsis or meningitis is not a useful independent 

predictor of abnormal cognitive development. The NICHD Neonatal Research Network found 

that neither early-onset nor late-onset sepsis was associated with cognitive outcome at 18-22 

months in ELBW infants after adjusting for other clinical factors (Vohr, Wright, Dusick, et al., 

2000). Similarly, Hack, Wilson-Costello, Friedman, et al. (2000) found that sepsis and 

meningitis were not significantly associated with cognitive development after adjusting for the 

effects of gender, birth weight, and social risk in ELBW infants seen at 20 months corrected age.

Postnatal Corticosteroid Therapy

There is much concern presently regarding the effect of postnatal systemic corticosteroid 

exposure (specifically, dexamethasone) on neurodevelopment in VLBW infants. Our search 

methods identified studies that justify such concern for the ELBW the subgroup. Postnatal 

systemic steroid therapy (dexamethasone) was a significant determinant of cognitive 

development in ELBW infants at 18-22 months in the NICHD Neonatal Research Network study 

(Vohr, Wright, Dusick, et al., 2000). After adjusting for clinical factors including need for 

oxygen at 36 weeks PCA and several clinical markers of severe illness, the study found that 

treatment with postnatal steroids increased risk of Bayley MDI <70 almost two-fold. The 

Victorian Infant Collaborative Study Group (1997) found that among infants 23-27 weeks 
76

gestation born 1991-92 and followed until five years of age, infants treated with postnatal 

dexamethasone had worse IQ scores than those not receiving steroids. This nonrandomized study 

was likely to be significantly confounded, however; since the steroid group had lower mean 

gestational age, and no mention is made of illness severity or other potential confounders. In a 

case control subanalysis using the same cohort, the investigators found that the IQ scores were 

significantly lower in the corticosteroid group, and the difference was much smaller.

Other

Seven studies examined factors that may be useful in identifying VLBW infants at highest 

risk for abnormal cognitive development. The identified evidenc e suggests that some of these 

factors are not independently associated with cognitive outcome, while others require further 

study.

Table 2.5. Association of Mental Retardation / Disability with other Risk Factors in LBW infants

Author, 

Year N

Mean BW, 

g; GA, 

week

Baseline

Predictors

MR / Disability 

measures

Association 

(% of MR / 

Disability in 

overall 

sample)

Applicability Quality

Wildin, 

1995

95385294

Wildin, 

1997

97422739

112 BW: 1944

GA: 29

SES status Bayley’s MDI & 

PDI

↔ m

mmm A

23 HC < 3%tile ↑*

13 HC-3-10%tile ↑*

Stathis, 

1999

99325758 40

GA: 28 (27-

28)

BW: 860 

(837-833)

HC> 10 % tile

McCarthy 

general 

cognitive index 

< 70

↑*

mm B

Koller, 

1997

97193708

203 BW: 1170

GA: 31

BW, GA, 

health index, 

neurological 

sta tus @ 1 yr, 

male gender; 

maternal 

educ.

Worse 

cognitive 

development 

pattern 

(Bayley’s 

scales)

↑*

mmm B

Ekert,1997

97251211

104 BW: 962

GA: 27

Visual evoked 

potentials

Abnormal 

neurodevelopmental 

outcome

↔

mm B

Finer, 1999

99436635

10 BW: : 663 

(440-968)

GA: 25 (24-

28)

ELBW 

requiring CPR

Abnormal 

neuromotor 

function

↔ m 

mm B

Van Thyroxine Rx ↓

Wassenaer

1997

98103082

158 BW: < 1500 

g

GA: 25-30 BW

Worse Bayley 

MDI

↑*

mm B
77

We identified evidence that examinations in the first 6 – 12 months of life may substantially 

refine estimates of risk of subsequent cognitive impairment. 

Wildin’s follow-up of this cohort at 40 months suggests that examinations at 6 and 12 

months add significant prognostic information to data from the newborn period when predicting 

long-term outcome (Wildin, Anderson, Woodside, et al., 1995; Wildin, Smith, Anderson, et al., 

1997).

Stathis, O'Callaghan, Harvey, et al. (1999) examined the relationship of head circumference 

and head-circumference growth velocity during the first year of life with cognitive development 

in 87 VLBW infants born between 1977 and 1986. Subjects were assessed using the McCarthy 

Scale at 6 years of age. The investigators found that head circumference <3% at 4 months, 8 

months, and 12 months, as well as head growth velocity between birth and 4 months were 

significantly associated with cognitive ability at 6 years.

Assessments of neurological status and head circumference at 1 year added significant 

prognostic information in Koller, Lawson, Rose, et al. (1997), with abnormal neurological status 

at 1 year showing an association with a pattern of very low, stable scores. 

Visual evoked potentials were not predictive of abnormal neurodevelopmental outcome in 

infants <32 weeks gestation (Ekert, Keenan, Whyte, et al., 1997). 

In a small study by Finer, Tarin, Vaucher, et al. (1999), infants <750 g at birth and requiring 

CPR in the delivery room were not different from controls matched for gestational age, sex, and 

year of birth with respect to cognitive development at median 28 months.

In analysis of subgroup data from a randomized controlled trial, van Wassenaer found that 

infants <27 weeks gestation treated with thyroxine supplementation performed better than 

placebo-treated controls on Bayley MDI at 2 years of age. Larger birth weight subgroups did less 

well (van Wassenaer, Kok, Briet, et al., 1997; van Wassenaer, Kok, de Vijlder, et al., 1997). This 

warrants further study.

Evidence That VLBW Is Associated With Disabilities Of 

Speech/Language Delay, Hearing Loss, Behavioral 

Disorders, And Learning Disabilities (Evidence Tables 5-6)

VLBW infants are at high risk for developing cognitive, neuromotor, and neurosensory 

disabilities including blindness and hearing loss. These disabilities in turn may lead to other 

disabilities in speech and language, behavior problems and learning disabilities affecting school 

performance. This is illustrated in the following example. Speech is the motor act of 

communicating using verbal expression and language is any means or form of communication 

(signs, symbols, vocal). In order for one to successfully communicate between listener and 

speaker, there must be an intact system of 1) sensation by hearing or seeing gestures in speech, 

2) perception or coding about the sound and gesture system, 3) comprehension or decoding of 

words and meanings in context, 4) formulation or organizing ideas into language structure with 

words and sentences, 5) motor planning of breathing, phonation, resonance, and articulation to 

output the message, and finally, 6) motor control or execution of motor plans (McMillan, 

DeAngelis, Feigin et al. 1999). Communication disorder results if there is impairment in any 

component of this input and output phases. Hearing loss leads to impaired sensation and 
78

perception and therefore, impaired ability to produce spoken language. Mental retardation or 

cognitive deficit may impair comprehension and formulation of ideas. Impaired neuromotor 

control may hinder production of intelligible speech. Neurologic dysfunction frequently 

accompanies behavioral disturbances and attention problems. These impairments may ultimately 

have consequences in social development, school performance, learning and achievement.

All of the above problems have been identified in disproportionate numbers in the VLBW 

infants. In this section, the incidence and severity of important disabilities in VLBW infants 

namely hearing loss, speech/language delay, behavioral disorders, learning disabilities, and 

school performance will be reviewed. This narrative examines the evidence that VLBW and the 

medical conditions and clinical factors that VLBW infants experience are associated with these 

disabilities. One hundred articles were reviewed but only 41 were felt to contain sufficient 

information and methodological quality to present. They were divided into sections of 

speech/language/communication outcomes, hearing loss, behavioral/social outcomes, and school 

performance/learning disorder outcomes.

Speech, Language, And Communication Disorder Outcomes

Because language is a large component of cognitive assessment, its evaluation is included in 

many intelligence and psychological studies such as the Stanford-Binet Intelligence test and 

Wechsler Scales of Intelligence and Bayley Scales of Infant Development. Nine studies (Table 

3.1) are included that focus on speech and language outcomes or specifically address the 

language subscale of cognitive studies with sufficient information and quality, rather than in 

aggregate with other subscales. The studies reviewed overwhelmingly corroborate strong 

association of VLBW with speech and language impairment.
79

Table 3.1. Association of LBW to Speech and Language Disorders 

Author, 

Year

N

(Controls)

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictor Measure

Association / % 

of Subjects with 

impairment 

Applica

-blity

Quality

Singer

2001

21163669

VLBW with 

BPD N=90

VLBW 

without 

BPD N=65

Term N=91

BW 956±248 

(SD)

GA 27 ± 2

BW 1252 ±178

GA 30 ± 2

BW 3451 ± 526

GA 40 ± 1

Cardiovascular 

PDA or 

pulmonary 

predictors: 

Bronchopulmonary 

dysplasia

General : BW, 

Neurologic risk

Other: Race, 

Socioeconomic 

status

Battelle 

Developmental 

Communication 

Subscale

Receptive DQ 

<85: 49% vs. 

34% vs. 30%

Expressive DQ 

<85: 44% vs. 

25% vs. 25%

Communication 

DQ < 85: 43% vs. 

31%, vs. 28%

mmm A

Wood

2000

20373840

283 GA: <25 weeks GA

Gender

Perinatal 

Factors‡

Multiple 

gestation

Bayley Scales of 

Infant 

Development

31 out of 283 

infants at 30 

months of age 

had various 

degrees of 

language delay

mm B

Lefebvre, 

1998

98387703

121 BW: 961 Neurobiologic 

risk score 

(NBRS)

Griffiths 

Developmental 

Scales:

71%

mm A

Wolke

1999

10075095

Preterm 

N=264

Full-term 

N=264

GA 29.5wks 

(29.3-29.7), 

BW 1288g 

(1247-1330)

GA 39.6 wks 

(39.5-39.7), 

BW 3407 (3351-

3463)

GA, IQ, 

socioeconomics

Griffiths Scales 

of Babies 

Abilities, 

Kaufman 

Assessment 

Battery for 

Children, 

Heidelberger 

Sprachentwicklu

ngstest 

language test

Preterm children 

tested 

significantly lower 

on all dimensions 

of cognition and 

language/speech mmm A

Smith

1996

97081985

High-risk 

preterm 

N=89,

Low-risk 

preterm 

N= 123,

Full-term 

N= 128

Preterm infants 

BW = 1600g 

and GA = 36 

wks.

Full-term infants 

GA 37-42 wks.

Illness acuity, 

maternal 

behaviors

The Sequenced 

Inventory of 

Communication 

Development

by direct 

observation

High-risk infants 

scored 

significantly lower 

than full-term 

infants in 

language scores 

at 6 and 12 

months corrected 

age

mmm B
80

Author, 

Year

N

(Controls)

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictor Measure

Association / % 

of Subjects with 

impairment 

Applica

-blity

Quality

Sajaniemi 

2001

11227991

63 Mean BW 1246 

437 g

Excluded infants 

with major 

disabilities

Cognition, 

temperament, 

and behavior at 

2 years of age

Bayley Scales of 

Infant 

development, 

Toddler 

Temperament 

Questionnaire, 

Infant Behavior 

Record, and 

Verbal scale of 

Wechsler 

PreschoolPrimary Scale of 

Intelligence 

(WPPSI)

Cognition, 

temperament and 

behavioral 

characteristics at 

2 years of age 

predict language 

impairment at 4 

years of age. mm B

Briscoe

1998

98300800

 Preterm 

N=26;

Full-term

N=26

GA: 26 (26-32)

BW: 1209 (815-

1985)

GA The Bus Story 

Test,

The BPVS-long 

form,

The Oral 

Vocabulary 

component 

31%

mm B

Saigal

2001

11483807

ELBW 

N=154

NBW 

N=125

BW 835

BW 3401

Birthweight 

500-1000g

GA

Ontario Child 

Health Study 

Questionnaire

 National Health 

Interview 

Survey, Survey 

of Disabled 

Children

Hearing loss:

7% vs. 5% (NS)

Emotional 

problems: 4%, 

Vs 1% (NS)

Learning 

disability: 34%, 

vs10% (p<0.001)

Limitations in 

school: 31% vs. 

9% (p<0.002)

mm B

Schendel 

1997

98033417

VLBW

N=367;

MLBW 

N=553;

NBW; 

N=555

GA: 28.4

BW: 1088;

GA:35.6

BW:2184

GA:39.4

BW:3414

BW Language 

component of 

Denver II

8.8% vs. 5.8% 

vs. 4%

mm

 

B

In a nonrandomized comparison trial by Singer, Siegel, Lewis, et al. (2001), preschool 

language outcomes of infants < 1500 grams born between 1989-1991 with (n=98) and without 

BPD (n=70) were assessed and compared with that of healthy term infants at 3 years of age. 

BPD (Bronchopulmonary Dysplasia) was defined as oxygen requirement for >28 days with 

radiographic evidence of BPD. Using the Battelle Developmental Inventory Communication 

Subscale Domain, receptive language (discrimination, recognition, understanding of words, 

sounds and gestures), expressive language (production and use of speech) and total 

communication skills were measured. The scores of each domain were converted to 

developmental quotient (DQ) with a mean of 100 and standard deviation of 15. VLBW infants 
81

with history of BPD not only scored significantly lower on all 3 language domains compared to 

the other 2 groups but the BPD group also had significantly higher incidence of DQ < 85 in the 

impaired range of functioning. The percentage of infants with receptive DQ < 85 were 49% in 

BPD group, 34% in VLBW without BPD group and 30 % in term group (BPD < VLBW and 

Term, p< 0.05 ANOVA). The percentage of infants with expressive DQ < 85 was 44% in BPD 

group, 25% in VLBW group and 25 % in term group (BPD vs. VLBW and Term, p< 0.05). The 

percentage of infants with communication DQ < 85 was 43% in BPD group, 31% in VLBW 

group, and 28% in Term group (p=NS). There were significant differences in receptive DQ: 84.7 

± 17 in BPD group, 91.5 ± 17 in VLBW group, and 97.3 ± 18 in Term group (BPD < VLBW < 

Term, p < 0.05). Expressive DQ between the three groups were also significant: 92.8 ± 22 in the 

BPD group, 99.7 ± 17 in VLBW group, and 101.3 ± 20 in term group (BPD < VLBW and Term, 

p< 0.05). In overall communication skills, BPD group again scored significantly lower than the 

other comparison groups: 89.4 ± 21 in BPD group, 96.4 ± 19 in VLBW group, and 99.8 ± 20 in 

Term group (BPD < VLBW and Term, p< 0.05). Even after controlling for lower IQ, VLBW 

infants with BPD have lower receptive language score while expressive and communication 

scores were no longer significant, indicating that BPD may specifically affect the receptive 

language domain above the effects of general IQ. Infants in the BPD group were significantly 

more immature and smaller, had higher neurologic risk score, intraventricular hemorrhage 

(IVH), seizures, retinopathy of prematurity, patent ductus arteriosus (PDA), and sepsis. Hearing 

loss was not more frequent in the BPD group. When controlled for these medical factors 

associated with BPD, BPD did not predict the 3-year Battelle scores. The medical factors that 

were predictive of language outcomes, however, were PDA and higher neurologic risk score 

(mainly due to IVH and seizures). In hierarchical stepwise multiple regression analysis, PDA 

lowered the DQ by 13 points, minority race by 6 points, lower socioeconomic status by 5 points 

and higher neurologic risk by 5 points. PDA (incidence 56% in BPD group and 18% in VLBW 

group; p=0.001) had a negative impact, not on cognitive and motor outcomes, but specifically on 

language development, even in the non-BPD group. BPD appeared to exacerbate the detrimental 

effect of PDA on language. This study does not report the number of infants in the BPD group 

having all of the above risk factors for developing language difficulties. It is not unusual in daily 

medical practice to care for an ELBW infant with BPD, PDA, IVH and born to a teenage single 

mother. The risk for these infants to develop significant speech/language delay is substantial.

Wood, Marlow, Costeloe, et al. (2000) studied outcomes of extremely premature infants born 

less than 25 weeks gestation (born in 1995). Twenty-three percent of the evaluated infants had 

speech delay: 5% had delay in speech and other systematized method of communicating, and 5% 

could not communicate by any method. Most of the infants did not have hearing loss.

In the study by Lefebvre, Gregoire, Dubois, et al. (1998), the predictability of the 

Neurobiologic Risk Score (NBRS) for neurodevelopmental outcome was determined in VLBW 

infants (born 1987-1992 at <28wks) at 18 months corrected age. Various items including 

duration of ventilation, pH, seizures, IVH, PVL, infection, and hypoglycemia were scored with 

absence being 0 and up to 4 points with increasing severity to obtain a total NBRS score (“low” 

= 4, “moderate” = 5-7 and “high” = 8) at discharge from the NICU. The NBRS scores 

significantly correlated (p = 0.0001) with severity of all subscales of the Griffiths’ developmental 

scales including the hearing-speech and persona l-social subscales (i.e. the higher the NBRS 

scores, worse the Griffiths’ score for hearing, speech and personal-social dimensions). Infants 

with “low,” “moderate” and “high” NBRS score had Griffiths’ Hearing and Speech DQ of 96 ± 

15, 89 ± 19, and 76 ± 22, respectively (p = 0.0001). Infants “low,” “moderate” and “high” 
82

NBRS score had Griffiths’ Personal-Social DQ of 104 ± 11, 95 ± 19, and 79 ± 30, respectively 

(p= 0.0001).

Wolke and Meyer (1999) studied 264 preterm infants, born <32 weeks in 1985-1986 in

Germany, at 6 years and 3 months of corrected age. There were 264 full-term control children 

matched for age, sex, socioeconomic status maternal education and marital status. Preterm birth 

was significantly associated with deficits in wide range of abilities including all measures of 

cognition, language comprehension and expression, articulation and prereading skills tested 

compared to that of full-term control children. Even when preterm children with severe mental 

retardation, and major neurosensory impairments were excluded from the analysis, scores of IQ, 

language and prereading tests were significantly lower. Problems in cognition and language 

occurred at multiple levels. Preterm children have specific deficit in simultaneous central 

information processing where their ability to perceive, process and logically reason/integrate 

stimuli at the same time is impaired. Specific deficits in language abilities included problems 

with grammatical rules, and detecting semantically incorrect sentences (p< 0.001), motor aspects 

of speech such as articulation and pronunciation (p<0.001), and prereading skills of rhyming 

tasks, sound-to-word matching and naming of number/letters (p<0.001). The incidence of 

serious language impairment in the preterm group was 13.7% vs. 0.8% in the control group 

(p<0.001). Deficits in speech <10th percentile were 3 to 5 times more frequent in the preterm 

group.

Smith, Landry, Swank et al. (1996) compared expressive and receptive language 

development in “high-risk”) preterm, “low-risk” preterm and full-term infants at 6 and 12 month 

corrected ages for preterm infants recruited 1990-1992. “High risk” was defined as having one 

or more severe medical complications including BPD needing oxygen more than 28 days and/or 

severe IVH Grade III-IV/PVL. At 6 months of age, the “high-risk” group of preterm infants had 

significantly lower receptive and expressive language scores than the full-term control infants. 

At 12 months of age, the “high-risk” preterm infants showed slower rates of improvement in the 

language scores and scored significantly lower than full-term controls in expressive language 

scores.

Sajaniemi, Hakamies-Blomqvist, Makela, et al. (2001) studied language development in 4 

year-old preterm infants born 1989-1991 in Helsinki. Children with major disabilities including 

cerebral palsy and mental retardation were excluded so that the final study group consisted of 63 

preterm infants with no major neurological impairments and with MDI >70 (from Bayley Scales 

of Infant Development), mean BW 1246 ±472g, mean GA 29.4 ±3. The study showed that 

cognitive, behavioral and temperament assessments as early as 2 years of age predicted impaired 

language functioning at age 4 years in infants without major disabilities. Twenty-two percent of 

cognitively normal preterm children at 2 years had language impairment at 4 year of age. In a 

logistic regression model, Bayley scores of 72, 82, 92, 100 and 106 corresponded to the 

following percent risk of developing language impairment: 90, 75, 50, 25, and 10%, respectively. 

Temperament (assessed by the Toddler Temperament Questionnaire at 2 years of age) as a whole 

(but not individual dimension) was statistically associated with language impairment at 4 years 

of age (p<0.05). Temperamentally, they were less active, less persistent, and less goal-directed 

with passive attitude toward environmental stimulus. Low scores of the Infant Behavior Record 

of the Bayley Scales as a whole were also related to impaired language functioning (p<0.01). 

The preterm infants were less cooperative and less reactive to their environment with high 

distractibility. Behavioral factors were more closely associated with later language impairment 

than temperament. A tentative explanation that the authors offer for the relationship between 
83

temperament and behavior at earlier age with later unfavorable language development is that 

these temperamental and behavioral tendency of premature infants inhibit early intentional 

communication leading to progressive language delay.

Briscoe, Gathercole, and Marlow (1998) demonstrated that across all measures of short-term 

memory and language outcomes, preterm infants (26-32 weeks and born 1991-1992) performed 

at a lower level, typically half standard deviation lower than full-term counterparts at 3-4 years 

of age. They scored lower on receptive and expressive vocabulary, expressive language, 

phonological short-term memory, and general nonverbal ability. These deficits were unrelated to 

the general IQ. By 24 months of age, at-risk preterm infants performed significantly worse on 

the Hearing and Speech subscale of the Griffiths’ Mental Assessment Scales. The Bus Story test 

identified “at-risk” preterm infants who developed specific language impairment without being 

cognitively impaired. Authors suggest that up to 31% of “at-risk”infants having language 

impairment may be identified with the Bus Story Test at 5 years of age.

A Canadian study by Saigal, Stoskopf, Streiner, et al. (2001) polled parents of ELBW infants 

501-1000 g born 1977-1982 at 12-16 years of age as well as term controls. Parents were polled 

using questionnaires (Ontario Child Health Study Questionnaire, National Health Interview 

Survey, and Survey of Disabled Children). The ELBW had significantly higher utilization rate 

of speech therapists (p< 0.002) but they had similar utilization rates as control group for social 

services or other counselors for emotional and/or behavioral problems. Parents of ELBW also 

reported more frequent disabilities: emotional problems (OR 2.5; 95% CI 1.07-6.32), learning 

disabilities (OR 4.8; 95% CI 2.35-10.4), special education (OR 8; 95% CI 4.1-15.4) and 

hyperactivity (p= 0.04). One child in each group required hearing aid. This study again 

emphasizes higher prevalence of functional limitations in most domains with ELBW who may 

require more educational and health care services.

The study by Schendel, Stockbauer, Hoffman, et al. (1997) compared neurodevelopment of 

VLBW (<1500g), MLBW (moderately low birth weight, 1500-2499g), and NBW (normal birth 

weight, =2500g) children who were born 1989-1991. Language delay was detected in 8.8%, 

5.8%, and 4% of VLBW, MLBW, and NBW infants, respectively (VLBW vs. NBW p = 0.01). 

Incidence of those suspicious for delay was even higher at 17%, 12%, and 8.5%, respectively 

(VLBW vs. MLBW p = 0.05; VLBW vs. NBW p = 0.001). 

Audiology Outcomes

Identification of hearing loss is critical since it may lead to lower cognition, speech and 

language delays as well as social, educational and behavioral problems. It is also frequently 

associated with other neurologic disabilities (Marlow, Hunt, and Marlow, 2000). The following 

21 RCT and non-randomized comparison studies (Table 3.2) reported the incidence of hearing 

loss in LBW infants. Hearing impairment incidence ranged 0 to 14% among VLBW infants. In 

the outcome studies, the details of hearing loss (i.e. specific test used, definition for hearing loss, 

and statistical analyses of hearing loss with confounding factors) were not consistently reported. 

To exclude these studies in this report for these reasons would exclude virtually all studies. 

Therefore, these studies are reported. Inconsistent results may stem from methodological 

differences.
84

Table 3.2. Association of VLBW with Hearing Loss

Author, Year N

(Controls)

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictor Measure

Association / % 

of Subjects with 

hearing 

impairment

ApplicabilityQuality

Northern 

Neonatal 

Nursing 

Initiative Trial 

Group, 1996

96304894

Plasma 

N=257;

Placebo 

N=261;

Control 

N=258

GA: < 32 

weeks

Use of fresh frozen 

plasma or 

plasma

substitute

Hearing loss 

of >= 50 dB,

Griffiths 

quotient

50-70 dB 2/203,

>70 dB 2/203,

Griffiths quotient 

for hearing and 

speech >3 SD 

below mean 

19/203

mmm A

Hack 

1996

97066007

1982-1988

N=34;

1990-1992

N=49

BW :624 ± 24

GA 24.4 ± 2;

BW 634 ± 75

GA 24.4 ±2

BW Unilateral or 

bilateral 

Deafness

1982-1988 0%

1990-1992 6%

mmm A

Hack

2000

20358826

221 BW: 813±125

GA: 26.4 ±1.8

BW, GA

SGA/IUGR,

Antenatal steroids

Jaundice, IVH

Unilateral or 

bilateral 

deafness;

 Hearing aid

9%

7%

mmm A

Wood

2000

20373840

424 GA: <25 

weeks

GA

Gender

Perinatal 

Factors‡ Multiple 

gestation

Impaired 

hearing (not 

needing 

hearing aid)

Impaired 

hearing not 

corrected 

with aid)

12%

3%

mm B

Singer

1997

98049057

VLBW with 

BPD 

N=122

VLBW 

without 

BPD N= 84

NBW 

N=123

BW 956±248 

(SD)

GA 27 ± 2

BW 1252 

±178

GA 30 ± 2

BW 3451 ± 

526

GA 40 ± 1

Bronchopulmonary 

dysplasia (BPD),

GA

Use of 

hearing aid

VLBW without 

BPD: 1%

VLBW with BPD: 

3%.

P=NS

mmm A

Schmidt B

2001

21298249

1202 GA: 26

BW:

Sample 1: 

782

Sample 2: 

783

Prophylactic 

indomethacin

Hearing loss

Requiring 

amplification

2% 

mmm A

Battin

1998

99002694

44 GA: 23-25

BW: ND

Extremely lowGA, 

BPD

Sensorineural 

hearing loss

9%

mm B

Vohr

2000

20295211

1151 GA: ND

BW: 401-

1000

BW Hearing 

impairment

Wearing 

hearing aid

11%

3% mmm B
85

Author, Year N

(Controls)

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictor Measure

Association / % 

of Subjects with 

hearing 

impairment

ApplicabilityQuality

Piecuch

1997

98012134

86 BW 500-999

GA: 24-25

GA

IVH

Behavioral 

testing for 

hearing

2/86 (NS)

mm B

Victorian

Infant

Collaborative 

Study Group, 

1997

97466059

Born 1979-

80 N=351

Born 1985-

87 N=560

Born 1991-

92 N=429

BW: 500-999

GA: ND

Time period of 

birth

Deafness 

requiring 

hearing aids

Incidence of 

deafness in each 

time period was 

0. mm B

Victorian

Infant

Collaborative 

Study Group 

1997

98026322

Born 1979-

80 N=351

Born 1985-

87 N=560

Born 1991-

92 N=429

NBW 1991-

92 N=242

ELBW 500-

999g

NBW >2499g

BW,

Time period of 

birth

Deafness 

requiring 

hearing aids

1985-87 ELBW:

0.05%

1991-92 ELBW: 

0.8% mm B

Ambalavanan 

2000

21031370

218 GA: 26

BW: 829

BW, GA, IVH,

AntenatalSteroids

Apgar score

Hearing aid 1.4% 

mm B

Cheung

1999

99146391

500-749g

N=26;

750-999g

N=63;

1000-1249

N=75

BW 660±56

GA 25(22-29);

BW 873±72

GA 26(24-30);

BW 1127±71

GA 28 (23-32)

GA

Apgar score

IVH

Sensorineural 

hearing loss

0.9%

(3/164)

m B

Doyle

2001

11433066

225 GA: 23-27

BW: ND

GA,SGA/IUGR

IVH

Hearing aid 0.9%

(2/22) mm B

Corbet

1995

95264244

BW 

GA 

BW 

GA 27 

Exosurf synthetic 

surfactant

Any Sensorineural 

hearing loss

Deafness 

>90dB

0

1% mm

B

Gerdes

1995

95264241

One dose 

N=314

Three dose 

N=283

BW 907±121

BW 911±125

Cardiovascular or 

Pulmonary: 

Surfactant use

Bilateral 

sensorineural 

Deafness;

Not requiring 

amplification

1 dose: 2%

3 dose: 0%

1 dose: 2%

3 dose: 1% mm B

Marlow

2000

20150342

SNHL N=15

Controls 

N=30

BW:960(600-

2914)

BW:1026 (410- 

2814)

BW

Apgar 

Illness severity 

(CRIB) 

SNHL 

(Sensorineural 

Hearing 

Loss)

Strong 

associations to: 

bilirubin+acidosis,

Bilirubin 

+netilmicin,

Creatnine + 

furosemide,

Neti lmicin + 

furosemide

mm B
86

Author, Year N

(Controls)

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictor Measure

Association / % 

of Subjects with 

hearing 

impairment

ApplicabilityQuality

Lee BE

1998

98442293

25 BW: <1250 g

GA: ND

Candidemia and/or 

Candidal 

meningitis

Hearing loss 

(neurosensory 

hearing loss 

in the better 

ear > 30)

Case: 14%

Control: 5%

m B

DeReginer 

1997

98041177

No CLD 

N=54;

Mild CLD 

N=54;

Severe 

CLD N=56

GA: 27-28

BW: 

1007-1030

Chronic lung 

disease

Sensorineural 

hearing loss

 of 30 dB in 

the better 

ear,

Visual 

reinforced 

audiometry

No CLD 0%

Mild CLD 0%

Severe CLD5.3%;

P< 0.05 in No 

CLD vs. Severe 

CLD group

mmm B

Kurkinen-Raty 

1998

98197235

PROM 

N=55;

No PROM 

Control 

N=56

BW : 1138

GA: 28.2;

BW: 1272

GA28.4

 Preterm rupture of 

membranes 

Hearing loss Early PROM: 7%

Control: 9%

m B

KurkinenRaty, 2000

20284814

Indicated 

del N= 81;

Spont del 

N= 94

BW:1240

GA 30.5;

BW 1608

GA 30.4

Preterm delivery 

for maternal or 

fetal indications

Hearing loss NS

mm B

a

 “DELAY” defined by 9 measures of performance on Denver Developmental Screening Test II at age 15 months corrected

NS: not significant; PROM premature rupture of membranes.

 

In a randomized controlled trial by the Northern Neonatal Nursing Initiative Trial Group 

(1996), infants <32 weeks born 1990-1992 were studied at 2 years of age for effect of 

prophylactic fresh frozen plasma infusion in reducing IVH. The incidence of hearing loss (in 

better ear) were as follows: 50-70 dB loss occurred in 2 out of 203 in FFP group, 4 out of 196 in 

gelatin group, 3 out of 205 in glucose group. Hearing loss > 70 dB occurred in 2 out of 203, 1 

out of 196, 2 out of 205, respectively. The number of infants with Griffiths quotient for hearing 

and speech >3 SD below the mean were 19 out of 203, 13 out of 196 and 20 out of 205, 

respectively. There was no statistical difference among the groups. 

At 20 month corrected age, evaluation of premature infants BW <750 g and born in periods I 

(1982 – 1988) and II (1990 – 1992) was undertaken by Hack, Friedman, and Fanaroff (1996). 

The incidence of deafness was 0 and 6% in the groups born in periods I and II, respectively.

In another excellent outcome study by Hack, Wilson-Costello, Friedman, et al. (2000), 

infants <1000g born between January 1992 and December 1995 were evaluated for major 

outcomes at 20 months corrected age. The incidence of deafness (unilateral or bilateral) was 9% 

(20/221) and 16 of 20 (7%) with hearing loss required hearing aid. The rate of deafness by birth 

weight group were as follows: 8% (n=12) in 500-599 g, 10% (n=31) in 600-699g, 8% (n=52) in 

700-799g, 11% (n=57) in 800-899g, and 9% (n=68) in 900-999g group. The rate of deafness by 

gestational age were as follows: 25% (n=8) in 23 week, 5% (N=21) in 24 weeks, 12% (n=42) in 

25 week, 9% (n=55) in 26 week, 12% (n=43) in 27 week, and 0% (n=24) in 28 week infants. 

The rate of deafness was similar in AGA vs. SGA infants 10% and 6%, respectively. Multiple 
87

stepwise logistic regression analysis identified the following factors as predictors of deafness: 

male sex (OR 2.79; 95% CI 1.02-7.62), sepsis excluding meningitis (OR 3.15; 95% CI 1.05-

9.48), and jaundice with maximum bilirubin level > 10 mg/dl (OR 4.8; 95%CI 1.46-15.73). Of 

note, in this study, formal hearing tests were not routinely performed so that the incidence of 

milder hearing loss may have been underestimated. 

In a large prospective cohort study by Wood, Marlow, Costeloe, et al. (2000), overall 

outcome of premature infants 20 through 25 weeks gestational age was evaluated. Twelve 

percent had impaired hearing not requiring hearing aid, 1% had hearing impairment not corrected 

with hearing aid, and 2% had severe hearing impairment not corrected even with hearing aid. 

In a study by Singer, Yamashita, Lilien, et al. (1997) comparing long-term outcome of 

VLBW infants <1500 g, with BPD (supplemental oxygen at 28 days with radiologic changes) 

and without BPD, the use of hearing aids was 3% and 1% (P=NS), respectively. The incidence 

of hearing loss in the full-term infant group was not reported. BPD, at least in this study, was not 

directly related to hearing loss.

In a randomized, placebo-controlled trial of prophylactic Indomethacin, Schmidt, Davis, 

Moddemann, et al. (2001) reported a similar incidence of “hearing loss requiring amplification” 

of 2% in both the treatment and control group of infants (BW 500-999g). 

In the study by Battin, Ling, Whitfield, et al. (1998) in British Columbia, 23-28 week infants 

born January 1991 to December 1993 were evaluated at 18 months corrected chronological age. 

Formal hearing tests (not specified) were done and the incidence of sensorineural hearing loss 

requiring amplification in infants 23-25 weeks was 9%. 

Vohr, Wright, Dusick et al. (2000) in the United States studied infants weighing 401-1000g 

and born January 1993 to December 1994. Infants were evaluated at 18-22 months-corrected 

age. Overall hearing impairment was 11% with highest incidence of 14% in the 601-700g BW 

group. Three percent of infants weighing 401-1000g required hearing aids with the highest rate 

in the 601-700 subgroup. 

Piecuch, Leonard, Cooper, et al. (1997) evaluated neurodevelopmental outcomes in 24-26 

week infants born 1990-1994 in the US. Eighty-six were evaluated at 32 months corrected age. 

Audiologic assessment occurred by behavioral testing and any questionable exam was evaluated 

further by brainstem-evoked responses or pure tone audiometry. Only 2 infants had conductive 

hearing loss attributed to recurrent otitis. 

 In the studies by the Victorian Infant Collaborative Study Group (1997 and 1997), the 

incidence of hearing loss requiring hearing aid was 3.4% in the 1979-80 cohort, 0.5% in the 

1985-87 cohort and 0.8% in the 1991-92 cohort. There was no statistical difference in the 

incidence among the groups. 

Ambalavanan, Nelson, Alexander, et al. (2000) reported the incidence of deafness to be 1.4% 

in infants < 1000 grams born January 1990 to December 1994. Cheung, Barrington, Finer, et al. 

(1999) reported the inc idence of sensorineural hearing loss (measured by certified clinical 

audiologists) at 0.9% in infants <1250 grams (born 1990-1993) at 3 years of age. By birth 

weight stratification, incidence was 1/26 (3.8%), 1/63 (1.6%) and 1/75 (1.3%) in the 500-749g, 

750-999 g and 1000-1249g group, respectively. 

In the study by Doyle (2001), the incidence of sensorineural deafness requiring hearing aid in 

23 - 27 weeks infants born in Australia between January 1991 and December 1992 was 0.9% 

(2/221) compared to 0% in full-term group at 5 years of age.
88

In a randomized controlled trial comparing outcomes of infants at 1year corrected age (born 

1986-1989) receiving placebo vs. Exosurf surfactant with birth weights 500-1350g, Corbet, 

Long, Schumacher, et al. (1995) reported the incidence of bilateral sensorineural hearing 

deafness to be 0 and 1%, respectively, which were not different. Hearing loss not needing 

amplification was 0 and 1%, respectively; also not significant. Although hearing evaluations 

were performed during the first year, the testing method and timing of the evaluations were not 

uniform among institutions. Hearing loss was defined as any degree of loss and deafness was 

defined as hearing threshold >90 dB. 

In a 1 year-outcome study by Gerdes, Gerdes, Beaumont, et al. (1995), premature infants 

(BW 700-1100 g, born 1989-1990) treated with 1 vs. 3 prophylactic doses of Exosurf synthetic 

surfactant were compared. There was no difference between the study groups in the incidence of 

bilateral sensorineural deafness or deafness not requiring amplification. The incidence of 

bilateral deafness was 2% and 0.4% in the 1 vs. 3 dose groups, respectively (RR 0.18; 95% CI 

0.026, 1.287). The incidence of deafness not requiring amplification was 2% and 0.7% in 1 vs. 3 

dose groups, respectively (RR 0.37; 95% CI 0.078, 1.709).

In a case-control retrospective study in United Kingdom, Marlow, Hunt, and Marlow (2000) 

studied clinical correlates of sensorineural hearing loss (SNHL) in 12 month-old infants <33 

weeks and born January 1990 to December 1994. “SNHL” was defined as > 50 dBHL loss on 

auditory brainstem response testing. “Moderate SNHL” was 41-70 dBHL, “severe SNHL” was 

71-95 dBHL and “profound SNHL” was >95 dBHL. The hearing loss was confirmed by later 

behavioral testing by distraction test, visual reinforcement, and pure tone audiometry appropriate 

to child’s development. Fourteen out of the 15 children were fitted with hearing aids (parent of 1 

child declined use). Of the 15 children with hearing loss, 2 had bilateral moderate loss at 4000 

Hz frequency, 5 had bilateral moderate SNHL over 500-4000 Hz range, 3 had bilateral severe 

SNHL, and 5 had bilateral profound SNHL. The authors reported that 47% of children with 

sensorineural hearing loss have evidence of CP compared to 7% in the normal hearing control 

group. Infants with SNHL had longer duration of ventilation, oxygen therapy, acidosis and more 

frequent use of dopamine and furosemide, and blood culture-positive sepsis indicating greater 

severity of illness in these infants compared to their matched controls. Risk factors that further 

increased the likelihood of developing sensorineural hearing loss were as follows: 1) serum 

bilirubin level > 200 μmol/l with acidosis {31% vs. 4%, OR: 8, 95% CI 0.9-71.6}, 2) bilirubin 

level > 200 μmol/l with netilmicin use {87 % vs. 14%, OR: 14.2, 95% CI 1.8-113.6}, 3) 

creatinine > 60 mmol/l with furosemide use {64 %% vs. 27%, OR: 8.9, 95% CI 1.1-74.5}, and 4) 

netilmicin with furosemide use {67% vs. 37%, OR: 5, 95% CI 0.99-24.8). The main drawback 

of this study was its small size (n=15).

Lee, Cheung, Robinson, et al. (1998) reported that infants (BW <1250g) who suffered 

candida sepsis/meningitis were more likely to die (60% vs. 28% in controls, OR 3.9, 95% CI 1.2-

12.6) but the survivors of candida infection did not have higher incidence of hearing loss or 

cerebral palsy. 

In the study by deRegnier, Roberts, Ramsey, et al. (1997) of infants <1500 g (born 1987 to 

1991), hearing loss was 0 in both the “No CLD” (room air at 28 days) and “Mild CLD” (oxygen 

at 28 days but not at 36 weeks PMA) groups. Hearing loss occurred in 3 out of 56 (5.3%) infants 

in the “Severe CLD” (oxygen at 28 days and at 36 weeks PMA) group (p<0.05, No CLD vs. 

Severe CLD group). Hearing at 1 year adjusted age was tested by visually reinforced 

audiometry. 
89

In infants born with PROM (premature rupture of membranes) compared to no PROM, 

Kurkinen-Raty, Koivisto, and Jouppila (1998) reported no difference in hearing loss (7% vs. 9%, 

OR 0.8, 95% CI 0.2- 3.2) at 1 year corrected age. Preterm delivery due to maternal or fetal 

indications did not increase hearing loss when compared to infants born spontaneously premature 

(6% vs. 3%, RR 1.9, 95% CI 0.5-7.8) even though they had higher incidences of RDS and BPD, 

pulmonary air leaks, and longer hospitalization days. However, they also had higher mortality 

rate so that the healthiest of the PROM group survived. 

 

Behavioral / Social Outcomes

Long-term behavioral outcome studies of premature infants born prior to 1980 showed that 

VLBW infants have higher incidence of behavior problems and attention-deficit/hyperactivity 

disorder (Botting, Powls, Cooke, et al., 1997; Hack, Breslau, Aram, et al., 1992; McCormick, 

Brooks-Gunn, Workman-Daniels, et al., 1992; McCormick, Gortmaker, and Sobol, 1990). The 

seven non-randomized comparison studies in this review (Table 3.3) explore whether there are 

persistent increased behavior problems in VLBW infants born since 1980 with utilization of 

significant technological and medical improvements in their neonatal care.

Table 3.3. Association of LBW to Behavior Outcomes

Author, 

Year

N

(Controls)

Mean BW, 

g; GA, week

Baseline 

(Range)

Predictor Measure

Association / % of 

Subjects with 

impairment 

ApplicablityQualit

y

Nadeau

2001

21163667

Extremely 

premature

N=61

Full-term 

controls

N=44

<1500g 

(1024± 204),

<29 wks (27 

±1.1.

GA 39. ± 1.6

BW 3453g ±

498 SD

GA,

Neuromotor 

function, 

Intelligence, 

Family adversity

Peers (Interviews, Revised Class Play) 

report increased sensitivity/isolation 

behaviors in prematurely born 

children

Teachers (Teacher Report Form) report 

significant inattention.

Parents (Child Behavior checklist) report 

hyperactivity.

mm A

Robson

1997

9055145

85 BW 1758± 

522g,

GA 32.6± 

3.4

Home 

environment, 

medical risk, 

temperament, 

developmental 

status

McCarthy Scale of Children’s abilities,

Parents’ Child Behavior Checklist, task 

performances. Attention problems are 

predicted by temperament, home 

environment and interaction between 

developmental status and quality of 

home environment.

mmm A

Breslau

1996

8836807

Urban:

LBW N=238

NBW N=176

Suburban:

LBW N=235

NBW 174

LBW = 

2500g

NBW = 

2500g

Urban vs. 

suburban sites,

Socioeconomics

GA, BW

Parent interviews, Teacher Report Form.

LBW is associate with ADHD more 

strongly in socially disadvantaged urban 

group than suburban group. mmm A
90

Author, 

Year

N

(Controls)

Mean BW, 

g; GA, week

Baseline 

(Range)

Predictor Measure

Association / % of 

Subjects with 

impairment 

ApplicablityQualit

y

Breslau

2000

20298367

LBW:

N=411

NBW

N=306

Urban site:

N=238 LBW 

<1500g

Suburban 

site: N=235 

LBW <1500g

Suburban vs. 

Urban,

LBW vs. NBW

Parents (Child Behavior Checklist),

Teachers (Teacher Report Form).

LBW have attention problems only in the 

urban setting group.

Urban LBW have more severe attention 

problems than urban NBW.

Suburban LBW have similar attention 

problems as suburban NBW.

Difference in externalizing behavior is 

accounted for by maternal smoking.

No difference in internalizing behaviors.

mmm B

Hille

2001

21319264.

USA 

N=80;

Canada 

N=150;

Germany 

N=78;

Netherlands 

N=100

BW853±114

GA 27 ± 2.3;

BW834±126

GA 27 ± 2.3;

BW888±101

GA 29 ± 2

BW882±105

GA29 ± 2.3

Countries,

Gender,

BW

Parents (Child Behavior checklist CBCL).

Total problem score: 

Boys: 3.3-9.8 points higher in LBW vs. 

control.

Girls: 3.7-5.9 points higher in LBW vs. 

control.

Social and attention difficulty scales were 

0.5-1.2 SD higher in LBW children vs. 

control.

Internalizing and externalizing behavior 

scores: no difference for all 4 groups 

(except for one cohort for internalizing 

scores)

mmm B

Katz

1996

97145056

Premature 

infants 

N=64,

Full-term 

infants N=40

GA: 29 wks,

BW: 1227g

(740-2240)

GA

CNS lesions: 

IVH, PVL

Increasing severity of lesions associated 

with increased error of commission.

Increased errors of both commission and 

omission in preterms compared to full 

term infants.

mmm B

Sajaniemi

1998

99041674

Preterm 

N=80

Full term 

N=80

BW: 1205

(560-2360)

BW: 3461

(2510-5360)

Prematurity(BW 

>1000g vs. 

<1000g)

Low Bayley 

scores,

Days on 

ventilator,

PVL, IVH, CP,

Days in NICU

In temperament, preterms are less 

active, more adaptive, more positive 

in mood, less intense, lower in 

threshold to respond than controls. 

On behavior, preterms less goal directed, 

less attentive, and lower in endurance 

than controls.

mmm B

Nadeau, Boivin, Tessier, et al (2001) evaluated behavior of 61 extremely preterm infants 

(gestational age <29 weeks and VLBW < 1500g) and 44 NBW infants born 1987-1990. The 

behaviors were evaluated at 7 years of age by parents, peers, and teachers who corroborated a 

definite link between extreme prematurity and behavior problems in school, specifically 

sensitive/isolated behaviors, inattention and hyperactivity. Premature birth was clearly 

associated with cognitive and neuromotor delays at 5 years and 9 months and these deficits 

accounted for development of behavioral problems. The children born prematurely were more 

frequently viewed by their peers as shy and withdrawn. In the mediational model, delayed 

neuromotor development (and not cognition) directly contributed to isolated behaviors. 
91

Intellectual functioning, namely deficits in sequential memory (concentrating and receiving 

auditory information in working memory and retrieving it in organized fashion) was uniquely 

related to inattention in a regression analysis. This suggested that prematurity acted through its 

association with intellectual delays in the specific dimension of sequential memory to result in 

inattention behaviors recognized by teachers. Hyperactivity frequently reported by parents was 

predicted by global IQ deficits. Family adversity examined at 5 years and 9 months was 

significantly associated with sequential memory problems and inattentive behaviors but not with 

sensitivity/isolation or hyperactive behaviors at 7 years.

Robson and Pederson (1997) took a multidimensional approach to measurement of attention 

problems in preterm infants and identifying predictors of attention problems in this prospective 

longitudinal study. The McCarthy Scales of Children’s Abilities test of behavior assessed 

inattention, impulsivity and hyperactivity. Parental report from the Child Behavior Checklist as 

well as task performance tests based on the vigilance task and the Matching Familiar Figures 

Test were also administered to identify attention problems at 5.5 years of age. Developmental 

status and quality of home environment correlated with increased hyperactivity detected on the 

McCarthy behavior test. The quality of home environment correlated with the parental reports of 

hyperactivity. Medical risk, infant temperament, quality of home environment, and 

developmental status correlated with task measures of attention. All three forms of testing for 

attention problems supported the hypothesis that the care giving home environment played a 

significant role in the development of self-regulating behaviors in low birth weight children in 

which safe, responsive, nurturing social home environment facilitated development of selfregulating behavior. Multiple regression analyses indicated that temperament, environment and 

the interaction between development and quality of home environment predicted attention 

problems in childhood.

Breslau, Brown, and DelDotto et al (1996), examined the association between LBW and 

ADHD (Attention Deficit Hyperactivity Disorder) and other behavioral disturbances in the 

DSM-III (Diagnostic and Statistical Manual of Mental Disorders, Third Edition) book of 

psychiatric disorders in urban and suburban socioeconomic populations. The children were born 

1983-1985 in Michigan with BW <2500 g and evaluated at 6 and 7 years of age. The study 

excluded children with severe mental retardation, severe CP and blindness and focused on the 

population of preterm infants in whom behavioral outcomes were less obvious than in severely 

impaired children. The National Institute of Mental Health Diagnostic Interview Schedule for 

Children-Parent version was used as well as Teacher’s Report Form to evaluate behavior 

problems. LBW was significantly associated with ADHD but not with separation anxie ty 

disorder, simple phobia, overanxious disorder, or oppositional defiant disorder. The data from 

the mothers’ interviews, teachers’ ratings and data based on combined algorithm all corroborated 

that LBW is significantly associated with ADHD and that this relationship is stronger in urban 

than in suburban community. When combining parents and teachers’ data, the rate of ADHD was 

higher in LBW group compared to NBW (13.9% vs. 4.1%; RR=3.4, 95% CI 1.5 to 7.5) in the 

urban group but not as strongly in the suburban group (6.9% vs. 3%; RR2.3, 95% CI 0.9 to 6.8). 

This association correlated with level of IQ with the children of IQ < 80 having the highest rate 

of ADHD. The teachers’ ratings also found a significant association between LBW and the 

Withdrawn Symptoms scale. There were significant differences in racial composition, maternal 

education, and single-parent status between the two socioeconomic groups. The urban group 

was primarily black, 25% of the mothers had not completed high school and greater than 30% 

were single. The suburban group was predominantly white, only 7% of the mothers failed to 
92

complete high school and 10% were single. Perinatal risk factors including single –mother 

status, maternal history of substance abuse/dependence and smoking during pregnancy in a 

multivariate analysis did not have significant associations with ADHD.

The study by Breslau and Chilcoat (2000) reevaluated behavior of this same group of preterm 

children at age 11 years. Both the behavior ratings by the mothers and the teachers who were 

blinded to the birth weight status, indicated that LBW was associated with attention problems in 

socioeconomically disadvantaged urban setting but not in suburban middle class setting. The 

urban LBW children had significantly higher incidence of “severe” attention problems by 11 

years of age compared to their urban normal birth weight counterparts whereas the suburban 

LBW had similar incidence compared to their suburban normal birth weight group. The effect of 

LBW on externalizing behaviors (delinquent and aggressive subscales of CBCL-Child Behavior 

Checklist) was eliminated when prenatal exposure to maternal smoking was considered. LBW 

did not contribute to internalizing problems (withdrawn, somatic complaints and 

anxious/depressed subscales of CBCL). However, the study does not report whether the behavior 

problems needed treatment or how they impacted their school performance. 

Hille, den Ouden, Saigal, et al. (2001) evaluated the behavior of VLBW infants from 4 

different countries (US, Netherlands, Canada, and Germany) at ages 8-10 years. Premature 

infants had similar behavior problems in attention, social and thought subscale scores of CBCL, 

which were 0.5 to 1.2 SD higher in LBW infants than in term controls across all countries. This 

suggests that these problems are not a function of cultural differences but are an indication of 

biological mechanisms specific to VLBW infants. There were no differences in internalizing or 

externalizing scales when LBW infants were compared to normative cohorts of their respective 

countries, except for internalizing score in one cohort. Problems with this study are that 

children in both the normative groups and the LBW groups were born in different years 

sometimes with wide gaps. For example, the LBW Canadian cohort was born 1977-1982 while 

the US LBW cohort was born 1984-1987. Also, each country assessed premature infants of 

different BW range. For example, US cohort included BW up to 2000g while the Canadian 

cohort included only infants <1000 gram. Because the CBCL were completed by the LBW 

parents, who were not blinded to their infant’s birth weight, there was potential for significant 

bias in their assessment of their child’s behavior. 

Katz, Dubowitz, Henderson, et al. (1996), in a comparison trial, studied 26-34 week 

premature infants (born 1983-1985) with or without intracranial lesions and full term infants at 

6-8 years of age. Attention was evaluated with 2 tests: Continuous Performance Test measuring 

errors of omission or commission, and the CBCL by parents. The authors observed increasing 

poor performance on attention skills with increasing severity of intracranial lesions. However, 

absence of intracranial lesions did not preclude development of attention problems (i.e. 

premature infants without identified lesions were also at risk for attention deficits compared to 

term controls). 

Sajaniemi, Salokorpi, and von Wendt (1998) compared behavior and temperament of VLBW 

infants 23-34 weeks, born 1989-1991 with that of healthy full-term controls at 2 years of age. 

Temperament was assessed with the Toddler Temperament Questionnaire, neurodevelopment 

with Bayley Scales of Infant Development and behavior with the Infant Behavior Record (IBR, 

part of Bayley Scales). There was no difference in temperament types (easy, difficult, and slow 

to warm up) between the groups. Preterm infants scored significantly different than controls in 5 

of the 9 dimensions of temperament: preterm infants were less active (p < 0.008), more adaptive 

( p< 0.02), more positive in mood (p< 0.004), less intense (p< 0.01), and lower in threshold to 
93

respond ( p< 0.003) than the controls. IBR showed that preterm infants were less goal directed 

(p< 0.0001), less attentive (p< 0.002), and lower in endurance (p< 0.0002) than the control 

infants. Preterm infants also performed less well on the Bayley test. Low Bayley scores were 

associated with temperament of high rhythmicity ( r= 0.24, p< 0.03), positive mood (r=0.21, p< 

0.04), lower persistence ( r= 0.33, p< 0.002), and high threshold to response (r= 0.29, p<0.008). 

Low Bayley scores correlated with behavior scores of poor social orientation (r= 0.42, 

o<0.0001), negative emotional tone (r=0.34, p< 0.001), poor cooperation (r= 0.48, p< 0.0001), 

short attention span (r=0.5, p< 0.0001), poor goal directedness (r= 0.47, p< 0.0001) and poor 

endurance (r= 0.49, p< 0.0001). High rhythmicity on temperament correlated only with increase 

in number of days on the ventilator (r=0.29, p< 0.009) among the perinatal and neonatal factors 

evaluated. PVL and IVH significantly correlated with behavior of short attention span (p< 

0.006). CP at 24 months is associated with IBR for object orientation (p< 0.01), shorter attention 

span (p<0.01), and lower endurance (p<0.01). Increased number of days in the NICU correlated 

with IBR scores for poor object orientation (r= 0.21, p< 0.05), and short attention span (r= 0.32, 

p< 0.003). Increased number of days on ventilator also correlated with IBR scores for poor 

object orientation (r=0.26, p< 0.01), negative emotional tone (r= 0.21, p< 0.05), short attention 

span ( r= 0.26, p< 0.01), and poor endurance (r= 0.22, p< 0.04). Although some correlation was 

weak, this study indicates that preterm toddlers have different temperament than full term 

toddlers in that they are more passive, have low energy, and more easily adaptive. For example, 

they do not become upset about falling or having a toy taken away, accept playing alone, do not 

fight rules, and sit quietly. As these qualities may appear desirable, it also indicates that they do 

not run off to explore new areas, are unmoved when listening to stories or looking at pictures, 

lack initiative and curiosity, and allow environmental stimulation to pass over them. This can in 

turn is a risk factor for developmental delay. This study shows that temperament and behavior 

are influenced by factors related to gestational age and cognition, with weak correlation to PVL, 

IVH and CP. 

Learning Disability/School Performance Outcomes

Four non-randomized comparison studies (Table 3.4) reported association of LBW and 

VLBW to learning disability and school performance in infants born since 1980. There was 

limited data identified based on the methodology of this review regarding learning disability and 

school performance outcomes of VLBW infants. This indicates important areas of research to 

identify problems, to institute assistance and maximize achievement.
94

Table 3.4. Association of LBW to Learning Disability and School Performance

Author, 

Year

N

(Controls)

Mean BW, 

g; GA, week

Baseline 

(Range)

Predictor Measure

Association / % of 

Subjects with 

impairment 

ApplicablityQuality

Hille

1994

8071753

LBW N=813 <32 wks,

<1500g

Perinatal 

factors:GA, BW, 

male gender. 

Socioeconomics 

Factors at 5 

years: 

neuromotor and 

speech delay, 

inattention, 

hyperactivity, 

poor school 

performance

Questionnaire VLBW infants more 

frequently experience 

school failure than 

the general 

population in The 

Netherlands. mmm A

Stathis

1999

99325758

ELBW N=87 BW 860 

(837-833) 

Head 

circumference,

Head

circumference 

growth velocity

ANSER Teacher 

questionnaire,

Du Paul Rating 

Scale for ADHD

Learning difficulty 

45%,

Reading problem32%

Math problems 33%, 

Spelling problem

28%,

Writing problem 29%

mmm

B

CherkesJulkowski

1998

98262696

Preterm 

N=28

Full-term 

N=20

BW 1880

BW 3318

GA Mothers’ 

perception,

Neurologic exam,

IQ

ADHD: 17 vs. 7%

Learning disabilities: 

17 vs. 14%

Language 

impairment: 3% vs. 0,

Mild neurologic 

impairment: 7% vs. 0

School concerns: 28 

vs. 21%

mmm B

Marlow

1993

8466264

Preterm N= 

51

Full-term N= 

59

BW < 1250g BW, IQ at 6 

years, motor 

skills, 

socioeconomics

Test of motor 

impairment, 

Suffolk reading 

Test, The basic 

mathematics test, 

The Schonell S1 

graded word 

spelling test and 

handwriting 

assessment.

48% of preterm 

children at 8 years of 

age have difficulty in 

one or more subjects 

compared to 19% in 

full-term. 

mmm B

Hille, den Ouden, Bauer, et al (1994) reported school performance of preterm infants (born 

1983) at 9 years of age in The Netherlands. Data were collected via questionnaires. Of the 813 

very premature infants (<32 wks or BW < 1500g) who participated in the study at 9 years of age, 

19% were in special education, 81% in mainstream education. Of the 658 children in 

mainstream education, 32% were in a grade below the level appropriate for their age and 38% 

had special assistance. Only 44% of the nondisabled, prematurely born children were in 

mainstream education at an age-appropriate level without special assistance. Perinatal risk 

factors such as GA <28 wks, BW <1250g, male gender, and socioeconomic status were 
95

significantly related to overall school outcome: 66% of infants GA <28 wks, and 55% of infants 

BW <1250g were either in a grade below their appropriate level or in special education. Twice 

as many boys than girls were in special education. Only 7% of the high socioeconomic children 

were in special education compared with 35% in low socioeconomic group. SGA, multiple 

pregnancy, congenital malformations, neonatal illness, serum bilirubin level, and thyroxine 

levels did not contribute to school outcome. Of the factors evaluated at 5 years of age, 

neuromotor delay, speech/language difficulties, behavioral problems including inattention, and 

hyperactivity were strongly associated with school performance at 9 years of age. Of the infants 

with severe developmental delay at 5 years, 98% were in a grade below their appropriate level or 

in special education compared with 20% without developmental delay. More than 50% of 

children with neuromotor or language delay required special education compared to only 10% of 

children with no delay. The majority of children needing special education at 5 years were still 

in special education at 9 years. Almost all children who performed poorly in school at 5 years 

performed poorly at 9 years. Of the children who were in mainstream education at 5 years of

age, mild developmental delay, inattention, hyperactivity, speech delay, male gender, and low 

socioeconomic status but not neonatal illness predicted need for special education at 9 years of 

age. 

Stathis, O'Callaghan, Harvey, et al. (1999) studied 87 infants weighing 500-999grams

born 1977-1986. Learning difficulty was defined as delay by at least 1 year in 1 or more areas of 

writing, reading, mathematics or spelling as reported by teachers in the ANSER questionnaire. 

Forty-five percent had learning difficulty with 32% having reading problems, 33% having 

mathematics problems, 28 % having spelling problems, and 29% having writing problems. The 

authors found that head circumference (HC) <3% and 3-10% at 8 months corrected age was 

strongly associated with school age learning problems (p = 0.004). Low head circumference 

growth velocity from birth to 4 months was also associated with learning problems at school age 

(p=0.01). Low HC at 8 months and low head growth velocity correlated significantly with low 

General Cognitive Index (GCI) at 6 years of age. However, the relationship between low HC 

and learning difficulties was independent of GCI scores. When confounding variables of 

gestational age, birth weight, maternal age, number of days on ventilator, and history of IVH 

were considered, the strength of the relationship between HC and learning difficulties again did 

not change. ADHD was evaluated by using the Du Paul Rating Scale by both the parents and 

teachers. Eighteen of 83 children (22%) were identified to have attention-deficit-hyperactivity 

disorder (ADHD). No significant association was found between HC or head growth velocity 

and ADHD. There were no normal birth weight controls for the study. However, the study does 

identify low HC at 8 months of age as an important predictor of learning disability. Study of 

school learning problems at 6 years may be too early and may miss children with more subtle 

difficulties. 

Cherkes-Julkowski (1998) studied 28 mildly preterm infants who were relatively well in their 

neonatal course and compared them with 20 full-term controls at 13, 15, 20, 30 months and 3 

years of corrected age. The preterm group consisted of children born <38 weeks (mean 48.86 ± 

21.56 days prior to term), birth weight less than 2250g, who had no congenital disorder, no ROP, 

and were discharged from the hospital prior to 42 weeks postconceptional age. Surprisingly, 

there was a significantly higher than expected incidence of minimal brain dysfunction including 

attention deficit disorder (17.8% vs. 7.1%), learning disabilities (17.8% vs. 14.2%), language 

impairment (3.5% vs. 0), mild neurologic impairment (7.1% vs. 0), and general school concerns 

(28.5% vs. 21.4%). In fact, only 25% had no concerns by Grade 5 compared to 57% in term 
96

controls. The signs of these disabilities manifested as early as 13-15 months of age and early 

identification of problems opened the possibility of early treatment. The mother’s perception of 

their infants’ competence was a sensitive marker for disabilities. Definitions of the above 

outcomes used by the authors were reasonable to enhance objectivity: “mild neurologic 

impairment” as mild impairment needing occupational therapy and no grossly abnormal motor or 

cognitive function; “learning disability” as having at least a 1.5 standard deviation discrepancy 

from IQ in 1 or more achievement areas as well as deficiency in reading, writing, spelling and 

comprehension; “school concerns” as placement in transitional first grade, formally recorded 

teacher concerns, referral and review by a multidisciplinary team. This article reinforces the 

concept that even seemingly “healthy” premature infants may have later sequelae needing special 

assistance. Major limitations of this study included small sample population and lack of 

consideration of important confounding variables.

Marlow, Roberts and Cooke (1993) studied behavioral and school outcomes of premature 

children born (1980-1981) at 8 years of age. There were 51 preterm children and 59 full-term 

controls. This study found disturbing evidence that even in the presence of normal IQ, 

premature children were much more likely to underachieve in school. On subjective and 

objective measures of school performance, 43 and 55%, respectively, performed satisfactorily in 

school compared with 71 and 81% in control children. Forty-eight percent of preterm children 

had difficulty in one or more subjects compared with 19% in controls. The teachers’ 

assessments correlated closely with testing results in reading, math and spelling. The IQ test at 6 

years also correlated with the educational tests. Both teachers and parents consistently reported 

behavior disorder in premature children, in particular restlessness, inability to settle, and 

hyperactivity. Other behaviors preterm children scored higher in were “fearful /afraid of new 

situations” (p= 0.01), “unresponsive/apathetic” (p=0.001), “poor coordination” (p= 0.001), 

“inattention” (p= 0.001), and “lack leadership” (p=0.003). Perinatal factors including 

intraventricular hemorrhages and PVL were not associated with school difficulties. Motor 

difficulties (balancing skills, ball skills) and mathematics test were best indicators of later school 

performance problems. 

Learning disabilities are difficult to identify at early school age and become more apparent 

with higher school levels. In fact, in the United States, only 28.7% of children with special 

needs are identified before the age of 5 years (Palfrey, Singer, Walker et al. 1987). Therefore, 

identification of early predictors of learning problems in VLBW infants may allow for early 

intervention.

Evidence That VLBW With Or Without Other Conditions Is 

Associated With Visual Disability (Evidence Tables 7-8)

This portion of the narrative provides evidence that VLBW infants with or without other 

conditions have increased visual disability. The narrative is organized as follows: 

1. Evidence that VLBW infants have increased visual disability 

2. Evidence that VLBW infants with ROP have visual disability

A. Visual disability related to increasing severity of ROP

B. Visual disability related to severe ROP: not treated vs. treated
97

C. Visual disability related to severe ROP: treated with cryotherapy vs. laser therapy

3. Evidence that VLBW infants with CNS abnormality have visual disability

4. Evidence that VLBW (i.e. prematurity) and/or ROP and/or CNS injury are positively 

associated with refractive error (myopia) and abnormal ocular motility (strabismus)

A. Abnormal visual function due to myopia

B. Abnormal visual function due to fixation instability (strabismus and nystagmus)

5. Evidence that VLBW infants with bronchopulmonary dysplasia and systemic 

glucocorticoid therapy have visual disability

6. Incidence of ophthalmic interventions in children with BW<1251 gm through 5 years age

Evidence That VLBW Infants Have Increased Visual Disability

Twenty-seven observational studies (Table 4.1) identified by this review clearly demonstrate 

that VLBW infants have increased visual disability compared to full term infants and that the 

risk of visual disability in VLBW infants varies inversely with gestational age (Cheung, 

Barrington, Finer, et al., 1999; Kurkinen-Raty, Koivisto, and Jouppila, 1998; O'Connor, 

Stephenson, Johnson, et al., 2002; Page, Schneeweiss, Whyte, et al., 1993; The Victorian Infant 

Collaborative Study Group, 1997; The Victorian Infant Collaborative Study Group, 1997; The 

Victorian Infant Collaborative Study Group, 1997; Vohr, Wright, Dusick, et al., 2000).

Table 4.1. Association of VLBW/Prematurity with Ophthalmology Outcomes 

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Predictors Outcome AssociationApplicabilityQuality

O’Connor

2002

21635822

505 BW : 1400

GA: 31 BW

ROP

Visual 

impairment

Blindness

mmm A

Hack 

1996

97066007

83

BW:

Sample 1: 687

Sample 2: 671

GA: 26

BW

Blindness

1982-1988

1990-1992 (10% vs 

2%)

mm A

Hack

2000

20358826

54 BW: 813

GA: 26.4 BW Blindness (1%) mmm A

Piecuch 

1997

97456215

445

BW

Sample 1: 668

Sample 2: 790

Sample 3: 842

GA

BW

IVH

Visual 

impairment mmm A

The Northern 

Neonatal 

Nursing 

Initiative Trial 

Group

1996

876 ND GABW

Visual 

impairment

Blindness (1%) m A
98

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Predictors Outcome AssociationApplicabilityQuality

Vohr

2000

20295211

1151 BW:

401-1000

Birth weight

Maternal 

disease 

(HTN)

Antenatal 

steroids

Blindness mm A

Wood

2000

20373840

283 GA: 22-25

BW: ND

GA

Gender 

Multiple 

gestation

Visual

impairment

Blindness 2% mmm A

Saigal

2001

11483807

154 BW: 835

GA: 27

BW

GA

visual 

impairment 57% mm B

Victorian

Infant

Collaborative 

study Group, 

1997

97466059

35 BW:

500-999

Ttime period 

of birth Blindness (5.6 % vs

6.2% )

mm B

Victorian

Infant

Collaborative 

study Group, 

1997

98026322

448

1985-1987

BW: 500-749

1991-1992

BW: 750-999

Prematurity/ 

LBW Blindness (4.3% vs

2.1% )

mm B

Kurfinen-Raty 

1998

98387235 156

BW :

Sample 1: 1138

Sample 2:1272

Preterm 

rupture of 

membranes

Visual 

blindness m B

Kurfinen-Raty 

2000

20284814

206

BW:

Sample 1: 1284

Sample 2: 1605

BW

GA

Antenatal 

steroids

Cord pH

Bronchopul

monary 

dysphasia

Visual 

impairment mm B

O’Shea

1997

98049056

216

BW:

Sample 1

673

Sample 2:670

Sample 3:688

BW 

GA

IVH

Blindness: (4%) mmm B

Gerdes

1995

95264241

Group 

1= 410

Group 

2= 416

BW :

700-1100g

Surfactant 

use

Visual

impairment

Blindness

mm B
99

Author, Year N Mean BW, g; GA, 

week

Baseline (Range)

Predictors Outcome AssociationApplicabilityQuality

Doyle

2001

11433066

225 GA: 23-27

BW : ND

Prematurity/ 

LBW Blindness (1.0%) mmm B

Cheung

1999

99146391

164 BW <1250

GA < 32

BW GA

Apgar score

IVH

Cardiovascul

ar and 

pulmonary 

predictors

Blindness (4 %) mm B

Emsley

1998

98238139

192 Mean BW:

Sample 1: 751.7

Sample 2: 697.1

Birth weight

GA

Blindness

Myopia

Squint

mm C

Finnstrom

1998

99041345 370 BW: 798

Retinopathy 

of 

Prematurity 

(ROP)

Visual

impairment m C

O'Connor, Stephenson, Johnson, et al. (2002) recently published their assessment of longterm (10-12 year), prospective follow-up of ophthalmic outcome of low birth weight children 

(<1701 gm) with and without ROP who were born in the mid-1980s. The cohort of former 

premature infants was compared to 11-year old controls that were born at full term. The rate of 

ophthalmic morbidity was 50.8% in the study’s premature cohort compared with 19.5% in the 

full-term control group. Ophthalmic morbidity was defined in terms of significant reduction in 

visual acuity tests (near and far acuity, contrast sensitivity) or presence of strabismus, myopia, 

color vision defect, or visual field defect. The rate of ophthalmic morbidity (i.e. greatest 

reduction in visual acuity or incidence of strabismus) was highest in eyes with severe (Stage 3 or 

4) ROP. They found that children born prematurely who had no or regressed mild ROP had 

similar visual acuities, but that the visual acuities of these premature infants were slightly, 

though significantly (p<0.001) reduced compared with full-term controls. They concluded that 

no or regressed mild ROP, by itself, had no major important long-term effect at 10-12 years of 

age on visual acuity. The premature cohort differed significantly from the full-term cohort with 

reduced visual functions (distant and near visual acuities, stereoacuity, visual field) and increased 

incidence of strabismus (19.3% vs. 3%, p<0.001) and myopia (22.4% vs. 8.9%, p<0.001). The 

prevalence of strabismus and myopia increased with increasing severity of ROP. Compromised 

stereoacuity was associated with maximum stage of ROP. All ocular dimensions were 

significantly smaller than published norms. This study shows that premature infants with or 

without ROP, and especially those with severe ROP, are at increased risk of visual impairments 

and disability compared with children who were born at full term. Visual disabilities are 

associated with low birth weight and severe ROP. Although ~55% of the original cohort was 

successfully tracked at age 10-12 years, this study is important for several reasons: 1) It is a 

geographically-defined, well-documented, population-based cohort. 2) It provides a long-term, 
100

natural history study of visual outcome in premature infants who did and did not have ROP in 

terms of acuity, myopia, strabismus, contrast sensitivity, and ocular growth. 3) It provides a 

long-term, natural history study of visual outcome in premature infants who did have severe 

ROP in an era prior to use of cryotherapy. 4) It compares ophthalmic outcome of children born 

prematurely with those born full-term. 5) It demonstrates the significant association between 

ROP, especially severe ROP, and ophthalmic morbidity and visual disability. It shows that more 

than 50% of infants born prematurely (<1701 grams) have an ophthalmic problem at 10-12 years 

of age. Some of these ophthalmic problems can be treated. This study emphasizes the fact that 

severe ROP is associated with the highest rates of visual impairments.

Hack, Friedman, and Fanaroff (1996) found that infants with 500-750 gram birth weights at 

20 months of age, the incidence of blindness was 2% for those born in 1990-92, compared to 

10% for those from 1982-88. A later study by Hack, Wilson-Costello, Friedman, et al. (2000), 

which examined the neurosensory status of ELBW infants (<1000 gm) born 1992-1995, found 

that the incidence of blindness was 1% for both birth weight strata of <750 gm and 750-999 gm. 

Piecuch, Leonard, Cooper, et al. (1997) found a similar incidence of blindness in the cohort of 

extremely premature infants (24-26 weeks gestation) followed from 1 to 4.5 years of age who 

were born during 1990-1994. One percent of these infants were blind (1/86) and 2% (2/86) had 

nystagmus related to severe ROP. Northern Neonatal Nursing Initiative Trial Group (1996) 

documented a 1% incidence of blindness in infants born less than 32 weeks gestational age in 

1990-1991 during a 2-year regional follow-up in the United Kingdom. The blindness of these 

infants was due to ROP and cortical blindness. 

Vohr, Wright, Dusick, et al. (2000) assessed multiple neurodevelopmental, neurosensory, and

functional outcomes at 18-22 months age in 1151 extremely low birth weight survivors 

(ELBW=400-1000 gm) born between 1993-1994 in 12 USA neonatal intensive care units 

(NICUs) participating in the NICHD-sponsored Neonatal Research Network. This recent, large, 

prospective study reaffirmed the strong inverse association of neurodevelopmental, 

neurosensory, and functional impairments, including visual disabilities, with gestational age. 

Visual impairment was noted in 21% of infants with birth weights 401-500 gm, 10% to 13% in 

infants with birth weights 501-800 gm, 5% in infants with birth weight 801-1000 gm. 

Specifically blindness was noted in 14% of infants with birth weights 401-500 gm, and in 1-4% 

of infants throughout the ‘100 gm’ birth weight strata from 501- 1000 gm. Overall, among 

infants between 401-1000 gm birth weight, 9% were visually impaired and 3% were legally 

blind in one or both eyes.

Saigal, Stoskopf, Streiner, et al. (2001) conducted a longitudinal cohort study of Extremely 

Low Birth Weight infants (ELBW= 5001-1000 gm) and compared neurosensory outcomes of 

ELBW infants with full term controls at 12-16 years of age. Neurosensory impairments were 

present in 28% of ELBW survivors compared to 2% of control subjects (p<0.001) Visual 

impairments were reported by participants’ parents in 57% of ELBW survivors (n=154) 

compared to 21% of control subjects (n=125) (p<0.0001, OR 5.1, 95% CI 2.88,9.05). The 

proportion of premature infants reported to have an ophthalmic problem in Saigal’s study is 

similar to that of O’Connor, although the patient population of Saigal’s study is restricted to 

higher risk ELBW infants. This study again illustrates persisting morbidity among ELBW 

survivors during adolescence and teenage years.

The following studies report the incidence of the most extreme visual disability, blindness, 

which is a smaller subset of the larger category of ‘visual impairment or disability’. The 

publications of the Victorian Infant Collaborative Study Group illustrate several important points 
101

about risk of blindness in ELBW infants (500-999 gm). First, the risk of blindness decreased 

since 1979-1980, but leveled during the 1980s and early 1990s. Second, the risk of blindness is 

higher in ELBW infants compared to normal birth weight controls. And thirdly, the risk of 

blindness is inversely related to birth weight or gestational age (The Victorian Infant 

Collaborative Study Group, 1997; The Victorian Infant Collaborative Study Group, 1997; The 

Victorian Infant Collaborative Study Group, 1997). Specifically, investigators of the Victorian 

Infants Collaborative Study Group followed ELBW infants over 3 time periods (1979-80, 1985-

87, 1991-92) and compared outcomes with normal birth weight controls. Survival and overall 

rate of disability, assessed at 2 years age, improved over the three time periods for both inborn 

and outborn ELBW infants, but the rates of disabilities were significantly greater in ELBW 

infants than in full-term controls at 2 years age. The proportion of inborn ELBW infants blind at 

2 years age was 6.7% (6/89), 4.3% (9/211) and 2.1% (5/237) in 1979-80, 1985-87, and 1991-92 

respectively. The proportion of outborn ELBW survivors assessed as blind was higher than 

inborn ELBW infants, and the incidence of blindness decreased in outborn ELBW infants from 

27.8% (n=5 of 18) to 5-6% blindness in the later two eras (1985-87: 5.6%, 1/19; 1991-92: 6.2%, 

1/16). None of the full-term controls was blind. When evaluated from the perspective of 

gestational age, the overall rates of blindness in infants born 23-27 weeks gestation was 

significantly lower in 1991-1992 (2.3%) compared with 1985-1987 (8.4%). The well-recognized 

inverse relationship of visual disability and birth weight was also demonstrated in further 

evaluation of children born in the era of 1991-1992 in which 9.3% of infants with birth weight 

between 500-749 gm had sensorineural disability (sight, hearing, cerebral palsy) in contrast to 

6.0% of infants who weighed 750-999 gm at birth. 

Two Finnish studies (Kurkinen-Raty, Koivisto, and Jouppila, 1998; Kurkinen-Raty, Koivisto, 

and Jouppila, 2000) and several American studies report incidences of blindness in premature 

infants similar to that reported in the Australian Victorian Studies. O'Shea, Klinepeter, Goldstein, 

et al. (1997) reported rates of blindness at 1-year follow-up in ELBW infants (501-800 gm) over 

three time periods spanning from 1979 through 1994. The proportion of children who sustained 

blindness were 2/24 (8%), 0/62 (0%), and 5/124 (4%) during 1979-1984, 1984-1989, 1989-1994 

respectively. Gerdes, Gerdes, Beaumont, et al. (1995) documented 2-4% incidence of blindness 

at 1 year of age in a USA cohort of premature infants (birth weight 700-1100 grams) treated with 

two different dosing regimens of surfactant (1 vs. 3 surfactant doses) and born during an era 

(1989-1990). This incidence is similar to that reported during the latest era of the Victorian 

Study. Gerdes et al also noted that 8-10% of the infants in the two surfactant study groups had 

visual defects at 1 year of age. 

Doyle, Casalaz, and The Victorian Infant Collaborative Study Group (2001) found that the 

prognosis of 5-year outcome of a geographically determined cohort of infants born between 23 

and 27 weeks of gestation during 1991-1992 in Victoria, Australia varied with gestational age, 

postnatal age, and the number of adverse events (co-morbidities). These infants were compared 

to ‘normal birth weight’ controls (BW>2499 gm). They found that the rate of survival with major 

neurosensory disability increased with decreasing ge stational age and with the number of adverse 

risk events in the NICU (intraventricular hemorrhage, cystic periventricular leukomalacia, 

surgery, postnatal glucocorticoid therapy). Similar to other studies of extremely low gestational 

age neonates, these authors found approximately 2% incidence of blindness.

Emsley, Wardle, Sims, et al. (1998) compared changes in survival and neurodevelopmental 

disability, including visual disability, between to two cohorts of extremely premature infants (23 

to 25 weeks gestational age) over time (cohort 1: 1984 to 1989 v. cohort 2: 1990 to1994. In 
102

addition to increasing survival and increasing neurodevelopmental disability over the two time 

eras, they found more survivors with blindness due to ROP (4% vs 18%), myopia (4% vs. 15%), 

and squints (8% vs. 13%) between cohort 1 (1984 to 1989) and cohort 2 (1990 to1994) 

respectively. The rise in neurodevelopmental disability was due to the rise in visual disability, 

which was related to ROP

Finnstrom, Otterblad, Sedin, et al. (1998) documented less favorable neurosensory outcome 

and growth at 3 years age in extremely premature infants (<1000 gm birth weight or >23 weeks 

gestation) born between 1990-1992 in Sweden. Four percent of the cohort had visual impairment 

at 3 years age. The visual impairment was primarily due to ROP (3% of all children), but also 

due to Candida infection and cortical blindness related to central nervous system injury. 

Kurkinen-Raty documented a 4-5% incidence of visual disability in infants born <37 weeks 

gestation (Kurkinen-Raty, Koivisto, and Jouppila, 1998) and 24-33 weeks (Kurkinen-Raty, 

Koivisto, and Jouppila, 2000) at 1 year corrected age during the period of 1990-1997. Wood, 

Marlow, Costeloe, et al. (2000) evaluated all children born ≤25 weeks gestational age in the 

United Kingdom and Ireland in 1995 at a median age of 30 months. They found that 

approximately 50% of the extremely, extreme premature infants had neurodevelopmental 

disability. Ten percent of the infants had visual disability that could not be fully corrected, and 

two percent of these infants were blind. Twenty-five percent had squint and 10 percent wore 

eyeglasses. 

In a prospective study of the relationship between apnea during hospitalization and 

subsequent growth and neurodevelopment in preterm infants (birth weight <1250 gm, and 

gestational age ≤32 weeks), Cheung, Barrington, Finer, et al. (1999) documented that the 

incidence of blindness varied inversely by birth weight (birth weight 500-749 grams: n=26: 4%; 

birth weight 750-999 grams: n=63: 2%; birth weight 1000-1249 grams: n =75: 1%).

These articles provide evidence that VLBW infants have increased visual disability and that 

the risk of visual disability in VLBW infants varies inversely with gestational age.

Evidence That VLBW Infants With Retinopathy Of Prematurity (ROP) 

Have Visual Disability

Retinopathy of Prematurity (ROP) is a proliferative, fibrovascular disease of immature retinal 

vessels, and is a leading cause of visual disability and blindness in infants. ROP is associated 

with a disruption in the normal growth and development of retinal blood vessels. The incidence 

and severity of ROP are directly related to the degree of immaturity of an infant (Cryotherapy for 

Retinopathy of Prematurity Cooperative Group, 1994; Dogru, Shirabe, Nakamura, et al., 1999; 

Palmer, Flynn, Hardy, et al., 1991; Schaffer, Palmer, Plotsky, et al., 1993). Thus, the more 

immature an infant, the greater the risk for any ROP and the greater the risk for severe ROP. 

Two thirds (66%) of infants with birth weight <1251 grams in the Multicenter Cryotherapy Trial 

for ROP had ROP, 17% developed moderately-severe ROP, and 6% developed severe 

(threshold) ROP (Palmer, Flynn, Hardy, et al., 1991).
103

Visual Disability Related To Increasing Severity Of ROP

Only 8 studies are noted in the following table (Table 4.2a). Tenstudies clearly demonstrate 

that long-term visual function (visual acuity, myopia, strabismus, etc) in VLBW infants with 

ROP is related to the severity of ROP and its treatment. Visual disability and impairments 

increase with increasing severity of ROP, even in infants with no apparent retinal residual.

Table 4.2a. Visual disability related to increasing severity of ROP in VLBW infants

Author, 

Year

N

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictors Outcome AssociationApplicabilityQuality

O’Connor

2002

21635822 505

Mean BW 

(range), g: 

1400 (iqr 

1150, 1562)

Mean GA 

(range), wk: 

31.06±3.09)

Birth weight

 ROP

Visual 

impairment

Blindness

mmm A

Cryo-ROP, 

1990, 

1996, and 

2001 (x3)

91024693, 

96180078, 

21375786,

21375787,

21375788

Repka

1998

98426775

291

BW: 800

GA: 26. 

Threshold

retinopathy 

of

prematurity

At 1year& 

5.5-year & 

10-year 

follow-up:

Cryotherapy 

vs. No 

Cryotherapy

Visual

impairment 

Blindness mm A

Dogru 

1999

99168711 78 GA: 26-28BW: 836-1016 Sever ROP

Low visual 

acuity 

scores

 m B

As noted previously, O'Connor, Stephenson et al. (2002) studied visual function in children 

born prematurely with and without ROP along with children born at full term at 10 to 12 years of 

age. They found that premature infants with or without ROP, and especially those with severe 

ROP, are at increased risk of visual impairments and disability compared with children who were 

born at full term. The rate of ophthalmic morbidity (i.e. greatest reduction in visual acuity or 

incidence of strabismus) was highest in eyes with severe (Stage 3 or 4) ROP. O’Connor et al also 

found significant differences between the premature cohort and the full-term cohort in 

prevalence of myopia and strabismus, and that each of these were significantly related to the 

severity of ROP. Compromised stereoacuity was associated with maximum stage of ROP. 
104

Similarly, Dogru et al found that infants with Stage 3 ROP had lower visual acuity compared to 

infants with Stage 1-2 ROP or no ROP at 18 to 24 months follow-up (p<0.0001). Infants who 

had regressed Stage 3 ROP are also at increased risk for myopia, astigmatism, anisometropia, 

amblyopia, and strabismus, and subnormal visual acuity. (Dogru, Shirabe, Nakamura, et al., 

1999)

One of the best studies that provides evidence that severity of ROP is related to visual 

disability is the National Eye Institute’s Multicenter Trial of Cryotherapy for ROP (CRYO ROP) 

(Cryotherapy for Retinopathy of Prematurity Cooperative Group, 1990; Cryotherapy for 

Retinopathy of Prematurity Cooperative Group, 1994; Cryotherapy for Retinopathy of 

Prematurity Cooperative Group, 1996; Cryotherapy for Retinopathy of Prematurity Cooperative 

Group, 2001; Cryotherapy for Retinopathy of Prematurity Cooperative Group, 2001). CRYO 

ROP had both a natural history study of ROP and a randomized clinical trial for infants with 

severe (threshold) ROP. The following is a summary of the long-term outcomes of the natural 

history study of CRYO ROP. The 10-year visual outcomes of infants with severe (threshold) 

ROP who were randomized in the CRYO ROP trial for threshold ROP are noted later in this 

narrative.

The natural history study of the 2759 untreated eyes of the Multicenter Trial of Cryotherapy 

for ROP (CRYO ROP) clearly demonstrated that adverse anatomical and functional outcomes 

are associated with the severity of ROP as noted by the location of the ROP process, the stage of 

ROP, the extent of the stage (i.e. number of sectors of the retina involved with ROP), and the 

presence of plus disease. The more posterior the location of acute ROP, the more advanced the 

stage of ROP, the more extensive the number of sectors of ROP, and the presence of plus disease 

are individually and collectively high risk, poor prognostic factors. The eyes at highest risk of 

unfavorable 1-year outcome were eyes with posterior Zone 1 ROP, Stage 3 ROP, and eyes with 9 

to 12 sectors in Zone II, Stage 3 ROP with plus disease. Eyes at lowest risk for unfavorable 1-

year outcome were no ROP, Zone II ROP with no plus disease, and any ROP in Zone III 

(Cryotherapy for Retinopathy of Prematurity Cooperative Group, 1994). The following table 

summarizes the proportion of eyes with unfavorable (i.e. disabling) visual function who had less 

than threshold ROP or threshold that was not treated with cryotherapy: 

Table 4.2b. Proportion (%) of eyes with unfavorable visual function

ROP (<Th or Th no treatment)

 Zone 1

 Zone 2, Stage 3+ (9-12 sectors)

 Zone 2, Stage 3+ (5-8 sectors)

 Zone 2, Stage 3+ (1-4 sectors)

 Zone 2, no + dz

 Zone 3

Abnormal 

Fixation

44

57

32

19

7

3

Nystagmus

6

39

9

11

5

2

Strabismus

25

33

30

35

16

12

Myopia (>2D)

40

63

55

46

<25

3

 No ROP 1 <1 6 3

Visual Disability Related To Severe (Threshold) ROP: (Treated and Not Treated)

Table 4.3 summarizes the functional outcomes throughout the 10-year follow-up of the eyes 

with severe ROP that did and did not have retinal ablation with cryotherapy.
105

Table 4.3. Unfavorable functional outcome (%) in eyes with threshold ROP by randomized 

treatment assignment (cryotherapy vs. no cryotherapy) during 1, 3.5, 5.5, and 10-year follow-up.

1 YR 3.5 YR 5.5 YR 10 YR

N examined/

Original 

number

246/291 236/291 234/291 255/291

 

Threshold ROP 

with 

Cryotherapy

Grating Acuity 

35% 

Blind 32% 

Grating Acuity (TAC) 26.1%

Recognition Acuity (HOTV) 

46.6%

Blind 37% (among eyes 

tested with HOTV)

Acuity 

47.1%

Blind 

31.5%

Distance acuity 

44.4%

Near acuity 42.5%

Contrast sensitivity 

39.7%

Threshold ROP 

with No 

Cryotherapy

Grating Acuity 

56% 

Blind 51% 

Grating Acuity (TAC) 

45.4%

Recognition Acuity (HOTV) 

57.5%

Blind 53% (among eyes 

tested with HOTV)

Acuity 

61.7%

Blind 48%

Distance acuity 

62.1% 

Near acuity 61.6%

Contrast sensitivity 

59.3%

The CRYO ROP Trial (table 4.2b) is the largest, prospective, longitudinal study of 

ophthalmic outcome of premature infants with severe (threshold) ROP in the USA (Cryotherapy 

for Retinopathy of Prematurity Cooperative Group, 1990; Cryotherapy for Retinopathy of 

Prematurity Cooperative Group, 1994; Cryotherapy for Retinopathy of Prematurity Cooperative 

Group, 1996; Cryotherapy for Retinopathy of Prematurity Cooperative Group, 2001; 

Cryotherapy for Retinopathy of Prematurity Cooperative Group, 2001; Cryotherapy for 

Retinopathy of Prematurity Cooperative Group, 2001). This NEI-sponsored multicenter trial 

began in 1986 to provide critical information regarding the natural history of ROP, as noted 

above (Cryotherapy for Retinopathy of Prematurity Cooperative Group, 1994), and to determine 

whether retinal ablation with cryotherapy for severe or ‘threshold’ ROP was beneficial in 

reducing retinal detachment and unfavorable retinal outcome. Threshold ROP was defined by the 

CRYO ROP trial as ≥5 contiguous or 8 cumulative clock hours of Stage 3 ROP with plus disease 

in Zone II. CRYO ROP confirmed the effectiveness and benefit of retinal ablation with 

cryotherapy for threshold ROP (versus no treatment) in terms of structural and functional 

outcomes at 1 yr, 3.5 yr, 5 yr, and 10 yr follow up (Cryotherapy for Retinopathy of Prematurity 

Cooperative Group, 1990; Cryotherapy for Retinopathy of Prematurity Cooperative Group, 

1996; Cryotherapy for Retinopathy of Prematurity Cooperative Group, 2001; Cryotherapy for 

Retinopathy of Prematurity Cooperative Group, 2001). ‘Unfavorable’ structural and functional 

outcomes included infants with poor visual function or blindness. Thus, unfavorable outcome 

represents extreme visual disability. Children with subnormal or normal vision were included in 

the ‘favorable’ outcome category. Functional outcomes at 10-years’ follow-up of infants with 

threshold ROP (with and without cryotherapy) include visual acuity (Cryotherapy for 

Retinopathy of Prematurity Cooperative Group, 2001), visual fields (Cryotherapy for 

Retinopathy of Prematurity Cooperative Group, 2001), and contrast sensitivity (Cryotherapy for 
106

Retinopathy of Prematurity Cooperative Group, 2001). This exceptional, successful effort of 

long-term tracking of high-risk infants vividly illustrates that ROP and its consequences are lifelong and dynamic, not stagnant. 

The important findings of the CRYO ROP natural history study and randomized cryotherapy 

trial can be summarized as follows:

• The more severe the acute ROP, the greater the risk for unfavorable ophthalmic outcome 

(i.e. visual function as well as late retinal and non-retinal complications). The increased 

risk for unfavorable outcome includes ROP that is moderately severe but less severe than 

threshold ROP, and thus never met study criteria for randomization for cryotherapy. The 

increased risk of unfavorable ophthalmic outcome was particularly true of ROP in Zone 

1, Stage 3 ROP, and ROP with plus disease. The increased risk reflects the underlying 

severity of the retinal damage, and the consequences of disruption in normal growth and 

development of the retinal vessels. As a point of reference, Myers, Gidlewski, Quinn, et 

al. (1999) found that 99% of normal full-term children (n=106) had normal visual acuity 

(classified as 20/40 or better). 

• Cryotherapy significantly reduced the incidence of blindness and unfavorable outcome, 

especially in Zone 2 threshold eyes. Despite this benefit, infants successfully treated with 

cryotherapy still had an unacceptably high risk of unfavorable functional outcome (44.4% 

of treated eyes). Again, unfavorable outcome was particularly true in eyes with Zone 1 

threshold ROP regardless of whether or not the eye received cryotherapy (i.e. poor 

outcome in 75% of zone 1 treated eyes and 92% of not treated eyes). As noted above, the 

unfavorable outcome of successfully treated eyes is most likely a reflection of the 

severity of the underlying retinal injury and of the disruption in normal growth and 

development of the retina.

• The 10-year follow-up revealed that the rate of retinal detachment among control (no 

cryotherapy) threshold eyes increased at 5.5 years (38.6%) and again at 10 years age 

(41.4%), after having been ‘stable’ during the first 3 years of follow-up. The rate of 

retinal detachment remained stable in treated eyes (22.0%).

• Visual fields: Eyes with severe ROP and not treated, have smaller visual fields by 27% to 

35% compared to eyes that never had ROP. Eyes treated with cryotherapy had a further 

reduction in the visual fields by 7%. 

• Contrast sensitivity: Eyes treated with cryotherapy had a 33.1% reduction in unfavorable 

outcome in terms of contrast sensitivity compared to control “no cryotherapy’ eyes 

(cryotherapy 39.7% vs control 59.3%). Unfavorable contrast sensitivity was defined as 

correct identification of <26 letters on the Pelli-Robson chart or blind. Favorable outcome 

included children who had normal or below normal contrast sensitivity (normal correct 

identification of 33 or more letters on the Pelli-Robson chart or roughly equivalent to a 

CS of 1.50 lu; below normal = detection of 27-32 letters (~1.2- to 1.5 lu)). Contrast 

sensitivity was outside the normal range in 3.1% of ‘no ROP’ eyes, 51.9% of cryotherapy 

eyes, and 65.4% of control ‘no treatment’ threshold eyes. Thus, with or without 

cryotherapy, eyes with threshold ROP had significantly worse color sensitivity than eyes 
107

that never had ROP. Comparison of eyes in patients with bilateral threshold ROP showed 

that cryotherapy had no apparent adverse effect on contrast sensitivity at 10 years followup. As a point of reference, Myers, Gidlewski, Quinn, et al. (1999) found that 4% of 

normal full-term children (n=106) had visual acuity outside the normal range. 

• At the 10-year outcome, treated and control threshold eyes are equally likely to have 

20/40 visual acuity, but this is the minority of threshold eyes.

• Retinal ablative therapy (cryotherapy or laser therapy) for threshold ROP is cost effective 

therapy that can improve the quality of life. 

Visual Disability Related To Severe (Threshold) ROP: (Treated With Cryotherapy 

Vs. Laser Therapy)

Table 4.4 summarizes the functional outcomes throughout the 10-year follow-up of the eyes 

with severe ROP that did and did not have retinal ablation with cryotherapy. 

Table 4.4. Visual disability related to severe (threshold) ROP

Author,

Year

Eyes 

Treated

(N)

Mean 

BW, g; 

GA, week

Baseline 

(Range)

InterventionOutcomes Efficacy Applica

-bility Quality

Myopia Diode Laser 

Eyes: 40%

Cryotherapy 

Eyes: 92%

Hypermetropia 

<+3.0 

Diopters

Diode Laser 

Eyes: 60%

Cryotherapy 

Eyes: 8%

B

Algawi 

1994

95001766

53 BW: 620-

1500 

GA: 24-32

Diode 

Laser: 21 

Eyes

Cryotherap

y: 32 Eyes

Clinical 

significant 

astigmatism

Diode Laser 

Eyes: 33%

Cryotherapy 

Eyes: 20%

 m

Myopia (mean 

spherical 

equivalent)

Laser Eyes: -3.05

Diopters

Cryotherapy 

Eyes: -5.08

Diopters

Connolly 

1998

98426776

46 BW: 731 

(440-

1318) GA: 

25 (23-

.32)

Laser: 23 

Eyes

- Argon 

(10)

- Diode 

(13)

Cryotherap

y: 23 Eyes

Visual Acuity 

20/50 or 

better

Laser Eyes: 81%

Cryotherapy 

Eyes: 38%

mm B
108

Author,

Year

Eyes 

Treated

(N)

Mean 

BW, g; 

GA, week

Baseline 

(Range)

InterventionOutcomes Efficacy Applica

-bility Quality

Unfavorable 

structural 

outcome

Diode Laser 

Eyes: 0%

Cryotherapy 

Eyes: 22%

Geometric 

visual acuity

Diode Laser 

Eyes: 20/33

(20/20-20/70)

Cryotherapy 

Eyes: 20/133

(20/25-phthisis)

Shalev 

2001

21331013

19 BW: 631 

(540-846) 

GA: 25 

(23-27)

Diode 

Laser: 10 

Eyes

Cryotherap

y: 9 Eyes

Mean refractive 

error

Diode Laser 

Eyes: -6.50 

Diopters

Cryotherapy 

Eyes: -8.25 

Diopters

 mmm B

Retinal ablation for threshold ROP with laser photocoagulation has emerged as an effective 

alternative to cryotherapy in preventing retinal detachment. The following studies have evaluated 

long-term ophthalmic outcome of cryotherapy versus laser therapy for treatment of severe 

(threshold) ROP. 

Algawi, Goggin, and O'Keefe (1994) evaluated ophthalmic outcome following diode laser 

versus cryotherapy for threshold ROP (CRYO ROP definition). The incidence of refractive error 

(myopia) is high in infants with threshold ROP regardless of whether they were treated with laser 

or cryotherapy. Algawi’s study demonstrated that threshold ROP treated with laser (n=15 eyes) 

had less myopia (40%, range –1.5 to -3.5 D) than eyes treated with cryotherapy (n=25 eyes) 

(92%, range -0.5 to –8. D)(p<0.0006). However, the cryotherapy group had less hypermetropia 

than the laser group (cryotherapy 8% vs laser: 60% at <+3.0 D, p<0.006). The authors concluded 

that myopia was a major complication of premature infants, especially in premature infants with 

severe ROP, and that laser therapy can reduce the risk and/ or severity of myopia. Any reduction 

in myopia is important in terms of long-term visual benefit. Connolly, McNamara, Sharma, et al. 

(1998) compared laser photocoagulation with trans-scleral cryotherapy in treatment of threshold 

ROP to determine if laser therapy resulted in better visual outcomes of eyes with threshold ROP. 

Twenty-five of 52 eyes randomized to cryotherapy vs. laser were assessed at 5.8 years (range 4.3 

– 7.6 yrs). The odds that a threshold eye treated with laser had a good clinical outcome were 6.91 

x greater than cryotherapy (95% CI 1.7-28.0,n=21), and laser treated eyes were less myopic 

(mean SE –3.05 D) than cryotherapy treated eyes (mean SE –5.08 D) (p=0.0072, n=23). The 

authors concluded that laser therapy was more likely to result in better visual acuity and less 

myopia compared to cyrotherapy. Shalev, Farr, and Repka (2001) randomized threshold ROP 

eyes to laser vs. cryotherapy and reassessed the visual outcome in 10 of 19 patients at 7 years. 

Laser therapy had more favorable outcome in terms of geometric mean visual acuity (laser 

20/33, range 20/20-20/70 vs. cryotherapy 20/133, range 20/25 to phthsis) (p=0.03). The mean 

refractive error of laser-treated eyes was -6.5 D (+1.25-12.75D) compared to –8.25 D (-0.25 to –
109

16.00) for cryotherapy-treated eyes. The 7-year assessment showed little change from the 3-year 

outcome. 

Evidence That VLBW Infants With CNS Abnormality Have Visual 

Disability (With No Or Mild ROP)

Six studies (Table 4.5) demonstrated that VLBW infants are also at increased risk for nonretinal ophthalmic diseases. Cortical visual impairment is visual impairment due to CNS damage 

to the optic radiation, striate cortex, and peristriate cortex (Hoyt and Good, 2001). Causes of 

cortical visual impairment in VLBW infants include hypoxic-ischemic-hemorrhagic and /or 

inflammatory injury (antenatal, perinatal, or postnatal) which may be manifested in the neonatal 

period as periventricular leukomalacia (echodense, echolucent, cystic), ventriculomegaly, 

intracranial hemorrhage, and posthemorrhagic hydrocephalus. 

Table 4.5. Evidence that VLBW infants with CNS abnormality have visual disability (with no or 

mild ROP)

Author, 

Year

N

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictors Outcome AssociationApplicability Quality

Lefebvre

1998

98387703

121

Mean BW: 

961+179g 

 (585-1450

Neurobiologic 

risk score Blindness mm A

Cioni

2000

10685987

29 BW: ND

GA: 31(24-36) PVL 

Multiple visual 

function

Abnormalities. (50 %) mm B

Wilkinson

1996

97087405

10

Mean BW: 114 

(range 700-

1725) g

PVL

Visual 

impairment

Blindness

mmm B

Pennefather 

1999

20002011 558 GA: < 32

ROP severity

GA in 

Preterm 

infants

Visual 

impairment

Cicatricial 

ROP

Strabismus

mmm B

Foreman 

1997

97271716 16 BW: 1413GA: 29

Prematurity/ 

LBW

Visual-motor

Visual –

perceptual 

skill

m B

Lefebvre, Gregoire, Dubois, et al. (1998) studied all infants less than 28 weeks gestational 

age who were born between 1987 and 1992 at Hopital Sainte-Justine and had three timed-cranial 
110

ultrasounds. They demonstrated that a Neurobiologic Risk Score, which was based on 

pulmonary, neurologic (seizures, IVH, PVL), infection, and hypoglycemia variables obtained 

during the NICU hospitalization, was significantly correlated with neurodevelopmental 

quotients, cerebral palsy, and other neurosensory disabilities, including visual-motor (eye-hand) 

coordination, i.e. the higher the score the worse the outcome

Neuroimaging of very low birth weight infants via cranial ultrasonography (US), cranial 

tomography (CT), and magnetic resonance imaging (MRI) techniques has provided strong 

evidence that central nervous system injury, especially periventricular leukomalacia, is 

associated with visual disability and other neurodevelopmental abnormalities, including motor 

and perceptual abnormalities. Visual disability is associated with abnormal MRI imaging in the 

postchiasmatic visual pathway, particularly the optic radiation and visual cortex. The 

concomitant occurrence of visual impairment with neurodevelopmental disability in premature 

infants is well documented and not surprising. Cioni, Bertuccelli, Boldrini, et al. (2000) showed 

that the degree of cerebral visual impairment (number of abnormal visual function tests) at 1 year 

of age was strongly associated with the degree of neurodevelopmental impairment at 1 year of 

age and with the extent of MRI evidence of cerebral white matter damage at full-term age. The 

degree of visual impairment was, in fact, the strongest independent determinant of 

neurodevelopmental scores in children born prematurely who had PVL and abnormal 

neurological examination at full-term equivalent. The degree of visual impairment at 1 year of 

age was also significantly associated with general developmental quotient at 3 years of age. 

Twenty-three of 29 (79%) children, who were born premature, developed PVL, and had 

abnormal neurological examination at full-term equivalent, had at least one abnormality of visual 

function at 1 year of age, and more than 50% had multiple abnormalities in visual function. 

Abnormal visual function was manifested in multiple ophthalmic outcomes, including abnormal 

visual acuity, ocular motility, and visual evoked potentials, as well as presence of strabismus and 

visual field deficits (Cioni, Bertuccelli, Boldrini, et al., 2000). This study illustrates the 

importance of assessing various aspects of visual function as well as the importance of a 

comprehensive neurodevelopmental assessment of children with a history of cerebral white 

matter damage. 

Whitaker, Feldman, Van Rossem, et al. (1996) conducted a 6-year follow-up, populationbased study in Central New Jersey of low birth weight infants (LBW = 501-2000 g, born 1984-

1987) that examined the independent relationship of cranial ultrasound abnormalities to 

cognitive outcomes at school age. This study not only confirmed that cerebral white matter 

damage, defined as periventricular leukomalacia (PVL) and/or ventricular enlargement (VE), is 

strongly associated with mental retardation and cerebral palsy, but that PVL/VE had a 

significant, independent effect on three measures of visual perceptual organization (abstract 

visual reasoning, visual-motor integration, visual perceptual skills). In fact, among LBW infants 

with normal intelligence quotient (IQ), those with PVL/VE performed significantly worse 

specifically on visual perceptual organization compared to children who had had no evidence of 

PVL/VE.

Wilkinson, Bear, Smith, et al. (1996) evaluated the neurological outcome of a cohort of 

surviving premature infants (n=10) born weighing <1500 grams during 1989-1990 who 

subsequently developed severe cystic periventricular leukomalacia. The 10 infants were 

evaluated at a mean corrected age of 27.3 months (range 13-50 months). All 10 infants (100%) 

with severe PVL had global developmental delay, quadriparesis, and evidence of visual 

impairment. 
111

Pennefather and Tin (2000) demonstrated that the ophthalmic outcome of VLBW infants 

may be affected by the presence of brain injury, such as white matter damage, in conjunction 

with or independent of ROP. Children with cerebral palsy (CP), who were <32 weeks gestation 

at birth and examined at 2 years of age, had a higher incidence of ocular abnormalities compared 

to preterm infants without cerebral palsy. Two-thirds (66.7%) of former premature infants with 

CP had significant ocular abnormality on examination at 2 years of age in contrast to only 20% 

of former preterm infants without CP. The following specific visual outcomes were documented 

in former preterm infants with CP vs. former preterm infants without CP (respectively): severe 

visual impairment (sufficient to cause nystagmus) was found in 16.7% of former preterm infants 

with CP vs. 0.6% in former preterm infants without CP: cicatricial ROP was present in 14.8% 

with CP vs. 1.6% without CP (p<0.0001): cortical visual impairment was found in 11.1% with 

CP vs. 0.2% without CP (p<0.0001): concomitant strabismus was present in 51.9% with CP vs. 

8.4% without CP (p<0.0001). 

Foreman, Fielder, Minshell, et al. (1997) evaluated visual-perceptual, attentional, and visualmotor skills in a highly-select group of school-age children, who were born at 27-32 weeks 

gestation and performed normally on all standard pediatric screening tests. This preterm cohort 

was compared to healthy children who were born at full term. The healthy, former preterm 

infants performed poorly on two measures of visual-motor skills at school age, but well on most 

tests of visual perception. This study is important because it illustrates that even in healthy 

preterm children with no detectable neurodevelopmental problems on screening examinations, 

may in fact have visual-motor disabilities when these functions are specifically tested.

Evidence That VLBW (i.e. Prematurity) and/or ROP and/or CNS Injury 

Are Positively Associated With Refractive Error (Myopia) And Ocular 

Motility (Strabismus)

Myopia in Premature Infants

There is long-standing evidence that the risk and degree of myopia increases with the degree 

of prematurity, degree of ROP severity, and with central nervous system injury (Algawi, Goggin, 

and O'Keefe, 1994; Connolly, McNamara, Sharma, et al., 1998; Cryotherapy for Retinopathy of 

Prematurity Cooperative Group, 1994; Emsley, Wardle, Sims, et al., 1998; Ling, Fleck, Wright, 

et al., 1995; O'Connor, Stephenson, Johnson, et al., 2002; Page, Schneeweiss, Whyte, et al., 

1993; Repka, Summers, Palmer, et al., 1998; Shalev, Farr, and Repka, 2001) (CRYO ROP 3.5 

year outcome). Myopia is the most common ophthalmic sequelae of premature infants and 

requires optical correction. (Table 4.6)

Table 4.6. VLBW and/or ROP and/or CNS injury are positively associated with refractive error 

(myopia) and ocular motility (strabismus).

Author, 

Year

N

Mean BW, 

g; GA, 

week

Baseline 

Predictors Outcome AssociationApplicability Quality
112

Author, 

Year

N

Mean BW, 

g; GA, 

week

Baseline 

Predictors Outcome AssociationApplicability Quality

O’Connor,

2002

21635822

505 BW : 1400 

GA: 31

BW

ROP

Visual 

impairment

Blindness

mmm A

Cryo-ROP 

1990

91024693

291 BW: 800

GA: 26. 

Threshold

Retinopathy 

Of

Prematurity

At 5.5-year & 

10-year followup:

Cryotherapy vs. 

No Cryotherapy

Visual 

impairment 

Blindness

mm A

Cryo-ROP 

1993

93191597 

291 BW: 800

GA: 26. 

Threshold

Retinopathy of

Prematurity

At 5.5-year & 

10-year followup:

Cryotherapy vs. 

No Cryotherapy

Visual 

impairment 

Blindness

mm A

Page

1993

94051493

190 GA: 27 

BW: 942 

ROP severity Myopia severity

Odds of myopia mm B

Page, Schneeweiss, Whyte, et al. (1993) found that 16% incidence of myopia at 12 months 

(4.5% had severe myopia (>4.0 diopters) in a cohort of children born <1250 grams (18/110). 

The authors noted that the greater the degree of prematurity, the greater the incidence of myopia 

at 12 months corrected age. Children with birth weight <751 grams were 3.2 times more likely 

than 750-1000 grams to develop myopia in first year. Children with birth weight <751 grams 

were 10 times more likely than children with birth weight 1000-1250 gm to develop myopia in 

first year. Furthermore, the likelihood of myopia at 12 months age doubled with each increment 

of ROP stage. As a point of comparison, Page et al reported that approximately 10% of the 

general population develop myopia during childhood. Furthermore, the severity of myopia may 

progress over time. More than 80% of the 50 children evaluated at 24 months age, demonstrated 

deteriorating vision as demonstrated by the fact that myopia increased from 16% to 38% (4.5% 

to 24% with severe myopia) and strabismus increased. Other adverse ophthalmic outcomes, such 

as astigmatism and anisometropia, were highly correlated with severe myopia. All children who 

had had Grade III or IV intraventricular hemorrhage developed esotropia. Among premature 

infants with birth weight <1251 grams, 24% to 57% of infants with ROP may have myopia at 24 

months age. There were higher rates of myopia with increasing severity of acute ROP (2.9% No 
113

ROP; 40% for more severe ROP). This study illustrates the significant and independent 

contributions of prematurity, ROP, and central nervous system injury in the development of 

visual disability in terms of myopia and strabismus.

O'Connor, Stephenson, Johnson, et al. (2002) demonstrated that the smaller ocular 

dimensions, due to disrupted and reduced ocular growth in children born prematurely who had 

no or mild ROP, contributed to myopia in premature infants.

Among children with threshold ROP in the CRYO ROP randomized trial, myopia was high 

in both threshold ROP groups regardless of treatment. As reported in both the 1-year and 3.5-

year follow-up studies, more treated eyes than control eyes could be refracted (due to media 

opacification and disruption in control eyes) (Cryotherapy for Retinopathy of Prematurity 

Cooperative Group, 1990; Cryotherapy for Retinopathy of Prematurity Cooperative Group 

1993).

Abnormal Visual Function Due To Fixation Instability (Nystagmus And 

Strabismus)

There is a strong positive association between the occurrence of strabismus and the degree of 

prematurity, the severity of ROP, abnormal cranial ultrasounds and neurodevelopmental 

abnormality, especially CP (Page, Schneeweiss, Whyte, et al., 1993; Pennefather, Clarke, Strong, 

et al., 1999; Pennefather and Tin, 2000) (Table 4.7). The presence of strabismus and nystagmus 

implies a central nervous system component or insult, which may or may not be independent of 

ROP. The ocular misalignments may result from CNS injury and/or as a direct result of retinal 

disease (e.g. ROP) and its treatment. The reported incidence of strabismus ranges from 3% in 

premature infants with no ROP to 34% in patients with regressed ROP. 

Table 4.7. Abnormal visual function due to fixation instability (nystagmus and strabismus) in 

VLBW infants

Author, 

Year

N

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictors Outcome Association Applicability Quality

Page

1993

94051493

190

GA: 27 (23-32)

BW: 942 (400-

1250)

ROP severity Myopia severity

Odds of Myopia mm B

Pennefather 

1999

20002011

Pennefather 

2000

20217908

558 GA: < 32 ROP severity

GA

Visual impairment

Cicatricial ROP

Strabismus

CP

mmm B

Page, Schneeweiss, Whyte, et al. (1993) reported that strabismus occurred in 6% of 

premature infants <1251 grams with no ROP, and in 38% of infants with Stage 3 ROP by 12 
114

months age. Strabismus continued to increase in frequency through second year (62% of Stage 3 

ROP had esotropia, which required surgical correction of esotropia). Among children with Grade 

III or IV IVH, 100% had strabismus (esotropia).

Pennefather, Clarke, Strong, et al. (1999) evaluated the risk factors for strabismus, diagnosed 

at 2 years of age, in children born <32 weeks gestation. Strabismus was present in 12.5% of this 

premature cohort. Strabismus increased with decreasing gestational age and with increasing 

severity of acute ROP. The increased risk of strabismus was independently associated with 

cicatricial ROP, refractive error, and poor neurodevelopment and cerebral palsy (particularly 

impaired motor skills and hand-eye coordination), and family history of strabismus. In 

Pennefather’s cohort, gestational age and regressed acute ROP were not independent risk factors 

associated with strabismus once the other independent factors noted above were considered.

Evidence That VLBW Plus Bronchopulmonary Dysplasia (BPD) And 

Systemic Glucocorticosteroid Therapy For Bronchopulmonary 

Dysplasia Are Associated Visual Disability

Ophthalmic examinations revealed that premature infants with BPD (neonatal chronic lung 

disease) and no detectable severe neonatal neurological abnormalities and no ROP > Stage 2) 

(mean GA 27.1 ±1.9 wk; mean BW 984 ± 299 gm) had greater incidence of strabismus and high 

refractive error compared to premature infants with hyaline membrane disease but no BPD 

(mean GA 30.5±2.5 wk; mean BW 1492 ± 475 gm) and healthy preterm infants (mean GA 32.4 

±1.6; mean BW 1746±372). Also, recognition acuity (i.e. skills required to perform a 

recognition-acuity task) was worse in the BPD and HMD groups vs. the healthy preterm group at 

36 and 48 corrected months age (significant at 36 months age). Grating acuity and visual field 

test did not differ among the 3 groups through 4 years age (Harvey, Dobson, and Luna, 1997).

The Victorian Infant Collaborative Study Group (2000) evaluated the association between 

postnatal corticosteroid therapy and sensorineural outcome in extremely premature infants 

(ELBW infants <1000 grams or <28 weeks gestation) born in Victoria, Australia 1991-1992. At 

5 years of age, 98 survivors treated with postnatal systemic glucocorticosteroids had significantly 

higher rates of blindness (steroids 5.2% v. no steroids 0.5%) (p<0.02), in addition to significantly 

higher rates of cerebral palsy and lower intelligence quotients. In the Victorian study, extreme 

prematurity, brain injury, ROP, BPD, and glucocorticoid therapy individually and/or collectively 

have an impact on visual disability.
115

Table 4.8. Association between VLBW plus bronchopulmonary dysplasia (BPD) and systemic 

glucocorticosteroid therapy for bronchopulmonary dysplasia with visual disability

Author/ 

Year

Eyes 

Treated

(N)

Mean BW, g; 

GA, week

Baseline 

(Range)

Intervention Outcomes Efficacy ApplicabilityQuality

Victorian 

Infant 

Collaborative 

study Group, 

2000

20307288

346

GA : 

Sample 1: 26

Sample 2: 27

BW :

Sample 1: 797

Sample 2: 932

Preterm

infants(120):

treated with 

corticosteroi

ds

infants not 

treated with 

corticosteroi

ds (226)

Blindness

Cortocosteroids 

group

5.2% 

No

Cortocosteroids 

group 

0.5%

P<0.02

mm B

Evidence That VLBW Infants Have Increased Incidence Of Ophthalmic 

Interventions Due To Visual Disability

Repka, Summers, Palmer, et al. (1998) evaluated the number of ophthalmic interventions due 

to ophthalmic disability required by children in the CRYO ROP trial through 5.5 years of age. 

He compared children with threshold ROP randomized in the CRYO ROP trial to children with 

varying degrees of ROP, of which 69 of 1208 had untreated threshold ROP. The frequency of 

ophthalmic surgical and medical therapies was higher in infants with threshold ROP who had 

cryotherapy (0.9 interventions per child) compared to children with other ROP and no 

cryotherapy (0.4 interventions per child). They demonstrated that children who had ROP are at 

even greater risk for long-term ophthalmic sequelae in terms of anatomic and functional 

problems, and thus need close ophthalmic evaluation and interventions. The most common 

treatments conducted on the randomized threshold ROP children were vitrectomy (26%), 

lensectomy (18%), amblyopia therapy (20%), strabismus surgery (10%), and infrequent cataract 

surgery (2%). In contrast, for the “other ROP/ no cryotherapy” group, the most common 

treatments performed were strabismus surgery (6%), and amblyopia therapy (7%). Late retinal 

detachments and glaucoma are additional potential late sequelae in children who had ROP as 

premature infants. Amblyopia therapy increased with increasing severity of ROP (3% in children 

with no ROP; 26% % in children with severe ROP). This study illustrates that the frequency of 

procedures to correct visual disability increases with severity of ROP. Long-term costs of both 

extreme prematurity and ROP include not only the initial ablative therapy for ROP and 

individual/family/societal loss due to vision impairment and blindness, but ongoing costs of 

caring for eye problems in children who were VLBW. Expenses include doctor’s office visits, 

time lost from work, eyeglasses, surgery, and special education.
116

Evidence That VLBW With Or Without Other Conditions Is 

Associated With Pulmonary Disability (Evidence Table 9)

This portion of the narrative examines the evidence that VLBW infants with or without other 

conditions have increased long-term, pulmonary disability. This narrative is organized as 

follows: 

1. Bronchopulmonary dysplasia: definition, background, and significance 

2. Pulmonary outcome measures

3. Evidence that VLBW is associated with pulmonary disability by duration of pulmonary 

follow-up 

4. Evidence that VLBW with BPD is associated with respiratory symptoms, use of 

respiratory medications, abnormal pulmonary function and exercise intolerance

5. Evidence that VLBW with BPD is associated with airway hyperreactivity, asthma

6. Evidence that VLBW with BPD is associated with rehospitalization

7. Evidence that VLBW infants with BPD is associated with long-term cognitive and /or 

motor disability

Bronchopulmonary Dysplasia (BPD): Definition, Background, And 

Significance

Bronchopulmonary dysplasia (BPD) is a chronic disease of the lung that effects almost 

exclusively premature infants. It is the most common chronic lung condition in childhood with 

the exception of asthma. The development of BPD occurs in infants who have immature lungs 

and/or require prolonged mechanical ventilation. BPD effects the entire tracheobronchialpulmonary tree. BPD is thought to be the consequence of injury to an immature lung and 

subsequent aberrant healing and development that follow injury. Advances in the care of VLBW 

infants over the last ten years have included many measures that have reduced the lethality and 

severity of BPD. Such advances include: widespread acceptance of antenatal glucocorticoid 

therapy, surfactant replacement therapy, improved techniques for mechanical ventilation, 

improved understanding of the role of mechanical ventilation in injuring the lung, improved 

nutritional support, and reduction in infectious complications of NICU care. Together these 

measures have reduced lung injury and subsequent BPD in more mature premature infants, i.e., 

gestational age greater than 30 weeks and birth weight greater than 1200 grams. However, a new 

population of infants born at less than 28 weeks gestational age and birth weight less than 1,000 

grams is at greatest risk for BPD due to improved survival of extremely premature infants over 

the last ten to fifteen years. The advances in care have not been sufficient to prevent the 

development of BPD in this new population. Thus there has been a shift in the population at risk 

for BPD. 

The reported incidences of BPD also depend upon the definitions of BPD, neonatal care 

practices, and the characteristics of the study population. There is no consensus on a single 

definition of BPD. The most commonly used definitions of BPD are based on need for 

supplemental oxygen at 28 days age or at 36 weeks postmenstrual age (PMA), with or without 

radiologic changes consistent with chronic lung injury at each of these time points. The BPD 
117

definitions by Shennan, Dunn, Ohlsson, et al. (1988) and by the recent NICHD/NHLBI BPD 

Workshop in June 2000 (Ehrenkranz and Walsh-Sukys, 2001) have diagnostic and prognostic 

importance. Shennan and associates’ definition requires specific abnormal physical findings, a 

characteristic chest radiograph and the requirement for supplemental oxygen, all at 36 weeks 

PMA. Children who meet this definition of BPD have a high chance of respiratory symptoms 

throughout the first year of life, rehospitalization for respiratory- related illnesses during the first 

year of life and abnormal formal pulmonary function studies at two years of age. The BPD 

definition from the recent NICHD/ NHLBI workshop is a severity-based definition of BPD. It is 

likely that this severity based definition for infants with gestational age less than 32 weeks and 

birth weight below 1,000 grams will be predictive of both pulmonary and neurodevelopmental 

outcome. 

The incidence and severity of BPD are inversely related to gestational age and birth weight. 

Data from the Vermont-Oxford Neonatal Network for 2000 (Vermont Oxford Neonatal Network 

Annual Report, 2000) are shown in Table 1 and provide a recent example of the clear 

relationship between birth weight and occurrence of BPD.

Table 5.1. Percent of infants with BPD* in Relation to Birth Weight

 in the Vermont Oxford Neonatal Network

Birth weight (g) Percent with BPD

501-600 74%

601-700 62%

701-800 51%

801-900 44%

901-1000 32%

1001-1100 26%

1101-1200 18%

1201-1300 14%

1301-1400 11%

1401-1500 8%

*BPD was defined as a requirement for supplemental oxygen at 36 weeks PCA. Data are from 352 NICUs reporting on 29,177 

live births with birth weights between 501 and 1500 grams.

Pulmonary Outcome Measures

Among the studies examined within this review, long-term pulmonary disability is assessed 

in numerous ways including formal measurement of pulmonary function and /or airway hyperreactivity and clinical evidence of pulmonary impairment. Outcome measures for clinical 

evidence of pulmonary disability include presence of respiratory symptoms: recurrent wheezing, 

asthma, cough, recurrent bronchitis, pneumonia or other respiratory infections, exercise 

intolerance, chronic supplemental oxygen requirement, need for respiratory medications, and
118

recurrent hospitalization primarily for respiratory reasons. All of these signs, symptoms, and 

problems indicate an underlying chronic lung disease.

Evidence That VLBW With BPD Is Associated With Long-Term 

Pulmonary Morbidity And Disability By Duration Of Follow-Up

Due to the fact the many of the studies reviewed contain multiple pulmonary outcomes 

measures and the fact that the clinical relevance of the findings is influenced by the timing of the 

follow-up evaluation, the evidence is initially presented according to duration of follow-up. 

1- 2 year follow-up 

Nine randomized controlled trials and nonrandomized comparison studies provided evidence 

that VLBW with BPD is associated pulmonary morbidity and dis ability at 1-2 year follow-up: 

(Table 5.2a) 

Table 5.2a. VLBW with BPD is associated with long-term pulmonary morbidity and disability by 

1-2 year of follow-up.

Author,

Year

N

(with

control)

Mean BW,g;

GA,week

Baseline

(Range)

Predictors Outcome Association

Applicability Quality

Kraybill

1995

95264242 118

Bw:

Sample 1:

1022

Sample2:

1028

VLBW:

700-1350g

Need for O2 

via nasal 

canula

Need for O2 

via CPAP

CLD

mmm A

Gerdes J

1995

95264241

508 BW 700-1100g Surfactant 

use

Asthma

CLD mmm A

(RCT)

Chye

1995

95314864 158

BW:1000-

1500g

GA:26-33

Bronchopulm

onary 

dysplasia

Growth

Rehospitalization

mm B

KurkinenRaty

1998

98387235 78

BW:1138

GA:28

Preterm 

rupture and 

no rupture

Chronic lung 

disease

mm B

KurkinenRaty

2000

20284814

103 BW: 1294

GA:30

Cesarean 

delivered

singleton

Chronic lung 

disease mm B
119

Author,

Year

N

(with

control)

Mean BW,g;

GA,week

Baseline

(Range)

Predictors Outcome Association

Applicability Quality

Gregoire

1998

98232532 217 BW: 997GA: 27

BPD

CLD

Respiratory 

readmissions

PICU 

admissions

mm B

Cheung

1998

99059896 10

BW:860

GA: 25 BW<1500g

Chronic lung 

disease

m

B

Als

1994

94358983

20 BW < 1250 g

GA 24-30 wk

Participation

In 

individualized 

developmenta

l care

Pulmonary:

BPD severity mm B

Iles

1997

97280982 33

BW:900g

(589-1891g)

GA:27 wk(24-

31)

BPD

Pulmonary 

arterial 

pressure mm C

Kraybill, Bose, Corbet, et al. (1995) reported results of long-term outcome at 2 years adjusted 

age of 118 VLBW infants (birth weights 700-1350 grams) who were enrolled in a double-blind, 

randomized, placebo-controlled, single-dose surfactant trial. Respiratory outcomes assessed at 2 

years adjusted age, which were not different between the two groups, revealed that 14% of the 

entire cohort were hospitalized during the second year, 14% still received regular bronchodilator 

therapy, 2 of 118 children had tracheostomies. These studies illustrate the increased long-term 

pulmonary morbidity in terms of need for regular respiratory medications and re-hospitalizations. 

Gerdes, Gerdes, Beaumont, et al. (1995) reported the pulmonary outcome at 1-year adjusted 

age among other neonatal outcomes of premature infants (birth weight 700-1100 grams, born 

1989-1990) who had been enrolled in a randomized, double-blind, parallel comparison of a 

single vs. triple-dose of surfactant therapy for respiratory distress syndrome. At 1-year follow-up 

evaluation, 16% had physical evidence of chronic lung disease, 3% were on respiratory support, 

3% were on respiratory medications, 6% had diagnosis of asthma, and 43% had been rehospitalized during the first year. 

Chye and Gray (1995) compared the need for rehospitalization within 12 months of age 

between premature infants with BPD (GA 26-33 weeks) and BW-matched controls without BPD 

(GA 26-32 weeks). Re-hospitalization was high in both preterm groups (with and without BPD). 

However, there was a significant increase in any rehospitalization in first year of life in preterm 

infants with BPD (58%) vs. preterm infants with no BPD (35%) (RR 1.7; 95% CI 1.2,2.4). 

There was a significant 2-fold increase in rehospitalization for respiratory illness in the first year 

of life in preterm infants with BPD (39%) vs. preterm infants with no BPD (20%) (RR 1.9, 95% 

CI 1.1, 3.2). BPD infants with home oxygen therapy (N=20) had approximately three-fold 

increased re-hospitalization for failure to thrive (30%) compared to control preterm infants (9%) 

(RR=3.3, 95% CI 1.2,8.9). Growth failure was common in both preterm groups (i.e. in infants 

with no BPD (1%) and with BPD (14%). 
120

Kurkinen-Raty, Koivisto, and Jouppila (1998) studied the long-term pulmonary outcome at 

1-year of age in 2 groups of premature infants (1990-1996): One group experienced early 

premature rupture of membranes (PROM) between 17 and 30 weeks gestation; the second 

group’s mothers delivered spontaneously without PROM. Later pulmonary complications 

included longer days of rehospitalization (PROM 5 vs. Spontaneous 1, P=0.01), and more 

symptomatic chronic lung disease at 1 year of age in PROM group than Spontaneous group 

(22% vs. 9%, OR 2.4, 95% CI 0.9, 6.5). This study illustrates that early PROM has long-term 

pulmonary consequences extending through 1-year of age. 

Kurkinen-Raty, Koivisto, and Jouppila (2000) studied the incidence of chronic lung disease 

at 1 year of age in premature infants delivered between 24 and 33 weeks gestational age for 

either maternal or fetal indications and compared these to premature infants of similar gestational 

age born to mothers who had spontaneous preterm delivery. The diagnosis of chronic lung 

disease (CLD) at 1 year of age was made if infants required oxygen, continuous bronchodilator 

therapy or steroid therapy because of respiratory signs and symptoms. Among children born 

‘preterm delivered for maternal or fetal indications’, 15% had CLD at 1 year compared to 3% of 

infants born ‘preterm after spontaneous delivery’ (RR 4.6, 95% CI 1.4, 1.6). This study 

demonstrated that premature infants who were born due to indicated maternal/fetal reasons vs. 

spontaneous preterm delivered infants had worse pulmonary outcome a 1 year age. 

Iles and Edmunds (1997) studied 33 infants who were born between 24-31 weeks gestation 

(median BW, range: 900, 589-1891) and who had BPD as defined by age 28 days and receiving 

supplemental oxygen (all 33) or at 36 weeks gestational age (30/33). They tested the ability of 

measurements of mean arterial saturation (MSaO2 ), arterial blood gases and pulmonary function 

to predict pulmonary outcome at 1 year of age when serial testing was performed every 3 

months. A MSaO2 of less than 90% in room air at 1 year of age was predicted between 35-40 

weeks gestational age by an (A-a) DO2 greater than 29 kpa (sensitivity 0.85 and specificity 0.88) 

and a PaCO2 greater than 7 kpa (sensitivity 0.88, specificity 0.78). The prediction was 

strengthened by combining the (A-a) DO2 > 29 kpa and PaCO2 > 7 kpa (sensitivity and 

specificity 1). This study demonstrates that an early laboratory abnormality is predictive of 

pulmonary dysfunction at one year of age. 

More severe BPD (i.e., BPD at 36 wk equivalent gestational age) is associated with greater 

pulmonary impairment and increased re-hospitalization. Gregoire, Lefebvre, and Glorieux (1998)

prospectively compared health, respiratory, and developmental outcomes at 18-months corrected 

age of three groups of premature infants (gestational age 24-28 weeks, born 1987-1992) 

according to duration of need for supplemental oxygen therapy. The reference group required 

oxygen for less than28 days age; the BPD-1 group required O2 ≥28 days age but < 36 weeks 

corrected gestational age (CGA) and the BPD-2 group consisted of infants requiring oxygen ≥36 

weeks CGA. The outcome measures of interest were persistent respiratory problems (asthma, 

tracheostomy, home oxygen therapy), hospitalizations, surgery, growth, and neurodevelopmental 

impairment. The BPD-2 group had more persistent respiratory problems (reference=4% vs. 

BPD-1= 4% vs. BPD-2=11%). Overall, 48% of the infants required re-hospitalization. The BPD2 group required more days of hospitalization, more hospitalizations for respiratory problems 

(reference = 2 vs. BPD-1 = 2 vs. BPD-2 = 6.3), and more hernia repairs compared to the 

reference or BPD-1 groups. The results of this study are similar to that of Shennan, Dunn, 

Ohlsson, et al. (1988) which found that premature infants who are still oxygen-dependent at 36 

weeks gestational age equivalent, have more abnormal pulmonary outcomes at 1 year. The BPD-
121

2 group had more neurodevelopmental disabilities at 18 months age. The differences remained 

even after adjusting for IVH or PVL (Gregoire, Lefebvre, and Glorieux, 1998).

Cheung, Peliowski, and Robertson (1998) reported on a highly-selected group of VLBW 

survivors (mean gestation = 25 weeks, range 24-30) born during 1993-1997. These infants 

experienced particularly severe respiratory disease with prolonged hypoxemia and required 

inhaled nitric oxide rescue therapy. These VLBW survivors (n=24) had an unusually high 

incidence of BPD (80%), of whom all had supplemental oxygen through 10 months corrected 

age. Follow-up at a mean age of 22 months revealed a 40% incidence of recurrent wheezing, 

10% required bronchodilator therapy, and 70% poor neurodevelopmental outcome.

3 year follow-up

One cross-sectional study provided evidence that VLBW with BPD is associated pulmonary 

and disability at 3-year follow-up: (Table 5.2b)

Table 5.2b. VLBW with BPD is associated with long-term pulmonary disability by 3 years of

 follow-up.

Author,

Year

Sample

(with

control)

Mean BW,g;

GA,week

Baseline

(Range)

Predictors Outcome AssociationApplicabilityQuality

Brooks BW<1500g

2001

211531225

8071* ND

BW 1500-

2499g

Asthma

 

mmm B

Brooks, Byrd, Weitzman, et al. (2001) studied over 8,000 infants at 3 years of age to estimate 

the independent contribution of birth weight to asthma prevalence among children <4 years age. 

They conducted a cross-sectional analysis using the 1988 National Maternal-Infant Health 

Survey and 1991 Longitudinal Follow-up Survey. They compared the diagnosis of asthma (based 

on parental report of physician-diagnosis of asthma) among three different birth weight (BW) 

groups: The reference group with birth weight (BW) ≥ 2500 gm; LBW group, BW≥1500-

2499gm; and VLBW group, BW < 1500 grams. Asthma was diagnosed in 6.7% of children < 4 

years age in the reference group; in 10.9% of the LBW group (OR=1.4, 95% CI 1.1-1.8); and in 

21.9% of the VLBW group (OR=2.9, 95% CI 2.3-3.6). More than half of the increased risk for 

asthma in VLBW children was explained by birth weight alone (attributable risk, 68%). This 

study found a strong, independent association between low birth weight and asthma, and that the 

effect of birth weight was most pronounced in the lowest birth weight category. The authors 

estimated that 4000 excess asthma cases were attributable to birth weight < 2500 grams in this 

1988 national birth cohort. The incidence of asthma in children with history of BPD was 20.4% 

(OR 3.4, 95% CI 2.4,4.8). The odds ratio of a physician diagnosis of asthma in VLBW/AfricanAmerican children was 2.5 (95% CI 2.0, 3.3). The odds ratio of a physician diagnosis of asthma 

in VLBW/white children was 3.1 (95% CI 2.2,4.3). These data support findings in other studies 

not included in this review that link an independent association between low birth weight and 
122

asthma. The authors emphasize the importance of identifying specific risk factors that contribute 

to the burden of asthma in young children since children <4 years of age account for 50% of total 

direct asthma costs (Pelkonen, Hakulinen, and Turpeinen, 1997).

6-12 years 

Two nonrandomized comparison studies provided evidence that VLBW with BPD is 

associated pulmonary disability at 6-12 year follow-up: (Table 5.2c)

Table 5.2c. VLBW with BPD is associated with long-term pulmonary disability by 6-12 year of 

follow-up.

Author,

Year

Sample

(with

control)

Mean BW,g;

GA,week

Baseline

(Range)

Predictors Outcome AssociationApplicabilityQuality

Gross

1998

98375435

96 BW:1173g

GA:28 wk

 Preterm

Pulmonary 

function

Respiratory 

symptoms

Asthma

Respiratory Meds

Rehospitalization

Worse

 

 mm B

Santuz

1995

96023205

12

BW:

1400 ± 335

(890-1900)

GA:30 wk:

(27-32)

 BPD

Pulmonary 

function

 mmm B

Gross, Iannuzzi, Kveselis, et al. (1998) compared long-term pulmonary outcomes at 7 years 

of age of a regional cohort of children born <32 weeks’ gestation (1985-1986) to a matched term 

group. The preterm cohort was divided in to those who in the neonatal period had no BPD 

(n=53) and those who had BPD (n=43). The two premature groups were compared to each other 

and to the children born full-term (38-42 weeks) (controls) (n=108). Pulmonary function studies

revealed that the BPD group had significantly greater airway obstruction with reduced forced 

expiratory flow indices compared to either the preterm no BPD group or the control term group 

(all P<0.0001). Lung function in preterm group with no BPD was similar to control term group. 

Pulmonary function tests revealed significantly worse pulmonary function in preterm infants 

with BPD at rest and after exercise compared to either preterm infants without BPD or control

term group. With respect to the exercise results, there was no statistically significant difference 

in baseline heart rate, oxygen consumption, respiratory quotient, or endurance among groups. 

Asthma was observed twice as often in the BPD group compared to the no BPD group or control 

term infants (BPD, 47% vs. No BPD 25% vs. Control 21%, P<0.001). With respect to use of 
123

respiratory medications, bronchodilator therapy was used more commonly for asthma in the BPD 

group (16%) compared to No BPD (6%) or term control group (3%) (P<0.01). Both preterm 

groups had more respiratory symptoms than the term group (wheezing in BPD, 30% vs. No 

BPD, 24% vs. Term, 7%, P<0.005; chronic cough: BPD, 12% vs. No BPD, 13% vs. Term, 0%, 

P< 0.01). Importantly, respiratory symptoms were significantly more common in both of the 

premature groups in comparison to term controls at 7 years of age. The former BPD group were 

twice as likely to be rehospitalized during the first 2 years of life compared to former preterm 

children with no BPD or term control group (BPD 53% vs. No BPD 26%, P<0.005). Both 

preterm groups were hospitalized more than the term group (3%, P<0.001). Collectively, these 

data demonstrate that former preterm children with no BPD had similar pulmonary function to 

term controls and that chronic respiratory disability related to BPD and VLBW status may 

continue to cause disability into school age.

Santuz, Baraldi, Zaramella, et al. (1995) assessed long-term pulmonary function at rest and 

during exercise in 12 children who had BPD during the neonatal period (gestational age 30 ± 2 

wk) at 6-12 years of age. They compared the former BPD patients to 16-year-old healthy 

children born at term. The authors demonstrated that asymptomatic school-age survivors of BPD 

showed clinically significant evidence of disturbances in ventilatory response to exercise and 

reduced aerobic capacity compared with healthy children, even if pulmonary function at rest was 

only slightly impaired. 

12-16 years follow-up

Two nonrandomized comparison studies provided evidence that VLBW with BPD is 

associated pulmonary disability at 12-16 year follow-up: (Table 5.2d)

Table 5.2d. VLBW with BPD is associated with long-term pulmonary disability by 12-16 year of 

follow-up.

Author,

Year

N

(with

control)

Mean BW,g;

GA,week

Baseline

(Range)

Predictors Outcome AssociationApplicabilityQuality

Saigal

2001

21376729 154 BW:

501-1000

 ELBW 

 Infants

 

Pulmonary 

Problem

(asthma or recurrent 

bronchitis/

pneumonia)

 

 mm B

Doyle

2001

21064379

 

 180 BW:1079g

GA: 27 wk BW<1501 g

Respiratory health 

and lung function at 

14 years age

 

 mm B

 

Saigal, Stoskopf, Streiner, et al. (2001) followed a regional cohort of ELBW survivors (birth 

weight 501-1000 grams, born in 1977-1982 in Canada) well into adolescence (12-16 years). 

With respect to pulmonary problems at the time of assessment, the proportion of adolescents 

who had asthma or recurrent bronchitis/pneumonia was 22% in former ELBW infants compared 

to 12% of full-term controls. With respect to past health problems and asthma, the proportion of 
124

children who had had a history of asthma or recurrent bronchitis/ pneumonia was 39% of the 

ELBW group compared to 17% of the controls. Although this excellent long-term study into 

adolescent years describes the outcomes of ELBW born during an earlier era of neonatal care 

(1977-1982), these data are still important in that they demonstrate that clinically relevant 

respiratory illnesses of ELBW infants may persist even through adolescence, and that they occur 

more frequently in ELBW infants compared to full-term controls. 

Doyle, Cheung, Ford, et al. (2001) conducted a prospective cohort study in Australia to 

compare respiratory health and lung function in adolescent children who were born weighing

<1501 grams (1/ 77 to 3/ 82) with those of adolescents of normal birth weight. The preterm 

babies were divided into two groups: ELBW infants with BW 500-999 grams (n=78); VLBW 

infants with BW 1000-1500 grams (n=102). The controls were term infants with BW greater 

than 2499g (n=42). BPD was diagnosed in 23% of the preterm group in the neonatal period. 

Readmission to the hospital due to respiratory illness was similar and high for both preterm 

groups. The incidence of asthma was similar in all three groups (ELBW, 15%; VLBW, 21%; 

and NBW, 21%). The respiratory health at 14 years of age was comparable between former 

preterm infants compared to full term controls in terms of asthma and most of the lung function 

tests. Preterm children who had BPD had significantly lower flow values. This study provides 

optimistic information about the long-term pulmonary outcome in former preterm children who 

had no BPD. 

Pulmonary Function Testing and Exercise Tolerance

With respect to monitoring long-term pulmonary outcomes in premature infants with BPD, 

several publications indicate that formal pulmonary function testing is abnormal in VLBW 

infants who develop BPD: (Baraldi, Filippone, Trevisanuto, et al., 1997; Gerhardt, Hehre, Feller, 

et al., 1987; Gross, Iannuzzi, Kveselis, et al., 1998) . Specific abnormalities reflect restrictive 

lung disease: reduction in forced expiratory flow volumes, reduction in forced expiratory flow 

rates, elevation in residual volumes and reduced compliance (Baraldi, Filippone, Trevisanuto, et 

al., 1997; Gerhardt, Hehre, Feller, et al., 1987; Gross, Iannuzzi, Kveselis, et al., 1998) . Other 

studies, not included in this review, have shown that these abnormalities improve gradually over 

the first two years of life with the greatest improvement seen in the first year (Baraldi, Filippone, 

Trevisanuto, et al., 1997; Gerhardt, Hehre, Feller, et al., 1987). Compliance and flow 

measurements are usually in the normal range by the age of two years (Baraldi, Filippone, 

Trevisanuto, et al., 1997; Gerhardt, Hehre, Feller, et al., 1987). However, evidence of residual 

lung dysfunction has been consistently found, especially in VLBW infants with severe BPD. 

Such dysfunction has included increased airway responsiveness to methacholine challenge, 

residual mild obstruction of flow and elevated residual volumes (Bader, Ramos, Lew, et al., 

1987; Blayney, Kerem, Whyte, et al., 1991).

Other reported measures used to assess the association(s) between VLBW, BPD, and 

subsequent pulmonary disability include the following: 1) exercise testing in children who have 

reached an age that allows cooperation; 2) presence of childhood wheezing, asthma; 3) parental 

questionnaire for respiratory symptoms; 4) rehospitalization (either all readmissions or those 

related specifically to respiratory illness); 5) echocardiographic determination of right ventricular 

dysfunction and/ or pulmonary vascular disease. (Bader, Ramos, Lew, et al., 1987; Blayney, 

Kerem, Whyte, et al., 1991; Brooks, Byrd, Weitzman, et al., 2001; Chye and Gray, 1995; Gross, 
125

Iannuzzi, Kveselis, et al., 1998; Jacob, Lands, Coates, et al., 1997; Mitchell and Teague, 1998; 

Santuz, Baraldi, Zaramella, et al., 1995; Subhedar and Shaw, 2000). 

There is evidence that measures of lung dysfunction in older children who have had BPD are 

associated with some degree of impairment in the area of aerobic exercise (Bader, Ramos, Lew, 

et al., 1987; Jacob, Lands, Coates, et al., 1997; Mitchell and Teague, 1998; Santuz, Baraldi, 

Zaramella, et al., 1995). At ages of six years and greater, arterial desaturation during exercise 

(Jacob, Lands, Coates, et al., 1997; Santuz, Baraldi, Zaramella, et al., 1995), carbon dioxide 

retention during exercise (Bader, Ramos, Lew, et al., 1987), and an increased occurrence of post 

exercise restriction of airflow which is reversible by bronchodilators has been found (Bader, 

Ramos, Lew, et al., 1987). However, as judged by the literature within this review, the deficits in 

exercise are subtle and do not interfere with daily activities.

The most frequently described consequences of pulmonary disability in the first two years of 

life are the need for respiratory medications and re-admission to the hospital. The evidence for 

this is noted below.

Evidence That VLBW Is Associated With Asthma Or Hyper-reactive 

Airway Disease

Three studies support associations between both VLBW and asthma and between VLBW 

with BPD and asthma. (Table 5.3). 

Table 5.3. Association of VLBW/Prematurity with asthma or hyper-reactive airway disease

Author, 

Year

Sample

(with 

control)

Mean BW, 

g; GA, week

Baseline 

(Range)

Predictors Outcome AssociationApplicability Quality

BW<1500g Brooks 

2001

21153125

8071* ND

BW 1500-2499g

Asthma mmm B

Cheung 

1998

99059896

10

BW: 860

GA: 25

BW < 1500 g,

Mosaic trisomy 

18 Potter’s 

syndrome

m B

Respiratory 

symptoms

Gross

1998

98375435 96

BW: 1173 g

GA: 28 wk Preterm

Asthma

mm B

More than one definition of asthma was used in the literature reviewed. A more restrictive 

definition was physician-diagnosed asthma (Brooks, Byrd, Weitzman, et al., 2001); an alternate 

definition was responsiveness to inhaled bronchodilator therapy (Gross, Iannuzzi, Kveselis, et 

al., 1998). Cheung et al defined asthma as recurrent wheezing in infancy (Cheung, Peliowski, 

and Robertson, 1998). The principle strength of the studies that address ‘VLBW and asthma’ as 

well as ‘VLBW with BPD and asthma’ is that the follow-up period is generally long, on the 

order of several years. The following studies support associations between both ‘VLBW and 
126

asthma’ and ‘VLBW with BPD and asthma’ (Brooks, Byrd, Weitzman, et al., 2001; Cheung, 

Peliowski, and Robertson, 1998; Corbet, Long, Schumacher, et al., 1995; Gross, Iannuzzi, 

Kveselis, et al., 1998). 

As noted previously, Brooks, Byrd, Weitzman, et al. (2001) studied over 8,000 infants 

(VLBW, LBW, and normal BW) at 3 years of age to estimate the independent contribution of 

birth weight to asthma prevalence among children <4 years age. This study found a strong, 

independent association between low birth weight and asthma, and that the effect of birth weight 

was most pronounced in the lowest birth weight category. 

Gross, Iannuzzi, Kveselis, et al. (1998) used the definition of asthma as ‘responsiveness to 

inhaled bronchodilators’, assessed with pulmonary function tests, as indicating the presence of 

asthma at the age of 7 years. Infants with a gestational age of 24 to 31weeks (n = 204) had a 47% 

incidence of asthma if they developed BPD in contrast to a 25% incidence of asthma if BPD did 

not develop. These figures compare with a 21% incidence of asthma in well, full term infants. 

Although bronchodilator responsiveness as studied by Gross and associates may not be 

equivalent to asthma these data at the least demonstrate persistent airway hyper-responsiveness 

associated with VLBW and with BPD.

Cheung, Peliowski, and Robertson (1998) reported recurrent wheezing, which may represent 

asthma and at the least represents hyper-reactive airways, in 40% of VLBW survivors. Saigal, 

Stoskopf, Streiner, et al. (2001) followed a regional cohort with BW less than 1,000 g in Canada 

through age 12 to 16 years. They found 25% of surviving ELBW infants had asthma in 

comparison to 14% of controls born at full term. 

Several authors (Bader, Ramos, Lew, et al., 1987; Gross, Iannuzzi, Kveselis, et al., 1998; 

Mitchell and Teague, 1998; Santuz, Baraldi, Zaramella, et al., 1995) have addressed the issue of 

exercise-induced airflow limitation. Alternative terminology for this phenomenon is exerciseinduced asthma or excerise-induced bronchospasm. Although these studies have generally 

involved relatively small numbers of patients they have the strength of being performed in 

childhood to early adolescence. These such studies have consistently reported increased exerciseinduced airflow limitation in infants with BPD (Bader, Ramos, Lew, et al., 1987; Santuz, 

Baraldi, Zaramella, et al., 1995).

Evidence That VLBW Infants Have Increased Rehospitalization For 

Respiratory Illness

Rehospitalization of former VLBW infants is a common event, especially among VLBW 

infants with BPD. Most hospitalizations are for respiratory conditions or growth failure, 

sometimes referred to as failure to thrive (Corbet, 1995). 

Eight studies provided the evidence that VLBW infants have increased rehospitalization for 

respiratory illness (Table 5.4). 
127

Table 5.4. Association of VLBW/Prematurity with rehospitalization for respiratory illness: 

pulmonary outcomes

Author, 

Year

Sample

(with 

control)

Mean BW, g; 

GA, week

Baseline 

(Range)

Predictors Outcome AssociationApplicabilityQuality

Corbet A

1995

95264244

1046

BW: 934

GA: 27

Single dose 

synthetic 

surfactant at birth 

(vs air placebo)

Growth

Rehospitalization

mmm A

Cheung

1998

99059896

10

BW: 860

GA: 25

BW < 1500 g,

Mosaic trisomy 

18 Potter’s 

syndrome

m B

Doyle

 2001

21064379

180 BW: 1079 g

GA: 27 wk BW<1501g

Respiratory 

health and lung 

function

mm B

Chye

1995

95314864

158

BW: 1000-

1500 g

GA: 26-33

Bronchopulmonar

y dysplasia

Growth

Rehospitalization

mm B

Respiratory 

symptoms

Gross 

1998

98375435

96

BW: 1173 g

GA: 28 wk Preterm

Asthma

mm B

Santuz 

1995

96023205 12

BW : 

1400±335 g 

(890-1900)

GA: 30 wk 

(27-32)

BPD

Pulmonary 

hypertension mmm B

Gregoire

1998

98232532

217 BW: 997

GA: 27

BPD

CLD

Respiratory 

readmissions

PICU 

admissions

mm B

Up = More severe pulmonary conditions associated with Lower birth weight 

Applicability: 3 people = well applicability; 1 people = narrow applicability

NHIHS = National Maternal-Infant Health Survey

BPD = Bronchopulmonary dysplasia

CLD = chronic lung disease

* = with control 

Re-admission to the hospital for respiratory illness becomes less frequent after two years of 

age. Thereafter, rehospitalization begins to approximate the rates seen in full term infants. This is 

approximately the same time that formal pulmonary function measures begin to enter the normal 

range as judged by the studies that have followed children long enough to be able to provide 

such data (Cheung, Peliowski, and Robertson, 1998; Chye and Gray, 1995; Corbet, Long, 
128

Schumacher, et al., 1995; Doyle, Cheung, Ford, et al., 2001; Gross, Iannuzzi, Kveselis, et al., 

1998).

Chye and Gray (1995) demonstrated that 58% of VLBW infants with BPD required 

rehospitalization within the first year of life in contrast to 35% of VLBW infants without BPD. 

In this same report 39% of children with BPD were rehospitalized for respiratory problems as 

compared with 20% of controls. These differences are significant with RR for overall 

hospitalization of 1.7 (1.2, 2.4) and RR for hospitalization due to respiratory illness of 1.9 (1.1, 

3.2). There was no full term control group, but hospitalization rates for full term infants within 

the first year of life are generally 3% or less (Gross, Iannuzzi, Kveselis, et al., 1998). Fourteen 

percent of patients with BPD were hospitalized for reasons related to poor growth, as compared 

with 1% of VLBW infants without BPD, RR 1.4 (1.7, 82). 

Gross, Iannuzzi, Kveselis, et al. (1998) also reported that 53% of patients with VLBW and 

BPD, as compared with 26% of their VLBW patients without BPD, required rehospitalization (P 

< 0.005). This study did report a control group born at term to have a 3% incidence of 

hospitalization in the first year of life (P < 0.001 versus both groups of VLBW infants). These 

data demonstrate that rehospitalization in the first two years of life is associated with both BPD 

with VLBW and VLBW. Although the former association is stronger the latter is significant.

Evidence That VLBW With Or Without Other Conditions Is 

Associated With Growth Impairment (Evidence Tables 10-12)

VLBW infants are at high risk for poor growth during the first years of life due to acute 

neonatal illnesses, developmental delays, chronic illnesses (e.g. bronchopulmonary dysplasia, 

gastroesophageal reflux, short-gut syndrome). Attaining appropriate growth and nutrition in 

VLBW infants continues to be a challenge during the initial hospitalization and after discharge 

from the neonatal unit. Long-term studies demonstrated definitive problems with postnatal 

growth. Understandably, the degree of prematurity and severity of the illness/hospital course 

have great impact and influence on growth. This narrative examines the evidence identified by 

the methods of this review that VLBW infants, with or without other conditions, are at increased 

risk for growth impairment. The narrative regarding VLBW and growth outcome is organized as 

follows: 

• Evidence that VLBW is associated with growth impairment

• Evidence that VLBW plus bronchopulmonary dysplasia is associated with growth 

impairment

• Evidence that VLBW plus antenatal glucocorticoid exposure is associated with growth 

impairment

• Evidence that VLBW plus necrotizing enterocolitis is associated with growth impairment

• Evidence linking VLBW plus postnatal nutrition with growth impairment
129

Evidence That VLBW Is Associated With Growth Impairment

Twelve observational studies provide evidence that VLBW is associated with growth 

impairment

Table 6.1. Association of VLBW/Prematurity with Growth Impairment 

Author,

Year N

Mean 

BW,g;GA. 

week

Baseline 

Range

Predictors Outcome

AssociationApplicabilityQuality

Ford

2000

20380862 206 GA: 29

BW:1075 BW< 1500 g Growth in Wt/Ht/HC mmm A

Wang, 

1998

98244087 514 GA: 28

BW: 955 BW < 1250 g Growth in Wt/Ht mm A

Growth 

Connors quotient

1999

11483801 198 BW:823

GA:27

BW

Weight

Growth 

<3%tile

High 

perinatal risk

Motor ability mm A

Avila-Diaz, 

2001

21334039 34 BW: 1294

GA: 30

Prematurity

Birth weight

Bone mineral 

content and 

bone area

mm A

KurkinenRaty

2000

20284814

175 GA: 30

BW: 1450

“Indicated” 

preterm / 

SGA

Wt/Ht/HC mm B

Saigal

2001

11483807

154 GA: 27

BW: 835

BW 500-

1000 g Weight z score mm B

Scherjon

1998

98429216

96

GA: 30 (26-

32)

BW: 1295 

(605-2295)

Raised U/C 

ratio

Wt/Ht

HC

 mm B

Lee

1998

98442293 35 GA: ND

BW: 789

Candidemia 

and/or 

Candidal 

meningitis

Growth 

retardation (Wt, 

Ht, HC > 2 SD 

below the 

mean)

m B

Finnström

1998

99041345

362 GA: = 23

BW: 798

BW = 1000 

g

Wt/Ht/HC mmm C
130

Author,

Year N

Mean 

BW,g;GA. 

week

Baseline 

Range

Predictors Outcome

AssociationApplicabilityQuality

Forslund 

1992

93044002 41 BW: ND

GA: 27-34 Prematurity Growth in wt/ht/HC m C

Growth rates 

for Wt, Ht, HC Duvanel 

1999

99207097 85 GA: 32

BW: 1154

Recurrent 

episodes of 

Hypoglycemi

a

HC at 12, 18 

mo, 5 yrs

m C

Gosch

1997

97379896 5

GA:28(26-29)

BW: 880 ELDW Growth in Wt/Ht/HC/BMI m C

Ford, Doyle, Davis, et al. (2000) compared growth and pubertal development in VLBW 

children (birthweight <1500 grams) and normal birth weight children (birth weight >2499 

grams) through 14 years of age. Children with CP were excluded. At ages 2,5, 8, and 14 years, 

the VLBW children were significantly shorter, lighter, and had smaller head circumference 

compared to normal birth weight group. The differences between the two groups were less 

apparent over time. At age 14, pubertal development was similar between the groups. 

Wang and Sauve, (1998) compared growth outcomes of VLBW infants (≤1250 grams birth 

weight) according to different growth references for normal term infants (NHCS/WHO 

reference, Canadian reference, and WHO reference) and validated the adjustments made for 

growth by corrected age. Children were followed through 3 years of age. More infants were 

identified as underweight at 12 and 18 months with the NCHS/WHO reference compared to the 

other two references. Postnatal growth was recorded according to chronologic age and adjusted 

age and expressed as standard deviation scores or Z-scores. The age adjusted Z-scores were 

always closer to zero compared to chronological age. The differences in Z-scores diminished 

over time, they still remained statistically significantly different, thus validating use of the 

corrected age through 3 years age. Regardless of the growth reference and whether the growth 

was plotted by adjusted age or chronologic age, the mean weight and height were still 

significantly lower in VLBW than term infants at 4-36 months of age. 

Connors, O'Callaghan, Burns, et al., (1999) determined that weight <3rd and <10th percentile 

at 2 years of age in ELBW infants (born 1987-1992) at high perinatal risk or neurological 

impairment is strongly associated with neurosensory developmental abnormalities and motor 

skills. 

Gosch, Brambring, Gennat, et al. (1997) reported that ELBW blind children also had 

significantly lower head circumference, length, and body mass indices than term blind children. 

Avila-Diaz, Flores-Huerta, Martinez-Muniz, et al. (2001) studied the bone density of 26 infants 

with mean GA 30 weeks and mean birthweight of 1294 grams for 6 months postnatally. Full 

term infants (n=16) had significantly higher (P<0.05) bone mineral content and bone area 

compared to preterm infants (n=26) even after correction for age. Preterm infants had a 
131

significantly higher rate of increase in bone mineral content /weight ratio in months 2 to 6 

suggesting “catch up” mineralization (P<0.001).
132

Evidence That VLBW Plus BPD Is Associated With Growth Impairment

It is well documented (Table 6.2) that VLBW infants with BPD are smaller and have 

difficulty gaining weight while in the neonatal intensive care unit (NICU). Recurrent illness and 

pulmonary exacerbations of BPD, increased metabolic needs and inadequate nutrient intakes all 

contribute to compromise growth in VLBW infants with BPD. 

Table 6.2. Association of VLBW plus BPD with Growth impairment

Author,

Year N

Mean 

BW,g;GA.week

Baseline 

Predictors Outcome Association Applicability Quality

DeReignier Wt.

1997

98041177

174 BW:1015

GA:28

GA

Apgar score

Severity of CLD

Necrotizing 

“enterocolitis”

Ht/HC mm B

Growth in 

Wt/Ht/HC BPD

Rehospitalization 

for poor growth

Chye

1995

95314864

78 BW: 1055

GA: 28

BPD on home O2

(20)

Rehospitalization 

for poor FTT

mmm B

Two studies reported these associations. deRegnier, Roberts, Ramsey, et al. (1997)

retrospectively studied 174 VLBW infants; 58 of each with no BPD, mild BPD, and severe BPD 

(mean gestation age 27.5 weeks, mean birth weight 1015 grams, born 1987-1991). Infants were 

matched for birth weight, sex, and race. Infants with severe chronic lung disease were found to 

be significantly lighter (P<0.01) and shorter (P<0.001) than infants with no or mild BPD at one 

year of life. 

Chye and Gray (1995) studied rehospitalization and growth of 78 VLBW infants with BPD 

(mean birth weight of 1055 grams, mean gestational age of 28 weeks) matched with infants 

without BPD. As noted previously in the pulmonary discussion, rehospitalization was significant 

in both groups in the first year of life. Growth failure (plotted on sex specific National Center for 

Health Statistics growth charts) was common in both preterm groups as demonstrated by the 

proportion of infants below the 10 percentile for corrected age at 4 months (BPD 30% vs. 

Controls 15%, P<0.05). In the BPD group, weight, length, and head circumference were always 

below that of the control group, but the differences were not significant at 8 and 12 months. 

Additionally, BPD infants with home O2 had a 3-fold increase in rehospitalization for failure to 

thrive. This finding is linked to the fact that more children in the BPD group required rehospitalization for poor growth in the first year of age compared to controls (BPD 14% vs. 
133

Control 1%, RR 14.0, 95% CI, 1.7,82). The primary reasons were related to poor feeding and 

gastroesophageal reflux.

Evidence That VLBW Plus Antenatal Glucocorticoid Exposure Is 

Associated With Growth Impairment

Table 6.3. Association of VLBW plus antenatal glucocorticoid exposure growth impairment 

Author,

Year N

Mean BW,g;GA. 

week

Baseline Range

Predictors Outcome Association Applicability Quality

French

1999

99115141 477

BW1416

(905-1810)

GA:30(26-32)

Antenatal 

corticosteroids

Growth in 

Wt/ Ht/HC mmm B

French, Hagan, Evans, et al. (1999) evaluated the effects of multiple courses of antenatal 

glucocorticoid therapies on birth size, growth, and neurodeveloment at 3 years age in preterm 

infants (born <33 weeks, born 1990-1992). Increasing number of repeated courses of antenatal 

steroids was associated with decreased birth weight ratio, and a reduction in birth weight of as 

much as 9% (P=0.014) and reduction in head circumference as much as 4% (P=0.0024). Growth 

at age 3 years was not related to increasing number of corticosteroid courses.

Evidence That VLBW Plus Necrotizing Enterocolitis Is Associated 

with Growth Impairment

There is limited data (Table 6.4), based on the methods of this review, regarding the 

association between VLBW plus necrotizing enterocolitis and growth impairment. Thus the lack 

of evidence should not be interpreted as no association. It is biologically plausible, and highly 

possible as suggested by the study of Ladd et al, that there is an association between VLBW plus 

NEC and growth impairment depending upon the severity of NEC and its long-term 

complications.

Table 6.4. Association of VLBW plus necrotizing enterocolitis exposure growth impairment 

Author,

Year N

Mean BW,g;

GA,week

Baseline Range

Predictors Outcome Association Applicability Quality

Ladd

1998

9835745

 

148

BW:1661

GA:31

Length of bowel 

resected or 

status of ICV

Severe 

growth 

retardation(<1

0 % tile

mmm

 

 C
134

Ladd, Rescorla, West, et al. (1998) retrospectively reviewed the long-term factors affecting 

outcome, including growth, of 249 premature infants (mean gestational age of 30 weeks; average 

birth weight 1500 grams; born between 1989 and 1994) who required surgical intervention for 

NEC. Postoperatively, the presence of an ileocecal valve (ICV) had no relation to survival unless 

there was less than 20 cm of small bowel remaining. When followed, there was no difference in 

weight percentiles with or without the presence of the ICV. At each visit, weight percentiles 

were below the 25 percentile and 60 % of patients reached below the 10th percentile at 1 year of 

life. However, by two years of life, less than 35% of subjects had weights less than the 10th

percentile. When 125 of the infants were stratified based on the amount of bowel resected, there 

was a trend towards reduced growth as bowel length resected increased.

Evidence Linking VLBW Plus Postnatal Nutrition With Growth 

Impairment

This review identified two studies (Table 6.5) which addressed the relationship between 

VLBW and postnatal nutrition with growth impairment. This is an important topic, given the 

improved long-term survival of VLBW infants, in which there is limited, current, good 

information in the literature. 

Table 6.5. Association of VLBW plus postnatal nutrition with growth impairment

Author/ 

Year

N

Mean 

BW, g; 

GA, week

Baseline 

(Range)

Intervention Outcomes Efficacy 

Applicability Quality 

O’Connor

2001

11483801

415 GA: 29 

(27-31)

BW: 1253 

(965-

4543)

Group 1: EHM-T fed 

(43)

Group 2: AA+OHA 

(finsh/fungal) (120)

Group 3: AA+DHA 

(egg-TG/fish) (126)

Group 4: Formula-fed 

(126)

Growth in 

Wt/Ht/HC

Growth (Wt, Ht, HC) no 

difference among the 4 

preterm groups in terms of 

gm/kg/day for weight; 

mm/wk for Ht and HC.

mm A

Growth in 

Wt/Ht/HC

No association was found 

between neonatal diet 

(Milk+Fortifier, 

Milk+Calsium phosphorus, 

or Preterm formula) and the 

Weight, Height, or HC

Wauben mmm B

1998

98387708

37 GA: 30

BW: 1300 Group 1: 

Milk + Fortifier (12)

Group 2: 

Milk + Calcium 

phosphorus (13)

Group 3: 

Preterm formula-fed 

(12)

Body 

composition

Growth 

assessment

 at 9 and 18 

months 

posterm

No association was found 

between neonatal diet 

(Milk+Fortifier, 

Milk+Calsium phosphorus, 

or Preterm formula) and 

whole body mass 

composition (Lean mass, 

Fat mass)
135

Author/ 

Year

N

Mean 

BW, g; 

GA, week

Baseline 

(Range)

Intervention Outcomes Efficacy 

Applicability Quality 

420 Trial 1

GA: 31

BW: 1397

Group A: 

Banked donor Breast 

milk fed until weight 

2000 g or discharge 

(207)

Group B: 

Preterm formula-fed 

(213)

No association was found 

between the neonatal diet 

(banked donor milk vs 

preterm formula ) and the 6 

anthropometrics at any 

follow up point ( 9 mo, 18 

mo and 7.5-8 yrs)

Morley m C

 2000

20167446

394 Trial 2

GA: 31

BW: 1387

Group A: 

Standard term formulafed until weight 2000 g 

or discharge (181)

Group B: 

Premature formula-fed 

(213)

Growth 

Assessment 

at 9 and 18 

months post 

term

No association was found 

between neonatal diet (term 

vs preterm formula) and the 

Weight, Height, HC and 

skinfold thickness at any 

follow up point (18 mo and 

7.5 yrs), except for a 

significantly lower waist to 

hip ratio at 7.5 yrs in infants 

fed preterm vs term formula 

solely (without 

supplementation with 

mother’s milk) (0.86 vs 

0.89, p<0.001)

Wauben, Atkinson, Shah, et al. (1998) studied the impact of multi-nutrient fortification of 

breast milk compared to supplementation of breast milk with calcium and phosphorous in the 

hospital, and of feeding breast milk only after discharge compared to formula feeding after 

discharge. They found no differences between groups with the multi-nutrient vs. 

calcium/phosphorous formulas in the hospital, but they did find a difference between groups fed 

only breast milk vs. prema ture formula after discharge in terms of less bone mineralization and 

greater percent body fat to 12 months age. They conclude that post-discharge dietary practices do 

have an impact on body composition. 

Morley and Lucas (2000) randomized 926 infants into two parallel neonatal diet trails for a 

total of approximately 4 weeks. Trial I included banked donor breast milk vs preterm formula 

(with or without mother’s milk supplementation). Trial 2 preterm formula vs. term formula (with 

or without mother’s milk supplementation. They found better neonatal growth in infants fed the 

preterm formula in contrast to those fed either banked donor breast milk or standard formula. 

The early, 4-week diet had no measurable influence on weight, length, head circumference at 9 

or 18 months post term or at 7-8 years of age.
136

Table 6. 6. Association of LBW/Prematurity to Growth Delay

Author Year N

(Controls)

Mean BW, g; 

GA, week

Baseline 

(Range)

Measure % of Subjects Applicability

Quality

Wt < 3rd %tile 20%

Ht < 3rd %tile 40% Cheung

1998

99059896

10

GA: 25 (24-

30)

BW: 860 

(340-1460) HC < 3rd %tile 30%

m

B

a

 All AGA

Abbreviation:

HC = head circumference

FTT = failure to thrive

NEC = necrotizing enterocolitis

ICV = ileocecal valve

EHM-T = exclusively human milk-fed until term CA
137

Chapter 4. Conclusions

Overall

We reviewed a large multiple of citations (>16,000) and included data from 170 articles in 

the analysis. Among the final articles abstracted for this review, the quality and methodology 

were variable, as expected, because we incorporated various study designs to address the key 

questions. Many of the final articles selected were of good to excellent quality. The study 

question “VLBW with or without other conditions was associated with disability” was a relevant 

and important question. However, the original intent of the majority (if not all) of the studies that 

evaluated the association of prematurity or conditions of prematurity with disability did not 

specifically address this question in this manner. Disability as defined by the U.S. Congress and 

interpreted by SSA was not the original intent of the studies reviewed. Despite these issues, the 

evidence of the articles reviewed overwhelmingly support the fact that VLBW with or without 

specific conditions was associated with increased risk of long-term disabilities. All of the articles 

reviewed evaluated disabling outcomes that occur ≥12 months of age and were likely to remain 

disabling ≥1 year. Unfortunately, most of the impairments were lifelong. The evidence to support 

the association of VLBW with specific outcomes is noted below.

Neurodevelopmental Disabilities

The evidence identified by our search methods clearly demonstrates that VLBW infants have 

high rates of neurodevelopmental disabilities, including cognitive (MR), neuromotor (CP), 

neurosensory (visual and auditory) impairments, and communication (language/speech)/ 

behavioral disorders compared with normal birth weight controls. The review also found 

evidence that VLBW infants have increased risk of long-term, clinically significant compromise 

in growth compared with normal birth weight controls. The evidence illustrates that VLBW 

infants with BPD have increased risk of significant pulmonary impairment that imposes a 

respiratory disability for variable lengths of time, especially in children who sustained severe 

BPD during their early neonatal course. The prevalence and severity of all these disabilities is 

even higher among ELBW infants.

Co-morbidities of prematurity, such as CNS injury, ROP, auditory/communication disorder, 

BPD, and feeding problems, individually and collectively play significant roles in subsequent, 

long-term disabilities. The co-existence of these morbidities is precisely the reason VLBW 

children have multiple handicaps. But even the presence of one handicap, e.g. visual disability, 

and/or hearing loss, greatly influences other realms of development and growth, and may lead to 

additional disabilities in speech and language, behavior problems and learning that affect school 

performance and limit daily function. 

Methodologically sound studies demonstrate that a greater proportion of VLBW and ELBW 

infants have multiple health problems and increased utilization of health care resources 

compared to full-term controls. These disabilities result in significant tangible and intangible 

costs to the individual child, its family, and society.
138

Robust, well designed, and carefully validated predictive models for MR and CP in VLBW 

infants, constructed with clinical information available at the time of hospital discharge do not 

yet exist. The ability to accurately predict neurodevelopmental outcome in the individual neonate 

on the basis of identifiable risk factors has had limited success. However, large and 

methodologically sound studies performed in a variety of settings have identified several risk 

factors that appear to have consistent and independent associations with subsequent abnormal 

cognitive and neuromotor development. In particular, cerebral white matter damage in the form 

of cystic PVL, severe (grade III or IV) IVH, and ventriculomegaly are the strongest indicators of 

risk for CP, neuromotor abnormalities, and MR. Timing of cranial ultrasonography is also 

critical to maximizing detection of the strongest risk factors. The 40-week adjusted gestational

age cranial ultrasound had the highest odds ratio for predicting CP.

Increasing evidence indicates that antenatal events contribute to the etiology and sequence of 

events leading to neurologic impairment, CP, and MR in VLBW infants. Antenatal 

inflammation, chorioamnionitis, and fetal hypoxia/acidosis may play important roles by 

stimulating a fetal inflammatory response that injures the immature cerebral white matter. Other 

antenatal events such as premature rupture of membranes (which may be related to antenatal 

inflammation and subclinical infection) and abruption have been identified as antenatal risk 

factors contributing to an increased risk of CP and/or neurodevelopmental disability in premature 

infants. The degree of prematurity and CNS injury in conjunction with these antenatal factors 

appear to influence the development of neurologic disability, including CP and MR.

Many studies strongly implicate BPD as an important contributor to subnormal cognitive and 

motor performance. BPD frequently co-exists with other disabling conditions commonly seen in 

VLBW/ ELBW infants, such as cerebral white matter damage and IVH, which impact cognitive 

and motor outcome. Our methods identified many studies documenting a significant independent 

relationship between bronchopulmonary dysplasia (BPD) and abnormal cognitive development 

in both VLBW and ELBW infants. Increasingly, evidence supports the association of postnatal 

administration of corticosteroids (specifically dexamethasone) for the amelioration or prevention 

of BPD as a contributor, independent of BPD, to developmental delay and CP. 

The relationship between biological/medical risk factors and social/parenting risk factors on 

subsequent neurodevelopmental outcome is complex. The interaction of these factors may have 

additive or synergistic positive or negative effects on an infant’s outcome. Although biomedical 

risk factors, such as PVL and ROP, are important determinants of subsequent disability in 

VLBW infants, it is also clear that social/parenting risk factors are critical, independent 

influences on the outcome of high-risk VLBW children. Neurologic and cognitive abnormalities 

are higher in infants with adverse parenting factors (e.g. abuse and/or neglect). The evidence 

illustrates the vulnerability of high-medical risk VLBW infants to parenting, social, and 

environmental risk factors. It also underscores the importance of having constructive parenting, 

social, and environmental milieu for children at increased risk for neurodevelopmental problems 

related to their biomedical risk of being VLBW.

Other risk factors that appear to have associations with cognitive development include race, 

gender, socioeconomic status as indicated by markers such as mother’s level of education, and 

illness severity as measured by objective scoring systems. The presence of deficits on physical, 

neurological, visual, auditory, and developmental examinations at 6 or 12 months may 

significantly refine assessment of risk for sustained neurodevelopmental abnormality. 

Knowledge of these risk factors encourages the attempt to develop a predictive model(s) using a 

large cohort of VLBW infants, followed by validation of the model in an independent group.
139

Speech and Language 

Strong evidence indicates increased risk of speech and language delays in VLBW infants. 

Factors associated with increasing this incidence include patent ductus arteriosus and intracranial 

ultrasound findings of cerebral white matter damage and IVH, as well as combined neonatal 

factors of duration of mechanical ventilation, acidosis, seizures, infection and hypoglycemia.

The data on the incidence of hearing loss in ELBW infants are conflicting: four studies report 

higher incidence ranging 9 to 14% and nine studies report low incidence or rates similar to their 

full-term controls. This discrepancy may be due to variations in testing methods used, which 

were frequently not reported in the studies reviewed. Infants with hearing loss are more likely to 

have had a high illness acuity in their neonatal course with combined exposures to severe 

hyperbilirubinemia and acidosis, hyperbilirubinemia and aminoglycoside use, elevated creatinine 

and furosemide use, and aminoglycoside and furosemide use.

The evidence is strong that VLBW infants have increased attention problems and more 

passive temperament. Intracranial lesions, CP, impaired cognition, and urban socioeconomic 

setting was associated with the increased incidence.

Available evidence suggests that VLBW infants are at higher risk for learning disabilities and 

future difficulties in school. Predictors of these problems in VLBW infants include small head 

circumference and decreased head growth velocity during the first several months of life.

Visual Disability

VLBW infants also are at increased risk for retinal and non-retinal ophthalmic disorders that 

lead to visual disability. This increased risk is primarily due to complications of prematurity, 

primarily ROP and CNS injury. The more immature the infant, the greater is its risk for any, as 

well as for severe ROP and CNS injury. The greater the severity of ROP, the greater is the risk 

for unfavorable structural and functional outcome (reduced acuity, blindness, abnormal fixation, 

strabismus, myopia, amblyopia). Infants with threshold (severe) ROP are known to be at very 

high risk for unfavorable structural and functional ophthalmic outcome. Treatment options for 

severe ROP, such as retinal ablation with laser therapy, are beneficial, but not always successful. 

Even when treatment is successful, the long-term visual outcome of infants with severe ROP is 

not satisfactory. Among threshold ROP eyes that are treated, 40 to 60% of the eyes have 

unfavorable visual outcome and 20 to 30% of the eyes become blind.

CNS injury is a separate, independent contributor to visual disability that often co-exists with 

ROP in the premature VLBW infant. The more severe the cerebral white matter damage, as 

demonstrated by cystic PVL, ventriculomegaly, and IVH, the greater the risk of cortical visual 

disability. The degree of visual impairment correlates very strongly with the degree of 

neurodevelopmental impairment. This evidence emphasizes the importance of ocular assessment 

of VLBW children with CNS damage, and neurodevelopmental assessment in VLBW children 

with visual disabilities.

The most common visual disabilities in VLBW infants resulting from ROP and/or CNS 

injury include significant reduction in visual acuity (including blindness), abnormal fixation, 

strabismus, and severe myopia. Visual fields, contrast sensitivity, and other visual functions may 

also be impaired. BPD also appears to contribute to greater visual impairment. Thus, ROP, CNS 
140

injury, and BPD individually and collectively contribute to visual disability in the premature 

VLBW infant. 

The first year of life is a critical period for visual development, and vision is a crucial 

determinant of early motor and cognitive development. Careful assessment of vision in visually 

high-risk infants is essential during the neonatal and infancy period, and must continue through 

the first several months and years of life to permit detection of abnormal acuity, strabismus, 

amblyopia, refractive errors, etc. Studies emphasize that premature infants at risk for ophthalmic 

disability, and those with documented ophthalmic sequelae early in infancy, require close, longterm follow-up due to evidence that infants may have progressive, ophthalmic deterioration over 

time. Omission of or inadequate follow-up may contribute to worsening visual outcome or 

blindness if appropriate timing of interventions for treatable conditions is missed. 

No single visual test at one point in time can adequately assess the various multiple visual 

functions. Meaningful evaluation of visual function requires comprehensive, repeated, long-term 

assessments for acuity, refractive error, ocular motility, fixation, visual fields, contrast 

sensitivity, and color vision in conjunction with neurodevelopmental assessment. The specific 

method and timing of the ocular tests must be in accordance with the infant’s age and 

capabilities. The reality of life-long therapeutic, educational, psychosocial, and socioeconomic 

significance and costs of visually disabled VLBW children highlights the importance of ocular 

assessment and appropriate timing of intervention. This, in turn, helps to minimize visual 

disability and to maximize the adaptation if visual disability exists.

Pulmonary Disability

The studies reviewed indicate that VLBW infants with BPD are at increased risk for longterm pulmonary disability. The greater the severity of BPD, the greater is the association with 

long-term pulmonary impairment and need for re-hospitalization. On the whole, VLBW preterm 

infants without BPD are comparable to full-term children in terms of pulmonary outcome. 

VLBW infants with less severe BPD may have respiratory disability primarily during the first 

two years of life. VLBW infants with more severe BPD may have persistent lung disease during 

young childhood and continuing through to their adolescent, young adult years. 

Preterm children with chronic lung disease due to BPD vary in their manifestations of 

pulmonary disability. Lung dysfunction can be demonstrated by formal pulmonary function 

testing and abnormal physical examination findings. The most frequently described 

consequences of pulmonary disability are increased respiratory symptoms (e.g. wheezing and 

cough), respiratory illnesses, and the need for respiratory medications. All of these reflect the 

underlying physiologic consequences of aberrant growth, development and function of injured 

premature lungs. Re-admission to the hospital for respiratory illnesses, such as asthma, 

pneumonia, recurrent bronchitis, and exacerbations of chronic lung disease, is unfortunately 

common in the first two years of life. The need for hospital admission for issues related to 

failure- to-thrive due to poor growth, surgeries or other reasons is also increased in VLBW 

infants with BPD compared to full term infants. Although it appears that premature infants in the 

current era of neonatal care do not have as severe BPD as in the era prior to the widespread use 

of antenatal steroids and surfactant, BPD still accounts for significant long-term, multi-system 

morbidity.
141

Poor Growth

Recent studies continue to provide evidence that VLBW infants have significantly lower 

weight and height, and may have abnormal body composition and bone mineralization, during 

the first years of life compared to children who were born full-term. Growth impairment in 

VLBW/ELBW infants is due largely to prolonged, acute neonatal illnesses and subsequent 

chronic illnesses (e.g. BPD, gastroesophageal reflux, short-gut syndrome). But failure to grow 

(i.e. weight <3rd and <10th percentile through 2 years of age) in high risk VLBW/ELBW infants 

is also strongly associated with neurosensory developmental abnormalities and motor skills that 

impact the child’s feeding ability. Attainment of appropriate growth and nutrition in VLBW 

infants is an important challenge that requires conscientious attention over the course of months 

and years after initial discharge from the neonatal unit. This is particularly true for children who 

have long-term disabilities related to BPD, short-gut syndrome from necrotizing enterocolitis, 

and neuromotor, neurosensory, cognitive, and/or neurobehavioral disorders within the context of 

an adverse social/parenting setting.
143

Chapter 5. Future Research

In this section, we propose two prospective health service research opportunities. These 

proposals would help SSA evaluate the application process of VLBW disability criteria and 

determine the appropriateness of the criteria for identifying high-risk VLBW infants. In addition, 

we propose concepts to improve identification of risk factors and outcomes.

Evaluation of the Application Process of SSA VLBW 

Disability Criteria

This proposed research concept involves more complete reporting of regional applications of 

the VLBW disability criteria based on the entire VLBW population within regions. The proposed 

research would document baseline risk factor data on all VLBW infants born within participating 

regions, follow surviving VLBW infants for specified periods of time with respect to prespecified, disabilities (1, 2, 3, 5, 10, 12 years of age), and document the proportion of VLBW 

who come to the attention of SSA, relative to the entire regional cohort of VLBW infants. This 

research proposal would accomplish several objectives:

• SSA could compare baseline characteristics of VLBW infants who do and do not come to 

the attention of SSA. 

• SSA could assess the consistency of applying SSA VLBW Disability Criteria. This 

would, in turn, provide greater insight into reasons for successful programmatic 

implementation and impediments of applying the criteria. It would provide insight 

regarding the effectiveness of identifying high-risk VLBW infants.

• Provide an opportunity for SSA to standardize uniformity in assessing disabilities in this 

high-risk cohort at different ages.

• Identify barriers to referring infants to SSA.

Determine the Appropriateness of the New VLBW Disability 

Criteria Proposed by SSA Based on the Evidence of This 

Report. 

This proposed research concept involves the evaluation of VLBW infants who do and do not 

meet the new disability criteria to ascertain the sensitivity, specificity, positive and negative 

predictive values of the new SSA disability criteria for VLBW infants. This second proposed 

research concept is a natural “next- step” linked to the first research concept proposed above. 

The combination of these two concepts affords the SSA the ability to know if the process and the 

criteria are achieving the objectives established by the SSA.
144

Proposal to Improve the Evidence of Predictors and 

Predictive Models

Improve Definitions of Predictors

The current literature provides evidence, which confirms that VLBW infants with or without 

various conditions are at increased risk for multiple long-term disabilities. Large and 

methodologically sound studies performed in a variety of settings have identified several risk 

factors (e.g. gestational age, CNS damage, ROP, BPD) that appear to have consistent and 

independent associations with subsequent abnormal neurodevelopmental outcome. The identified 

demographic and clinical factors are important, helpful, and necessary evidence, but current 

definitions of clinical risk factors have limitations. Each risk factor has a spectrum of severity. 

Three examples for possible definition refinement include 1) criteria for screening and diagnosis 

of cerebral WMD, 2) criteria for high-risk ROP, and 3) criteria for high-risk BPD. More specific 

definition of the predictors may better characterize an infant’s risk for having a specific 

disability(ies).

In addition to refining predictor definitions, the development of a robust, well designed, and 

carefully validated predictive model, constructed with clinically significant factors available at 

the time of hospital discharge, could create a “profile” of a VLBW infant at risk for specific 

disabilities. Such a predictive model does not yet exist. A series of models could be developed 

and validated to incorporate new factors and information noted during the specified times of 

follow-up. The presence or absence of deficits on physical, neurological, and developmental 

examinations at subsequent follow-up appointments (e.g. at 6, 12, 24 months of corrected age) 

may significantly refine assessment of risk for sustained disabilities. Refinement of risk factors 

invites a systematic, collaborative effort to develop a series of predictive models using large 

regional cohorts of VLBW infants, followed by validation of the model in an independent group.

Identify New Predictors

Current predictors of disabilities in VLBW infants are markers of the underlying 

complications and morbidities. Multiple levels of risk factors exist, including demographic and 

clinical factors, as well as physiologic, biochemical, molecular, and genetic factors. Most of the 

factors beyond demographic and clinical data are not well described. Better understanding of 

pathogenesis and the “biochemical, molecular, and genetic” epidemiology of a disease process 

could provide a more comprehensive profile of the “condition(s)” that predispose to VLBW 

infants to certain disabilities. Current research is underway to refine our molecular and clinical 

understanding of the determinants of major morbidities (CNS damage, ROP, BPD) of extremely 

low gestational age neonates. These and other studies should refine our ability to improve 

criteria for infants at risk for adverse outcomes. 
145

Feasibility of Future Research Proposals

These proposals are ambitious. The logistical issues of organizing, funding, and 

implementing these long-term collaborative endeavors present enormous, but achievable, 

challenges. The fact that large scale follow-up of VLBW infants over many years can be 

accomplished is reflected in the studies reviewed. Regions that have committed leadership and 

established neonatal programs for achieving the objectives noted above should be solicited in 

order to ensure the success of this endeavor. 

The follow-up of VLBW infants is a major public health concern. Prospective neonatal 

health services research that facilitates linkage of significant risk factors with outcomes is 

essential to care providers in assessing care practices and to agencies providing health services. 

Research efforts to identify amenable determinants of premature birth, CNS damage, ROP, and 

BPD are in progress. Research promoting the identification and dissemination of “best care 

practices”, as well as determinants of prematurity and its consequences should be encouraged 

and supported.

The VLBW child with long-term disabilities is a challenge to his/her family, teachers, 

physicians, and society. This challenge often stems from the complexities of the child’s issues 

coupled with inadequate resources and support for effective assessment and intervention on a 

long-term basis. The standard techniques currently available to evaluate function are often not 

adequate to describe the extent and nature of impairment. Educational interventions will vary for 

children with different disabilities. Although specific educational programs exist for children 

with disabilities, they may not be widely accessible. The potential for a child with multiple 

handicaps to live independently and productively is often compromised if access to effective 

rehabilitation is not available or limited. For prematurely born children who sustain 

complications that result in neurodevelopmental and neurosensory disability, effective efforts 

must be made to identify these children and their specific issues/needs early in infancy. These 

children need recurrent reassessment of their abilities and/or disabilities over time in order to 

detect progression of disabilities and to provide appropriate early intervention or rehabilitation to 

maximize their capabilities and limit their disabilities.
147

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differ from those followed up with difficulty. Arch Dis 

Child Fetal Neonatal Ed 1998;79(2):83-7.

Tin W, Milligan DW, Pennefather P et al. Pulse 

oximetry, severe retinopathy, and outcome at one year 

in babies of less than 28 weeks gestation. Arch Dis 

Child Fetal Neonatal Ed 2001 Mar;84(2):F106-F110.

Torrioli MG, Frisone MF, Bonvini L et al. Perceptualmotor, visual and cognitive ability in very low 

birthweight preschool children without neonatal 

ultrasound abnormalities. Brain Dev 2000;22(3):163-8.

Valkama AM, Paakko EL, Vainionpaa LK et al. 

Magnetic resonance imaging at term and neuromotor 

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Mar;89(3):348-55.

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Neurodevelopmental and functional outcomes of 

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1998 Jul;87(7):780-5.

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Neonatal cranial ultrasound abnormalities in low birth 

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Prediction of 12-month neurodevelopmental outcome 

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attainment, and prereading skills of 6-year-old very 

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Longitudinal Study. Dev Med Child Neurol 1999 

Feb;41(2):94-109.

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10;343(6):378-84.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

3

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Akerman 

1992

93255928

Location: Sweden

Years of Birth: ND

Median GA (range), wk: 7 pairs < 

37 wks

Median BW (range), g: 37 < 2500 g 

(23 of these > 37 wks)

Male: 46%

Race: ND

Enrolled: 35 parents who were 

expecting twins

Evaluated: 68 (34 twin pairs)

Number of sites: 1

ND

(35 parents who were 

expecting twins)

ND

(One child in a twin pair was 

stillborn)

Low born twins (68, 

or 34 pairs)

Prospective longitudinal 

cohort 

(at 9, 18 months, and 4 

years)

Thompson 

1993

93234177

Location: South African

Years of Birth: 1988 to 1989

Mean GA (range), wk: 32±2.5 

(26.8-40)

Mean BW (range), g: 1044±149 

(600-1250)

Male: 50%

Race: ND

Enrolled: 143

Evaluated: 143

Number of sites: 1

BW <1250 g ventilated 

infants

Survived to hospital 

discharge

Infants <900g and 

<28week are not routinely 

ventilated

VLBW ventilated 

infants (143)

Prospective cohort 

(2 years)

Rademaker 

1994

95003452

Location: Netherlands

Years of Birth: 9/1989-9/1992

Mean GA (range), wk: 25-32

Mean BW (range), g: 820-2200

Male: 70%

Race: ND

Enrolled: 20

Evaluated: 20

Number of sites: 1

GA = 32 weeks

Unilateral parenchymal 

involvement on cranial 

ultrasound 

associated with GLH 

Germinal 

layer hemorrhage or IVH

ND Preterm infants (GA 

32 weeks or less) 

with diagnosis of 

unilateral 

parenchymal 

involvement (20)

Prospective cohort
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

4

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Vonderveid

1994

94297368

Location: Italy

Years of Birth: 1987-1988

Mean GA: ND

Mean BW : ND (only range: 500-

1499 g)

Male: ND

Race: ND

Enrolled: 634

Evaluated: 390 (alive at 2 yrs)

Number of sites: 8

All newborns with BW: 500-

1500 g BW

Admitted in one of the 8 

participating NICUs

Born between 1/1987-

12/1988

ND Sample 1:

VLBW (500-1000 g): 

(191)

Sample 2:

LBW (1000-1499f):

(443)

Prospective cohort study

( 24 mo CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

5

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Kraybill

1995

95264242

Location: USA

Years of Birth: 1986-1989

Sample with F/up at 1 year

Mean GA:

 Sample 1: 28.2 ±1.9

 Sample 2: 28.1 ±2.0

Mean BW: 

 Sample 1: 1022 ±177

 Sample 2: 1028 ±184

Male:

Sample 1: 51% Sample 2: 52%

Race:

 Sample 1: White: 21%, Black: 

53%, Hispanic: 23%, Other; 4%

Sample 2: White: 34%, Black: 

42%, Hispanic: 22%, Other: 2%

Enrolled: 323 (survivors at 1 yr)

Evaluated: 258 (at 1 yr f/up)

Sample with F/up at 2 years

Mean GA: Sample 1: 28.3 ±1.8

 Sample 2: 28.1 ±1.8

Mean BW: Sample 1: 1043 ±165

 Sample 2: 1005 ±184

Male:

Sample 1: 49% Sample 2: 43%

Race:

 Sample 1: White: 35%, Black: 

60%, Other:5%

 Sample 2: White: 43%, Black: 

54%, Other: 3%

Enrolled: 136 (survivors at 2 yrs)

Evaluated: 118

Number of sites: 2 

Premature VLBW: 

700-1350 g

(Detailed description 

available in another article)

ND At 1 yr f/up 

Sample 1:

Synthetic Surfactant 

at

Birth via ET tube: 5

ml/kg (136)

Sample 2:

Air placebo via ET

tube at birth (122)

At 2 yr F/up

Sample 1:

Synthetic surfactant 

at birth (57)

Sample 2:

Air placebo (61)

Randomized placebocontrolled double blind 

trial 

(at 1 year and at 2 years 

CA) 
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

6

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Speechley

1995

96356544

Location: Canada

Years of Birth: 1978-1980

Mean GA:

 Sample 1: 37 (28-43)

 Sample 2: 40 (37-44)

Mean BW:

 Sample 1: 2790 (850-4550)

 Sample 2: 3503 (2660-5170)

Male:

 Sample 1: 56%

 Sample 2: 50%

Race: 

 Sample 1: whites : 90%

 Sample 2: whites: 90%

(Original study: was a randomized 

interventional study of having a 

family volunteer visit the home on a 

regular base for 6 months)

Eligible (for the original study): 828

Enrolled (for the original RCT): 

312 

Evaluated (at 12 yrs): 253 

Number of sites: 1

All infants born at a tertiary 

care hospital in Ontario

Born between 1978-1980

Transferred to NICU or 

Normal Neonatal Nursery 

(NNN)

Family residence

more than 120 Km from 

hospital

Newborn’s survival was in 

question

Language barrier

Refused to participate to the 

original RCT.

Sample 1:

Former NICU

graduates: [116]

Sample 2:

Former NNN 

graduates [137]

Prospective, longitudinal, 

comparative, 

observational study 

(12 yrs)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

7

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Hack

1996

97060805

Location: US

Years of Birth: 1/1977 to 12/1979

Mean GA (range), wk: 30±2

Mean BW (range), g: 1177±218

Male: ND

Race: Mother black race 56%

Enrolled: 249

Evaluated: 249 (363 controls)

Number of sites: 1

 VLBW infants, BW 

<1500gm, survived to 2 

years of 

age

NBW: randomly selected 

NBW 

children (the selection 

method was 

described in the prior 

papers)

ND VLBW infants

 (249)

Sample 1: AGA 

(199)

Sample 2: SGA 

(50) 

NBW infants: (363)

Prospective cohort 

(8 years) 

Hack

1996

97066007

Location: US

Years of Birth: 7/1982-6/1988, 

1/1990-12/1992

Mean GA (range), wk:

Sample 1: 25.9±2 (22-31)

Sample 1: 25.7±2 (22-31)

Mean BW (range), g:

Sample 1: 688.6±73 (560-740)

Sample 2: 670.6±56 (502-742)

Male: 

Sample 1: 28%

Sample 2: 29%

Race: White

Sample 1: 31%

Sample 2: 37%

Enrolled: 280

Evaluated: 280

Number of sites: 1

BW 500-759 g

Survived to 20 months 

corrected 

Age

ND Sample 1: VLBW 

survived infants 

born in 1990-1992 

(surfactant/dex 

era) (114)

Sample 2: VLBW 

survived infants 

born in 1982-1988 

(surfactant and 

less dex. era) 

(166) 

Prospective cohort 

(followed to 20 months 

corrected age)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

8

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Northern Neonatal 

Nursing Initiative 

Trial Group

1996

96304894

Location: UK

Years of Birth: 1990-1992

Mean GA (range), wk: 29 (27-31)

Mean BW (range), g: 1253 (965-

1543)

Male: 39%

Race: ND

Enrolled: 776

Evaluated: 776

Number of sites: 16

GA <32 weeks; resident in 

northern UK

ND Experiment 1: fresh 

frozen plasma 

treatment (257)

Experiment 2: gelatin 

plasma substitute 

(261)

Glucose controls 

(258)

Randomized controlled

trial 

(2 years)

Sethi

1996

96334245

Location: UK

Years of Birth: 1989-1992

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

SES: ND

Enrolled: 93

Evaluated: 92

Number of sites: 1

Liveborn infants BW <1501 g

Survived until discharged

ND VLBW infants 92 Prospective cohort 

(2 years)

Wilkinson

1996

97087405

Location: Australia

Years of Birth: 1/1989-12/1991

Mean GA (range), wk: 27.7 (23-34)

Mean BW (range), g: 1144 (700-

1725)

Male: 50%

Race: ND

Enrolled: 12

Evaluated: 10

Number of sites: 1

All NICU admissions <35 

weeks GA or BW<1500g 

who had cranial US with 

cystic PVL

ND VLBW preterm 

infants (10)

Retrospective cohort
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

9

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

DeReginer 

1997

98041177

Location: US

Years of Birth: 1987-1991

Mean GA (range), wk:

Sample 1: 28.0±1.5

Sample 2: 27.1±1.2

Sample 3: 27.5±1.7

Mean BW (range), g:

Sample 1: 1030±140

Sample 2: 1007±122

Sample 3: 1007±140

Male: ND

Race: ND

Enrolled: 174

Evaluated: 164

Number of sites: 2

BW =1500 g survived until 

Discharged

Able to match to a patient in 

other 

two respiratory groups

Presence of LBW 

independent of chronic lung 

disease known to adversely 

affect neurodevelopment, 

sensory, or growth, i.e. 

severe intracranial 

abnormalities, congenital 

anomalies or viral 

infections, etc.

Unable to match to a 

patient in other groups

Died after discharged (6)

Lost to follow-up (4)

Sample 1: 

No chronic lung 

disease (58)

Sample 2:

Mild chronic lung 

disease (58)

Sample 3:

Severe chronic lung 

disease (58)

Retrospective chart 

review with marched 

subject group

(1 year of adjusted age)

Dezoete

1997

97359687

Location: New Zealand

Years of Birth: 1990-1992

Mean GA (range), wk: 26.7±1.9

Mean BW (range), g: 834.6±120.0

Male: 51%

Race: European 63%, Maori 20%,

Other 22%

SGA: 32%

Enrolled: 110

Evaluated: 105

Number of sites: 1

BW<1000g and survived to 

hospital discharge.

Died after discharge

Congenital malformations

Lost to follow-up

VLBW infants (105) Prospective cohort

(18 months)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

10

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

O’Shea

1997

98049056

*overlapped 

sample with 

98190123

Location: US

Years of Birth: 1979-1994

Mean GA (range), wk:

Sample 1: 25 (22-31)

Sample 2: 25 (22-30)

Sample 3: 25 (22-29)

Mean BW (range), g:

Sample 1: 673 (522-790)

Sample 2: 670 (527-800)

Sample 3: 688 (520-793)

Male: 

Sample 1: 49%

Sample 2: 51%

Sample 3: 48%

Race: White

Sample 1: 61%

Sample 2: 60%

Sample 3: 56%

Enrolled: 513

Evaluated: 513 ? 216 (1 year of 

age)

Number of sites: 2

BW 501-800g

Born to mother’s residing in 

17 countries in NW 

N.Carolina

Survived to 1 year of age

ND Sample 1: VLBW 

infants born 

between 7/1/1979 

and 6/30/1984 

(120 ? 24)

Sample 2: VLBW 

infants born 

between 7/1/1984 

and 6/30/1989 

(175 ? 63)

Sample 3: VLBW 

infants born 

between 7/1/1984 

and 6/30/1994 

(218 ? 129)

Retrospective cohort 

(1 year corrected age)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

11

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Piecuch

1997 

97456215

Location: US

Years of Birth: 1979-1991

Median GA (range), wk:

Sample 1: 25.9±1.5 (24-29)

Sample 2: 25.8±1.6 (24-32)

Sample 3: 26.3±1.5 (24-32)

Sample 4: 27.1±1.4 (24-34)

Sample 5: 27.8±1.7 (25-35)

Mean BW (range), g:

Sample 1: 560±28

Sample 2: 653±28

Sample 3: 747±29

Sample 4: 850±29

Sample 5: 942±30

Male: 

Sample 1: 25%

Sample 2: 24%

Sample 3: 48%

Sample 4: 47%

Sample 5: 48%

Race: ND

Enrolled: 518

Evaluated: 445

Number of sites: 2

BW<1000g

Discharged from Mt. Zion 

Hospital + M.C. & UCSF

Genetic diagnosis

{Died after discharge (14)

Lost to follow-up (58)

Late genetic diagnosis (1)}

Sample 1: BW 500-

599 (15)

Sample 2: BW 600-

699 (38)

Sample 3: BW 700-

799 (92)

Sample 4: BW 800-

899 (135)

Sample 5: BW 900-

999 (165)

Prospective cohort 

(1 year)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

12

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Piecuch

1997 

98012134

Location: US

Years of Birth: 1990-1994

Mean GA (range), wk:

Sample 1: 24

Sample 2: 25

Sample 3: 26

Mean BW (range), g:

Sample 1: 668±91 (450-850)

Sample 2: 790±115 (550-1000)

Sample 3: 842±158 (505-1260)

Male: 

Sample 1: 50%

Sample 2: 73%

Sample 3: 50%

Race: ND

SES: high social risk

Sample 1: 89%

Sample 2: 43%

Sample 3: 68%

Enrolled: 94

Evaluated: 86

Number of sites: 1

24, 25 or 26 week GA

Non-anomalous

Born at University of 

California, 

San Francisco

ND

(Died after discharge (2)

Accidental severe central 

nervous system insult after 

discharge (1)

Lost to follow-up (5)}

Sample 1: GA 24 

weeks (18)

Sample 2: GA 25 

weeks (30)

Sample 3: GA 26 

weeks (38)

Prospective cohort 

(at 12months, 18 

months, 2 1⁄2 years, 4 1⁄2

years. 7-8 years)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

13

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Singer

1997

98049057

Singer

2001

21163669

Location: US

Years of Birth: 1989-1991

Mean GA (range), wk: 

Sample 1: 27±2

Sample 2: 30±2

Controls: 40±2

Mean BW (range), g: 

Sample 1: 956±248

Sample 2: 1252±178

Controls: 3451±526

Male: 

Sample 1: 52%

Sample 2: 43%

Controls: 50%

Race: White

Sample 1: 55%

Sample 2: 48%

Controls: 51%

SES: Hollingshed classification: 

Sample 1: 3.5±1

Sample 2: 3.6±1

Controls: 3.6±1

Enrolled: 464

Evaluated: 206 (123 controls)

Number of sites: 3

Cases (sample 1&2): 

premature infants, BW < 

1500g

Controls: term infants with 

no diagnosed medical 

illness or abnormalities at 

birth, >36 weeks, 

GW>2500g

Major congenital abnormality

Drug exposure

Maternal illness

HIV

Maternal mental retardation

>2 hours driving time from 

hospital

Sample 1: VLBW 

infants with BPD 

infants (122)

Sample 2: VLBW 

without BPD (84)

Sample 3: Full term 

infants (123)

Prospective cohort 

(followed to 3 years 

corrected age)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

14

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Victorian Infant 

Collaborative study 

Group, 1997

98026322

*This study is also 

in CNS table

Location: Australia

Years of Birth: 

1979-80, 1985-87, 1991-92

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 453 (242 controls)

Evaluated: 448 (242)

Number of sites: 3

ELBW infant (Sample 1-3ts, 

BW 

500-999 g born in Victoria, 

Australia survived to 

age of 2 years

Controls:

Normal birth weight (>2499 

g) 

infants born in 1991-1992

Excluded infants born in 

1979-1980 for current 

review

ELBW infants (448):

Sample 1: born in 

1985-1987 (212)

Sample 2: born in 

1991-1992 (241)

Controls: Normal BW 

(>2499 g) infants 

(242)

Retrospective cohort 

(2 years)

Victorian Infant 

Collaborative study 

Group, 1997 

97466059

Location: Australia

Years of Birth: 1979-80, 1985-87, 

1991-92

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 36

Evaluated: 35

Number of sites: 3

ELBW infants, BW 500-999 

g born outside the level III 

perinatal centers in 

Victoria, Australia survived 

to age of 2 years

Excluded infants born in 

1979-1980 for current 

review

ELBW infants (36):

Sample 1: born in 

1985-1987 (19)

Sample 2: born in 

1991-1992 (16)

Retrospective cohort 

(2 years)

Cheung

1998

99059896

Location: Canada

Years of Birth: 12/93-10/97

Mean GA (range), wk: 25 (24-30)

Median BW (range), g: 860 (340-

1460)

Male: 67%

Race: ND

Enrolled: 24

Evaluated: 10

Number of sites: 1

VLBW survivors, BW < 1500 

g, 

Requiring inhaled nitrous 

oxide 

(INO) (continues to be 

hypoxenic) 

at >90% O2 and MAP 15 ±

2)

Mosaic trisomy 18

Potter’s syndrome

Survived to 1 year of 

chronological age

VLBW infants treated 

with INO (10)

Prospective cohort 
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

15

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Finnström

1998

99041345

Location: Sweden

Years of Birth: 1990-1992

Mean GA (range), wk: ND

Mean BW (range), g: 798±144

Male: ND

Race: ND

Enrolled: 370

Evaluated: 362

Number of sites: ND

BW = 1000 g and GA = 23 

weeks

Survived to the age of 1 year 

ND Preterm infants (362) Prospective cohort of a 

previously published 

study 

(followed to the median

corrected age of 36 

months)

Gregoire

1998

98232532

Location: Canada

Years of Birth: 1987-1992

Mean GA (range), wk:

Sample 1: 27.3±1.1

Sample 2: 26.8±1.3

Comparison: 27.9±0.8

Mean BW (range), g:

Sample 1: 997±195

Sample 2: 930±178

Comparison: 1129±181

Male: 

Sample 1: 45%

Sample 2: 56%

Comparison: 45%

Race: ND

Enrolled: 217

Evaluated: 217

Number of sites: 1

Inborn infants GA 24-28 

weeks, 

Admitted to NICU

Survival to 18 months CA

ND Sample 1: BPD-1 

group – preterm 

infants who 

received O2 at 28 

days but not at 396 

weeks’ GA (48) 

Sample 2: BPD-2 

group – preterm 

infants with oxygen 

dependency at 36 

weeks’ GA (93)

Comparison: preterm 

infants who were 

not oxygendependent at 28 

days of age (76)

Prospective cohort 

(18.5±1.1 months )
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

16

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Kurkinen-Raty 1998

98387235

(All+Lung)

*sample from the 

same big 

population as 

20284814

Location: Finland

Years of Birth: 1990-1996

Mean GA (range), wk:

Cases: 28.2 (23.8- 37.2)

Controls: 28.4 (22.9-36.9)

Mean BW (range), g:

Cases: 1138.3±434

Controls: 1272.4±547.2

Male: ND

Race: ND

Enrolled: 78 (78 controls)

Evaluated: 78 (78)

Number of sites: 1

Preterm PROM between 17-

30 weeks gestation; 

singleton; delivered > 2 hr 

after rupture

Controls: preterm no PROM; 

spontaneous preterm 

delivery matched for GA 

and year of delivery.

Rupture unconfirmed or 

transient

Sample 2: Preterm 

rupture (78)

Sample 2: Preterm 

delivery no rupture 

(78)

Retrospective cohort
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

17

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Lee

1998

98442293

Location: Canada

Years of Birth: 1990-1995

Mean GA: ND

Mean BW:

 Sample 1: 763 ±157

 Sample 2: 807±176

Male: ND

Race: ND

Enrolled: ND (total N not given, 

data only for enrolled cases with 

candidemia: N= 29)

Evaluated: 50

Assessed for outcome: 35 (14 

cases and 21 controls)

Number of sites: 2

For cases:

Prematures with BW<1250 g

Admitted in the NICU s of 

UAH and RAH from 1990-

1995

Diagnosis of candidemia: by 

at least one positive blood 

culture

Diagnosis of candidal 

meningitis:

By isolation of candida in the 

CSF or >45x10 6 WBCs in 

the CSF and candidemia.

For controls:

Prematures with BW <1250 

g

Admitted to the same NICUs

during the same period 

without

candidal infection

Neonates with major 

congenital anomalies

Sample 1:

Premature infants 

<1250 with 

candidemia and/ or 

candida

meningitis (25)

 Sample 2:

 Premature neonates 

with BW <1250 

matched with cases 

for BW, GA, sex and 

admission dates, 

without candidal 

infection (25)

Retrospective

longitudinal comparative

study with case control

design and cases

defined based on

exposure to candidemia

and matched controls

( f/up between 37 and 

70 mo CA)

Average age at

assessment: for cases

:31 ±19 mo, and for

controls: 28 ±20 mo 

Lefebvre

1998

98387703

Location: Canada

Years of Birth: 1987-1992

Mean GA (range), wk: 27.0±1.2

Mean BW (range), g: 961±179

 (585-1450)

Male: 52%

Race: ND

Enrolled: 139

Evaluated: 121

Number of sites: 1

GA<28 weeks

3 or more cranial 

ultrasounds

Survival to discharge

ND Preterm infants 

(121):

Low risk (50)

Moderate risk (37)

High risk (34)

Prospective cohort (CA 

18.6±1.2 [17-19] 

months)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

18

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Millet

1998

98212544

Location: France

Years of Birth: ND

Mean GA (range), wk: 31±3 (25-

36)

Mean BW (range), g: 1243±400

Male: 75%

Race: ND

Enrolled: 60

Evaluated: 40 (20 controls)

Number of sites: 1

Neonates considered at risk 

of neurologic impairment

Severe neurologic 

abnormalities (HIE, PVL, 

brain malformations and 

congruental infections) 

Premature infants 

(40)

Term infants (20)

Prospective cohort (3-6 

months correlated age)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

19

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Piecuch

1998

98446413

Location: USA

Years of Birth: 

 Sample 1: 1989-1991

 Sample 2: 1984-1986

 Sample 3: 1979-1981

Mean GA:

 Sample 1: 29 ±2

 Sample 2: 30 ±2

 Sample 3: 30 ±2

Mean BW:

 Sample 1: 1221 ±142

 Sample 2: 1235 ±140

 Sample 3: 1246 ±146

Male:

 Sample 1: 56%

 Sample 2: 50%

 Sample 3: 46%

Race: ND

Enrolled: 563

Evaluated: 450

Number of sites: 4

Prematurity

BW: 1000-1499 g

Discharged from NICUs of 5 

Hospitals 

Born in one of the three time 

periods: 

1989-1991 (Recent)

1984-1986 (Middle)

1979-1981 (Early)

Congenital anomalies Comparison of the 

outcome of infants 

1000-1499 g born in 

three time periods:

Most recently born

Born at a middle 

period

Born at an early 

period

Sample 1: 

Born most recently, 

between 1989-1991 

(186)

Sample 2:

Born in a middle 

period, between: 

1984-1986 (155)

Sample 3:

Born in an early 

period, between 

1979-1981

(109)

(Not clearly stated)

Retrospective

longitudinal comparative

cohort study

Age for outcome

assessment was not

specified. It could be

done up to 7.5-8 yrs of

age

(Mean ages of f/up were:

 24, 54, 75 mo for the 3 

periods)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

20

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Sajaniemi

1998

99041674

Location: Finland

Years of Birth: 1989-1991

Mean GA:

 Sample 1: 28.9 (23-35)

 Sample 2: 39.4 (36-43)

Mean BW:

 Sample 1: 1205 (560-2360)

 Sample 2: 3461 (2510-5360)

Male: ND

Race: ND

Enrolled: ND

Evaluated : 160

Number of sites: 1

For Preterm Group (sample 

1):

GA: 23-34 wks

Mother being referred to 

University Central Hospital of 

Helsinki for threatened 

preterm delivery

Born between 1989-1991

For Full term group (Sample 

2):

Born in Metropolitan Helsinki

Visiting pediatric services in 

Helsinki for acute infectious 

diseases

For Preterm group

If mothers had 

chorioamnionitis

If mother had insulin 

dependent diabetes

Children with congenital 

anomalies, by U/S

For Full term group

Chronic diseases

Developmental delay

Sample 1:

Preterm infants

(80)

Sample 2

Full term enrolled at:

20-28 mo of age (80)

Retrospective

comparative study

(24 mo CA)

Scherjon

1998

98429216

Location: Netherlands

Years of Birth: 1989

Mean GA: ND 

[median and range given: 30.4 

(26.1-32.8)]

Mean BW: ND 

(median and range given: 1295

(605-2295)]

Male: ND

Race: ND

Enrolled: 106

Evaluated: 96 (at 3 yrs)

Number of sites: 1

Pregnant mother admitted to 

Obstetric Department of 

Amsterdam university with 

threatened preterm delivery

 GA < 33 wks.

Admitted during a 10 month 

period in 1989 

Pregnancies with known 

congenital or chromosomal 

anomalies

Infants born

prematurely between

26-33 wks (96)

Prospective

observational cohort

study

(3 yrs CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

21

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Cheung

1999

99146391

Location: Canada

Years of Birth: 1990-1993

Mean GA (range), wk:

Sample 1: 25 (22-29)

Sample 2: 26 (24-30)

Sample 3: 28 (23-32)

Mean BW (range), g:

Sample 1: 660±56

Sample 2: 873±73

Sample 3: 1127±71

Male: total 57%

Race: ND

Enrolled: 187

Evaluated: 164

Number of sites: 2

BW<1250 gm

GA < 32 weeks

Mild or no significant 

respiratory 

disease (O2 < 30%, RR < 70)

Major congenital 

abnormalities, syndromes

Infants with neurologic insult 

after discharge from NICU.

Sample 1: 

BW 500-749 g (26)

Sample 2:

BW 750-999 g (63)

Sample 3:

BW 1000-1249 g (75)

Prospective cohort 

(followed to 24 months 

adjusted age)

Duvanel

1999

99207097

Location: Switzerland 

Years of Birth: 1982-1990

Mean GA:

 Sample 1: 31.9 ±2.1

 Sample 2: 31.9 ±1.7

Mean BW (range)

 Sample 1:1142 ±285

 Sample 2: 1186 ±229

Male: 

 Sample 1: 47%

 Sample 2: 57% 

Race: ND

Enrolled: : ND 

Evaluated: 85

Number of sites: 1

Prematurity (< 34 weeks GA)

SGA (BW < 10% percentile)

Cases: hypoglycemia: 

glucose level < 47 mg/dl

Controls-matched: (not 

specified for which 

parameters): blood glucose 

> 47 mg/dl

.

Major malformations

Metabolic diseases

Periventricular leukomalacia

Grade IV cerebral 

hemorrhage

Psychiatric illness detected in 

follow up study

Very low socioeconomic 

status

Sample 1 

Hypoglycemic (62)

Sample 2: 

Euglycemic (23)

Retrospective 

longitudinal cohort

study with case control 

design. Cases defined 

based on exposure.

Control group matched

with cases (not specified

for which parameters)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

22

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Pennefather, 1999

20002011

Pennefather, 2000

20217908

* This study is 

also in eye table

Location: UK

Years of Birth: 1/1/90-12/31/91

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 566

Evaluated: 558

Number of sites: ND

All surviving children <32wk 

GA 

born in geographically 

deprived 

region in Northern UK

Survived to 2 years old

No examined at age 2 

years old

Preterm infants (558) Prospective cohort and 

retrospective review of 

patient records 

(2-3 

years)

Ambalavanan

2000

21031370

Location: US

Years of Birth: 1/1990 to 12/1994

Mean GA (range), wk: 26±2

Mean BW (range), g: 829±123

Male: 45%

Race: African-American 66%

Enrolled: 218

Evaluated: 218

Number of sites: 1

ELBW infants, BW <1000 g ND ELBW infants (218) Retrospective cohort 

(followed to 18 months 

of age)

Cioni

2000

20150341

Location: Italy

Years of Birth: 1/1989 to 2/1994

Mean GA (range), wk: 31±2.8

(24-36)

Median BW (range), g: ND

Male: ND

Race: ND

Enrolled: 29

Evaluated: 29

Number of sites: 1

All premature newborns with 

brain lesions on HUS who 

have abnormal 

neurological exam at term 

who are enrolled in 

neonatal follow–up study

Severe ROP (> stage 3), 

major refraction problems, 

and optic nerve atrophy, 

and infants with 

“congenital diseases”

All premature 

newborns with brain 

lesions who have 

abnormal neurological exam at term 

(29)

Prospective cohort 

(1 yr [8-16 months] and 3 

years [30-47 months])
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

23

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Hack

2000

20358826

Location: US

Years of Birth: : 1/1/1992-

2/31/1995

Mean GA (range), wk: 26.4±1.8

Mean BW (range), g: 813±125

Male: 43%

Race: ND

Enrolled: 333

Evaluated: 221

Number of sites: 1

BW<1000g Major congenital 

malformations

VLBW infants (221) Prospective cohort

Jankov

2000

20188680

Location: Canada

Years of Birth: 1990-1996

Mean GA (range), wk:

Sample 1: 23 (20-28)

Sample 2: 25 (23-33)

Mean BW (range), g:

Sample 1: 669 (400-750)

Sample 2: 515 (255-745)

Male: 

Sample 1: 51%

Sample 2: 46%

Race: ND

Enrolled: 281

Evaluated: 269

Number of sites: 1

Infants = 750 g and GA = 20 

weeks who received CPR in 

the 

delivery room

Charts were not available 

for review (5)

Major congenital 

abnormalities (4)

Those infants not intubated 

in the delivery room (3)

Sample 1: 

Resuscitated 

(198)

Sample 2: Nonresuscitated (71)

Retrospective cohort
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

24

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Kurkinen-Raty, 2000

20284814

*sample from the 

same big 

population as 

98197235

Location: Finland

Years of Birth: 1990-1997

Mean GA (range), wk:

Cases: 30.5±2.1

Controls: 30.4±2.1

Mean BW (range), g:

Cases: 1294±469

Controls: 1605±427

Male: ND

Race: ND

Enrolled: 103 (103 controls)

Evaluated: 103 (103)

Number of sites: 1

Cesarean delivered 

singleton, GA 24-33 weeks

Controls: spontaneous 

delivered singleton after 

regular contractions and/or 

preterm rupture of the 

membranes no more than 

24 hrs before. The 

mothers were matched 

one-to-one by gestational 

age at delivery plu7s or 

mines 1 week.

ND Sample 1: Indicated 

preterm (i.e., 

preterm birth 

‘indicated’ for 

maternal/fetal 

reasons)(103)

Sample 2: 

Spontaneous 

preterm delivery 

due to preterm 

labor (103)

Retrospective cohort
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

25

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Marlow

2000

20150342

Location: UK

Years of Birth: 1990-1994

Mean GA: ND

(Median and Range)

 Sample 1: 28 (26-31)

 Sample 2: 28 (26-31)

Mean BW: ND

(Median and range)

 Sample 1: 960 (600-2914)

 Sample 2: 1026 (410-2814)

Male: ND

Race: ND

Enrolled : 27 

Evaluated: 15 

Number of sites: 1

For sensorineural hearing 

loss (SNHL) group

GA: <33 wks

Family resident of Greater 

Bristol area

Records at Hearing 

Assessment Center of Royal 

Hospital for Sick children.

Born during 1990-1994

Diagnosis of SNHL of 50 dB

For control group:

Matched controls 2:1 to 

cases

Admitted to the same NICUs 

as cases

Matched for sex and GA and 

next and preceding 

matching children in the 

admission books of St 

Michael’s and Sothmead 

hospitals

ND Sample 1:

SNHL group [15]

Sample 2:

Control group [30]

Matched with cases 

for sex, GA, 

admission dates in 

NICU

Retrospective case 

control study with a 

longitudinal component 

(unclear if retrospective 

or prospective)

(12 mo CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

26

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Victorian Infant 

Collaborative study 

Group, 2000

20307288

*some subjects 

overlapped with 

Doyle, 2001

Location: Australia

Years of Birth: 1991-92

Mean GA (range), wk: 

Sample 1: 25.5±1.3

Sample 2: 27.3±1.9

Mean BW (range), g:

Sample 1: 797±147

Sample 2: 932±149

Male:

Sample 1: 61.2%

Sample 2: 39.5%

Race: ND

Enrolled: 346

Evaluated: 346

Number of sites: 4

BW<1000 or GA<28

consecutive births, survived 

to 5 years of age

ND Preterm infants 

(120):

Sample 1: infants 

treated with 

corticosteroids 

Sample 2: infants not 

treated with 

corticosteroids (226)

Non-randomized

comparison trial

(5 years)

Wood

2000

20373840

Location: UK and Ireland

Years of Birth: 1995-1996

Mean GA (range), wk: 22-25

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 314

Evaluated: 283

Number of sites: 276

GA 20-25 weeks survivors ND Preterm infants (283) Prospective cohort 

(30 [28-40] months)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

27

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Doyle

2001

21326609

Victorian Infant 

Collaborative study 

Group, 1997

97290716

J Paediatr Child 

Health

*some 

subjects were 

overlapped with 

20307288 (stated in 

text)

*possibly 

overlapped with 

98026322

Location: Australia

Years of Birth: 1991-92

Mean GA (range), wk: 23-27

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 225

Evaluated: 225 (265 controls)

Number of sites: 1

Cases: GA 23-27 weeks,

survived to 2 and 5 years of

age

Controls: randomly selected 

contemporaneous normal 

birth weight controls (BW > 

2499 g)

ND Sample 1: 

Preterm survivors

(N= 401)

Controls: Randomly 

selected 

contemporaneous 

normal birth weight 

controls (BW>2499 

grams) (N=265)

Prospective cohort 

(Doyle - 5 years; 

Victorian – 2 years)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

28

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Gaillard

2001

21221175

Location: UK

Years of Birth:1994-1996

Mean GA: ND

 (only median and range given)

 Sample 1: 26 (23-34)

 Sample 2: 26 (23-33)

Mean BW: ND 

 (only median and range given)

 Sample 1: 852 (520-2710)

 Sample 2: 745 (580-1620)

Male:

 Sample 1: 57%

 Sample 2: 50%

Race: ND

Enrolled: 100

Evaluated: 84

Number of sites: 1

Retrospective cohort :

All infants born from 

1/1/1994 to 12/31/1996

Born at Liverpool Women’s 

Hospital

Ventilated beyond 27 

postnatal days

If transferred from another

hospital after first postnatal

week (mostly surgical

referrals)

If ventilated after 27

postnatal days after a

surgical procedure requiring

anesthesia

Sample 1 :

Ventilated beyond 27 

(but not 50) postnatal 

ds (56)

 

Sample 2:

Ventilated beyond 

49ds ( 28)

First component:

Retrospective 

longitudinal cohort with 

case-control design and 

cases defined based on 

exposure (length of 

ventilation). Unmatched.

(3 years)

Second component:

Retrospective 

longitudinal cohort study

With two historical 

control groups

(3 years)

Roth

2001

21262686

Location: UK

Years of Birth: 1979-1988

Mean GA (range), wk:

Sample 1: 29 (24-32)

Sample 2: 29 (24-32

Mean BW (range), g:

Sample 1: 1350 (600-2500)

Sample 2: 1324 (535-2390)

Male: 

Sample 1: 49%

Sample 2: 53%

Race: ND

Enrolled: 854

Evaluated: 782

Number of sites: 1

GA < 33 weeks

During 1980, for logistic

reasons, only infants who 

were either less than 1250 g 

or mechanically ventilated 

were enrolled

ND Sample 1: 

children had been 

studied by linear 

array US scanning 

(205)

Sample 2: 

children had been 

studied by mechanical sector scanning 

(577)

Retrospective 

cohort 

(followed to age of 7 

years and 2 months, and 

10 years and 6 months)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

29

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Saigal

2001

21376729

* Important paper

Location: Canada

Years of Birth: 1977-1982

Mean GA (range), wk:

Cases: 27±2

Controls: “Term”

Mean BW (range), g:

Cases: 835±124

Controls: 3401±481

Male: 

Cases: 31%

Controls: 36%

Race: ND

SES: middle class

Cases: 30%

Controls: 30%

Enrolled: 179 (145 controls)

Evaluated: 154 (125)

Number of sites: 1

ELBW survivors, BW= 501-

1000g

Controls: term infants

recruited at 8 years of age 

from a random list obtained 

through the directors of 2 

school boards and matched

for gender, age, and SES to 

each case

ND

(Died after discharge (10)

Lost to follow-up (8)

Refusal (5)

Unable to be reached (2)

Controls:

Lost to follow-up (10)

Refusal (8)

Unable to be reached (2))

Cases: ELBW infants 

(154)

Controls: Term 

infants (125)

Prospective cohort 

(followed to 12-16 years 

age)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

30

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Schmidt

2001

21298249

Location: Canada, USA, Australia, 

New Zealand, Hong Kong

Years of Birth: 1996-1998

Mean GA:

 Sample 1: 25.9 ±1.8

 Sample 2: 26 ±1.9

Mean BW:

 Sample 1: 782 ±131

 Sample 2: 783 ± 130

Male: 51%

Race:

Sample 1:White: 69%, black: 13%, 

Asian: 5%, other: 12%

Sample 2: White: 67%, black: 14%, 

asian: 7%, other: 12%

Enrolled: 2756

Evaluated: 1202

Number of sites: 32

BW: 500-999g

2 hrs old

Born in 1 of the 32 

participating centers in 

Canada, USA or Australia.

Born during 1/1996-3/1998

Excluded total 981 (not 

eligible)

Unable to administer study

drug within 6 hrs of birth , 

n=469

Structural heart disease

Renal disease or both, or 

strongly Suspected (n=24)

Dysmorphic feature or 

congenital abnormalities likely 

to affect life expectancy or 

neurologic development or to 

be associated with structural 

heart disease or renal disease 

(n=49)

Maternal tocolytic therapy with 

indomethacin or another 

prostaglandin inhibitor within 

72hr before delivery (n=245)

Overt clinical bleeding at

more than one site (n=8)

Platelet count <50.000 (n=25)

Hydrops (n=9)

Not considered viable (n=171)

Unlikely to be available for 

f/up (n=31)

Sample 1:

Indomethacin group 

[574]

Sample 2:

Placebo group [569]

Randomized, 

multicenter, 

placebo/controlled,

double-blind trial

(18 mo CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

31

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Akerman 

1992

93255928

General: BW, GA, Twinning

Other: Mother’s negative or 

ambivalent expectations 

concerning the twin 

pregnancy

Interviews with mother prior to 

delivery

CNS:

Motor delay

Cognitive delay

Behavioral disorders

Ophthalmology: Visual Impairment

Audiology:

Deafness

Speech

Griffith’s Mental Development Scales: 

including locomotor, personal-social, 

hearing and speech, hand and eye 

coordination, performance, and practical 

reasoning scores

Thompson 

1993

93234177

Birth weight 

GA

ND CNS:

Motor delay

CP

Cognitive delay

Mental retardation

Ophthalmology: Visual impairment

Audiology: Hearing disorders

Griffith’s scale

Rademaker 1994

95003452

CNS:

1) Intracranial / 

Intraventricular hemorrhage

2) White Matter Disorder

3) Periventricular 

leukomalacia

US grading 

GLH-IVH

CNS:

Cognitive delay

Mental retardation

Post Hemorrhagic Hydrocephalus 

(PHH)

Ophthalmology: Visual impairment 

Audiology: Hearing disorders

Griffith’s mental development scale

Amiel-Tison, Greniers and Touwen 

scores

IQ
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

32

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Vonderveid

1994

94297368

General:

1) BW (in 100 g intervals)

2) GA (in wks)

3) Gender

4) SGA(<10% vs > 10%)

5) Type of pregnancy 

6) Fetal presentation

7) Antenatal steroid

8) Place of birth

9) Apgar score 1 min

10) Apgar score 5 min

11) Transport 

12) On admission to NICU: 

Spontaneous respirations 

(present or absent); Body 

temperature (<35 vs >35); 

PH (<7.00 vs 7.00-7.09 vs 

> 7.09); PCO2: 80 vs 60-79 

vs 40-59 vs <40

Pulmonary:

1) RDS

2) Maximum FIO2 required

CNS:

1) Peri-intra-ventricular 

hemorrhage

2) PVL

Others:

1) Sepsis

2) Maximum bilirubin level

3) Hypoglycemia (< 25 mg/dl)

4) Hyperglycemia (>175 

mg/dl)

5) Acidosis (pH<7.20)

ND CNS--Audiology-Ophthalmology:

1) Neuromotor disorders:

ÿ impairment

ÿ disability

ÿ handicap 

ÿ (including CP, Blindness, 

Deafness)

2) Developmental quotients

1) Each limb was evaluated 

separately: 

ÿ 0= nl function

ÿ 1= impairment with no loss of 

function

ÿ 2= mild motor disability

ÿ 3= severe motor disability

ÿ 4= complete loss of function

2) Cerebral palsy:

Monoplegia, diplegia, paraplegia, 

hemiplegia, quadriplegia)

3) Developmental quotients:

Brunet-Lezine test

(24 mo CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

33

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Kraybill

1995

95264242

General:

1) Surfactant (single dose 5 

ml/kg given via ET tube at 

birth)

Infants were treated, as soon as after

birth, either with 5 ml/kg of surfactant

or air placebo, via ET tube.

1 yr assessment (NCMH and HCHD 

cohort):

General:

Overall survival

Pulmonary:

Need for O2 via Nasal canula

Need for O2 via CPAP CLD

2 yr assessment (NCMH cohort only)

General:

Overall survival

Hospitalization for respiratory illness

Pulmonary:

Bronchodilator regular use

Tracheostomy

1 and 2 yr assessment:

Growth:

Height for age

Weight for age

HC for age

Mean MDI score 

MDI scores < 2 SDs

Mean PSI score

PDI scores < 2 SDs

Severity of impairments

Types of Impairments

Any surgery

Assessment between 28 ds-12mo:

Ophthalmology:

ROP

Tx for ROP

ROP presence at latest exam

Severe ROP

No further specifications given, except 

for the followings:

Oxygen via Nasal canula : providing 

alveolar O2 concentrations of : 26%-

40%, based on NC flow and NC O2 

concentration

Bayley Scale of Infant Development:

1) MDI= Mental Development Index 

Score

2) PDI: Psychomotor Development 

Index Score

ROP : (no further definitions)

1) No ROP,

2) Mild/moderate

3) Severe

CP (no further definitions)

1) Mild

2) Moderate/Severe

Severity of impairments:

1) Severe

2) Mild/Moderate

Types of impairments:

1) MDI<69

2) MDI: 69-84

3) Moderate/severe CP

4) Mild CP

5) Bilateral sensorineural deafness

6) Deafness not requiring 

amplification

7) Bilateral blindness

8) Visual defect

(1 yr and 2 yr CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

34

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Speechley

1995

96356544

General:

1) Former NICU graduate 

(of any BW)

2) Gender

Not further specified Physical health outcome at 12 yrs

1) Chronic physical health 

(mother’s report)

2) Lifetime hospitalizations 

(mother’s report)

3) Physical impairments (mother’s 

report)

4) Perception of child’s heath 

(child’s report)

5) Perception of child’s health 

(mother’s report)

Emotional and social wellbeing at 12 

yrs:

1) Internalizing problems (child’s 

report)

2) Externalizing problems (child’s 

report)

3) Social competence (child’s 

report)

4) Social support (child’s report)

5) Self esteem (child’s report)

6) School performance (mother’s 

report)

Based on responses on an interviewer 

administered and self-report 

questionnaire.

Physical health outcome at 12 yrs

1) Chronic physical health (mother’s 

report): Precoded 25 chronic 

illnesses

2) Lifetime hospitalizations (mother’s 

report)

3) Physical impairments (mother’s 

report):response to a question 

asking whether their child had any 

physical impairments

4) Perception of child’s heath (child’s 

report): 4-item scale

5) Perception of child’s health 

(mother’s report): 4-item scale

Emotional and social well being at 12 

yrs:

1) Internalizing problems (child’s 

report) 3-item scale

2) Externalizing problems (child’s 

report) 3-item scale

3) Social competence (child’s report) 

36-item scale

4) Social support (child’s report) 24-

item scale

5) Self-esteem (child’s report) 10-item 

scale

6) School performance (mother’s 

report) 5-item scale
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

35

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Hack

1996

97060805

General : 

1) VLBW vs. NBW

2) GA

3) SGA/IUGR

4) Sex

CNS: Neurosensory 

Development IA+II, I

Other: Maternal Factors, race, 

education, height, martial 

VLBW<1500gm (AGA+SGA) to 

compare growth with FT NBW infants

CNS: Major neurosensory abnormal.

Growth: 

Weight

Height

Head Circumference

ND

Hack

1996

97066007

General: Birth Weight 500-750 gm CNS: 

Cerebral palsy

Motor and cognitive delay

Ophthalmology: Blindness

Audiology: Deafness

Neurosensory status

BSID: MDI, PDI
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

36

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Northern 

Neonatal 

Nursing Initiative 

Trial Group

1996

96304894

Cardiovascular or Pulmonary 

Predictors: use of FFP or 

plasma substitute to expand 

vascular volume prophylactically

ND CNS Outcomes:

Motor delay

Cerebral palsy

Seizure disorder

Post hemorrhagic hydrocephalus

Ophthalmology:

Visual impairment

Blindness

Audiology Outcomes:

Hearing disorders

Speech

Other outcomes:

a. blind, deaf, or unable to walk –

combined outcome

b. no severe disability – combined 

outcome

c. overall developmental quotient –

Griffith’s

Motor delay: Griffith’s gross motor 

quotient >350 below mean

Griffith’s quotient for speech + hearing 

>350 below mean

1)

Sethi

1996

96334245

General Predictors:

1) Birth weight

2) <1000g

3) 1000g - 1500 g

CNS Outcomes:

Cerebral palsy

Cognitive delay

Seizure disorder

Ophthalmology outcomes:

Blindness

ROP - eye exam

Audiology outcomes:

Deafness

Other outcomes:

Survival

"abnormal neurodevelopmental 

outcome" - not defined

"major impairment" - any CP

blindness, deafness, "significant" 

developmental delay or 

hydrocephalus requiring a shunt

deafness OAE testing before discharge 

and at 7 months

"minor impairment" - squint, refractive 

error, mild auditory impairment (< 50 

dB loss), stable epilepsy, or needing 

speech therapy assessment
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

37

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Wilkinson

1996

97087405

CNS predictors:

Periventricular leukomalacia 

(severe cystic PVL)

Changes not seen on first scan

Multiple cysts must be present 

(excludes cases with flare only)

The cysts are bilateral

The cysts are distributed in the 

periventricular area involving the 

region of the trigones and variable 

involvement anterior to the trigones

CNS outcomes:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Ophthalmology outcomes:

Visual impairment

Blindness

Audiology outcomes:

Hearing disorders

Not specifically defined. Spastic 

quadriparesis, cortical blindness, 

seizures presumably self-evident.

DeReginer 

1997

98041177

Cardiovascular/ Pulmonary: 

Chronic lung disease

Classification based on the duration

of supplemental oxygen 

requirements.

“No CLD” – breathing room air at 28 

days

“Mild CLD” – requiring supplemental 

oxygen at 28 days but not at 36 

weeks PMA

Sever CLD” – requiring oxygen at 28 

days and 36 weeks PMA

General:

Motor and cognitive delay

Cerebral palsy

Opthalmology: 

Visual impairment

Blindness

Audiology: 

Hearing loss

Deafness

Growth: 

Weight Z score

Length Z score

Head circumference Z score

Other: any adverse outcome

Bayley PDI & MDI
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

38

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Dezoete

1997

97359687

General:

 1) Birth weight

 2) GA

 3) SGA/IUGR

CNS: Intracranial/Intraventricular

Hemorrhage 

Cardiovascular/

Pulmonary: Chronic Lung 

disease 

Clinical measures CNS:

Motor delay

Cerebral palsy

Cognitive delay

Ophthalmology: 

Visual impairment

Blindness

Audiology: 

Deafness

Stratify outcome into 4 categories base 

on severity of disability:

“Severe disability” / Category I – =1 of 

the following: (1) Sensorineural 

deafness (requiring hearing aids). (2) 

Bilateral blindness. (3) Severe 

cerebral palsy. (4) Developmental 

delay (adjusted Bayley mental scores 

2 or more SD below mean).

 Category II - – =1 of the following: (1) 

Adjusted Bayley mental scores 

between 1 and 2 SD below mean. (2) 

Mild-moderate CP w/o developmental 

cognitive delay. (3) Impaired vision 

requiring spectacles.

Category III – Presence of tone disorder 

or motor delay (adjusted Bayley motor 

score more than one SD below mean 

but adjusted mental score within 

average rage.)

Category IV / “apparently normal” – (1) 

No apparent tone disorder, and (2) No 

apparent developmental delay when 

mental and motor scores adjusted for 

GA.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

39

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

O’Shea

1997

98049056

*overlapped 

sample with 

98190123

General: BW, GA, Yr of birth

CNS:

1) Intracranial/ Intraventricular 

hemorrhage

2) White matter disorder

3) Periventricular leuko-malacia

Hemorrhage disease diagnosed by 

cranial US finding, classified by 

Stewart’s method

CNS: 

Cerebral palsy 

Cognitive delay

Major neurosensory impairments

Ophthalmology: Blindness

Growth:

Head Circumference<10th percentile 

at 1 yr

Weight<10%

Length<10%

Other: Rehospitalization

CP – presence of definitely abnormal 

position and posture attributable to 

impaired neuromotor function

Bayley scales – MDI, PDI

Piecuch

1997 

97456215

General: 

1) Birth weight

2) GA

3) SGA/IUGR

4) Social Risk

CNS: Intracranial/Intraventricular 

Hemorrhage, Periventricular 

leukomalacia

Cardiovascular/Pulmonary: 

Chronic lung disease

Other: 

1) Inborn-Outborn

2) Year of birth

3)Sex

Well defined in text CNS: 

Motor delay

Cerebral palsy

Cognitive delay

Ophthalmology: Visual Impairment

Audiology: Hearing Disorder

Neuromotor problems, OP 

Neurosensory-blindness/hearing loss

Cognitive outcome-abnormal if <2 SD 

below mean testing
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

40

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Piecuch

1997 

98012134

General predictors:

1) GA

CNS predictors:

1) intracranial/ intraventricular 

hemorrhage

2) periventricular leukomalacia

Cardiovascular or pulmonary 

predictors:

1) chronic lung disease

Other predictors:

1) social risk: economic

2) social risk: substance abuse

CLD - at 36 weeks PCA, requirement 

for supplemental O2

IVH grade 3 or 4 & PVL, according to 

sonogram

Social risk economic - maternal 

education <12 grade; complete 

unemployment in household; or 

government assistance for health 

insurance

Social risk substance abuse - positive 

toxicology screens or confirmed 

history of drug or alcohol abuse

CNS outcomes:

cerebral palsy

cognitive delay

Ophthalmology outcomes:

visual impairment

Audiology outcomes:

hearing disorders

Visual – Near point tests or Snellen eye 

charts

Audiologic - behavioral testing followed 

by BAER or pure tone audiometry.

Cognitive outcome - Bayley scales at 12 

and 18 months; Stanford-Binet at 

2.5-4 years; McCarthy scales at 4-6 

years.

Abnormal neurological outcome - CP, 

quadriplegia, dysplegia, hemiplegia

Suspicious neurological outcome –

clumsiness, tremors

Severe neurosensory abnormalities –

Bilateral hearing loss, blindness

Mild neurosensory abnormalities - high 

frequency hearing loss without 

hearing aids, visual deficit without 

glasses

Singer

1997

98049057

Singer

2001

21163669

Cardiovascular or pulmonary 

predictors: 

1) Bronchopulmonary 

dysplasia

General : BW, Neurologic risk

Other: Race, Socioeconomic 

status

BPD: preterm,<1500g BW, oxygen 

for >28 days with radiographic 

evidence of CLD

CNS outcomes:

Cerebral palsy

Cognitive delay

Mental retardation

Ophthalmology outcomes:

Visual impairment

Audiology outcomes:

Hearing disorders

Speech

Language

Communication disorder

Bayley Scales of Infant Development

Language (speech/communication) 

measured by Battelle Developmental 

Communication Subscale Domain‡

receptive, expressive and total 

communication scores converted to 

DQ mean 100 and SD 15.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

41

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Victorian Infant 

Collaborative 

study Group, 

1997

98026322

*This study is 

also in CNS 

table

General: BW

Other: period of time when born

Each sample were subdivided into 

BW=500-749 g and BW=750-999 g

1985-1987 vs. 1991-1992

CNS:

Cerebral palsy

Neurodevelopmental:

Cognitive and motor delay

Disability

Ophthalmology:

Blindness

Audiology: 

Deafness or hearing aid

CP was not defined

Bayley Scales of Infant Development

DQ, using the published mean and SD

Disability: “Severe” – bilateral blindness, 

cerebral palsy with the child unlikely 

ever to walk, or a DQ score <-3SD; 

“Moderate” – bilateral sensorineural 

deafness requiring hearing aids, 

cerebral palsy in children not walking at 

2 but expected to walk, or a DQ score 

from –3SD to <-2 SD; “Mild” – cerebral 

palsy but walking at 2 , or a DQ score 

form –2 SD to <-1 SD.

Victorian Infant 

Collaborative 

study Group, 

1997 

97466059

Other: time period of birth ND CNS:

Cerebral Palsy

Cognitive delay

Post Hemorrhagic Hydrocephalus 

(PHH) 

Ophthalmology: Blindness

Audiology: Deafness

Other:

Sensorineural disability: severe, 

mental, moderate, none.

CP neurologic exam 

Bayley MDI, PDI scores

Blindness-not stated

Deafness-not stated

Degrees of sensorineural delay are 

defined as an aggregate measure and 

are approximated. 
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

42

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Cheung

1998

99059896

Cardiovascular or Pulmonary 

Predictors:

Inhaled nitric oxide (INO)

ND CNS Outcomes:

Post Hemorrhagic Hydrocephalus 

(PHH)

"Neurodevelopmental outcomes"

Intraventricular hemorrhage

Audiology Outcomes:

Deafness

Pulmonary Outcomes:

BPD or CLD (with or without meds)

Aspiration pneumonia

Growth Outcomes:

Wt, HC, length (height)

PDI + MDI of Bayley Scales of Infant 

Developmental Index were used.

"Neurodevelopmental" outcomes:

Disability: one of more of:

1. CP (all types or severity)

2. Legal blindness (corrected visual 

acuity of the better eye <20/200

3. Hearing loss (sensorineural 

hearing loss of >30 dB in the better 

ear)

4. Severe mental retardation (MDI >3 

SD below the mean)

Delay: does not have disability and 

either MDI or PDI was >2 SD below 

the mean.

Normal: free of disability or delay 

and MDI and PDI were within 2 SD 

of the mean.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

43

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Finnström

1998

99041345

General Predicators

1) GA

2) SGA/IUGR

3) Apgar score

4) Other: gender

CNS Predicators

1) Intracranial/Intraventricular 

hemorrhage 

2) Periventricular 

leukomalacia

Ophthalmology Predicators

1) Retinopathy of Prematurity 

(ROP) 

Cardiovascular or Pulmonary 

Predictors

1) Chronic Lung Disease

2) Other: Mechanical 

ventilation 

Other Predicators

1) Other: PDA

Self-explanatory CNS Outcome: 

Cerebral palsy

Ophthalmology:

Visual impairment

Audiology: 

Deafness 

Growth:

Height

Weight 

Head circumference

CP: spastic diplegia, spastic hemiplegia, 

spastic hemiplegia 

Scheffzek’s categories of functional 

disabilities are not defined in this article. 

They refer to a previous article which is 

written in German. “Major Handicaps” 

(category 3-4) CP, severe visual 

impairment, CP+ severe visual 

impairment, mental retardation and 

cardiomyopathy, hearing less

Gregoire

1998

98232532

Cardiovascular/Pulmonary: 

1) Chronic Lung Disease

2) Bronchopulmonary 

dysplasia

Compared O2 dependence at 28

days with O2 dependence at 36 

wk

ND CNS: 

Cerebral palsy

Motor and cognitive delay

Audiology: Hearing Disorders‡

Free field audiograms 

Pulmonary: 

Respiratory readmissions

PICU admissions

Growth: Weight, height, head 

circumference

Other: Health Outcomes

Giffith’s Mental Development Scales 

Neurologic examinations
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

44

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Kurkinen-Raty 

1998

98387235

(All+Lung)

*sample from 

the same big 

population as 

20284814

General : PROM Diagnose was through clinical 

assessment or with the use of a 

PROM-test, which detects insulin 

growth factor binding protein-1 in the 

cervico-vaginal secretions, or with the 

use of a nitrazine test.

CNS:

 Motor delay

 Cerebral delay

Ophthalmology: Visual Blindness

Audiology: Hearing disorders

Pulmonary: Chronic lung disease

Growth: weight percent

Other:

Days of re-hospitalization

Steroid therapy at followed up 

Neurologic exams

Diagnosis of CLD was made if infants 

required oxygen, continuous 

bronchodilator, or steroid tx because 

of respiratory signs and symptoms.

Diagnoses of RDS were made based on 

need for respiratory support, 

radiologic findings, and clinical 

assessments
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

45

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Lee

1998

98442293

General:

1) Candidemia and/or 

Candidal meningitis

Diagnosis of Candidemia: by at least 

one positive Blood Culture

Diagnosis of Candidal meningitis:

by isolation of Candida in the CSF or 

>45x10 6 WBCs in the CSF and 

candidemia.

CNS:

Neurodevelopmental disabilities 

(NDDs) 

Cognitive delay

Cerebral palsy 

Ophthalmology:

Legal blindness 

Audiology:

Hearing loss 

Growth:

Growth retardation

1) Bayley Scales of Infant 

development; MDI, PDI for ages < 

24 mo.

2) Stanford-Binet Intelligence Scale 

and Peabody Development Motor 

Scales for ages > 24 mo

3) Scores obtained by psychologists, 

psychometricians, pediatricians 

specialized.

Neurodevelopmental Disabilities:

1) Cerebral palsy (all types and 

severity)

2) Legal blindness (corrected VA of 

the better eye<20/200)

3) Hearing loss (neurosensory 

hearing loss in the better ear > 30 

dB) (done by certified audiologist

4) And/or cognitive delay (MDI>3 

SDs below the mean)

Growth retardation: Weight, Height, HC 

> 2 SDs below the mean

(Between 3-6 yrs CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

46

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Lefebvre

1998

98387703

Other: Neurobiologic risk score 

(NBRS)

Items in NBRS: ventilation, PH, 

surgeries, IVH< PVL, infection, 

hypoglycemia-items scored zero or 

greater in progression

CNS:

Cerebral palsy 

Cognitive delay

Other neurodevelopmental 

impairment

Ophthalmology: Blindness

Audiology: hearing disorders-free 

fetal audiogram

Neurologic exam

Griffith’s mental development scale 

Mental retardation-Griffith’s mental 

development scale

1) Global developmental quotient 

(DA)

2) Mild/moderate: DA 80-89 or CP

3) Severe: DA<80, severe CP 

unilateral blindness or severe 

hearing defect 

4) Normal: more of the above

Areas of Griffith’s Developmental 

Scales:

- Locomotor

- Personal-social

- Hearing and speech

- Eye and hand coordination

- Performance

Control mean DA=110+or- in literature 

Millet

1998

98212544

CNS: 

 MRI findings at 3-6 months

ND CNS: 

Motor delay

Cerebral palsy

Cognitive delay

Behavioral disorders

Ophthalmology: Visual impairment

Audiology: Hearing loss

GI: Dysphagia 

Neurodevelopmental outcome poorly 

defined 
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

47

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Piecuch

1998

98446413

General:

1) Birth in a recent period vs 

early period vs midpoint 

period

(the authors wanted to assess 

whether changes in neonatology 

for the care of VLBW infants 

have changed the outcome of 

LBW infants: 1000-1500g)

2) Birth weight

3) GA

4) Gender

5) Place of birth (inborn vs 

outborn)

6) Weight for age (AGA vs 

SGA)

CNS:

1) Intracranial hemorrhage 

(ICH)

Pulmonary:

1) Duration of mechanical 

ventilation

2) Duration of O2 

requirements (CLD)

Birth in a recent period: 1989-1991

Birth in an early period : 1979-1981

Birth in a midpoint period:1984-1986

CNS:

1) Neurologic: normal, suspect, 

abnormal

2) Cognitive: Average or above, 

Mild delays, Moderate/severe 

delays

Ophthalmology-Audiology:

Significant visual and/ or auditory 

deficits (B/L blindness or need for 

hearing aids)

Neurologic:

1) Normal

2) Suspect: (clumsiness, tremors, 

mild tone and reflexes changes, 

but without fixed impairment)

3) Abnormal: moderate/ severe: fixed 

impairments such as CP, 

diplegias, hemiplegias

Sensory

1) Visual acuity screening

2) Behavioral screening assessment

Cognitive:

< 24 mo: Bayley Scale

>24 mo: Stanford-Binet scale

Carthy Scale

7-8 yrs: Wechsler Intelligence Scale for 

Children Revised 

1) Average or above

2) Mild delays: 1-2 SDs below mean

3) Moderate/severe delays: > 2 SDs 

below mean

Time of outcome assessment not 

specified: 

It could be done up to age 7.5-8 yrs

(Mean age at assessment in the cohort 

was: 24 mo)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

48

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Sajaniemi

1998

99041674

General:

1) Prematurity per se

2) Premature with BW< 1000 

g vs premature with BW > 

1000 g 

3) Pre-eclampsia

4) SGA

5) Duration of NICU stay

CNS:

1) PVL

2) IVH

Pulmonary:

1) Duration of ventilation

Not further specified CNS:

Neurologic outcome

Developmental outcome

Temperament profile

Behavioral profile

Neurologic outcome:

1) Cerebral palsy

2) Free of major disabilities

Developmental outcome:

1) Bayley Scales of Infant 

Development

2) Mental Development Index (MDI)

Temperament: Toddler Temperament 

questionnaire (TTQ) (contains 97 

statements) 9 temperament dimensions:

1) Activity

2) Rhythmicity

3) Approach

4) Adaptability

5) Intensity

6) Mood Persistence

7) Distractability

8) Threshold

Behavior: Infant Behavior Record:

1) Social responsiveness

2) Attention

3) Affect

4) Energy level

5) Goal directedness during the test

( 24 mo CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

49

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Scherjon

1998

98429216

CNS:

1) U/C ratio: Doppler finding 

of umbilical/cerebral artery 

pulsatility index (U/C ratio: 

raised vs normal)

2) Neonatal Cranial 

Ultrasound findings

General:

1) Fetal growth ratio 

2) GA

1) U/C ratio:

The ratio between umbilical artery 

and cerebral artery pulsatility index 

(used as a marker of fetal blood 

redistribution to the brain, and indirect 

marker of placental insufficiency)

2) Neonatal cranial Ultrasound:

Normal: 

No intracranial or subependymal 

bleeding, Echodensities less bright 

than choroid plexus

Moderate:

IVH (< 50% of lumen filled)

some echodensity brighter than 

choroid plexus, lasting less than 3 

days.

Abnormal:

IVH (>50% of lumen filled)

Intraparenchymal bleeding

Some echodensities brighter than 

choroid plexus and lasting longer 

than 3 days

 

3) Fetal growth ratio (observed 

birth weight divided by expected 

mean BW for GA)

Growth:

Growth (Weight, Height, HC)

CNS:

Neurodevelopmental outcome 

Behavioral outcome

Hempel outcome:

1) Specific for toddlers

2) Observed children while playing in 

a standardized situation

3) 89 items

Motor aspects of Hempel examination:

Classification of infants:

1) Normal

2) Mildly abnormal (e.g., slight 

asymmetry, or mild hypo-, hypertonia which does not lead to 

handicapping condition)

3) Abnormal (e.g., CP, which leads to 

handicap in daily life)

Behavioral aspects of Hempel 

examination:

1) Information based on parental 

questionnaire on child’s cognitive 

function and 

2) language skills

 (level of activity, nocturnal enuresis, 

eating, sleeping disturbances, language 

development, comprehensibility, 

passive understanding, number of 

words used in sentences)

Hempel outcome assessment was done 

by a person blind to prior medical 

history of child.

( 3 yrs CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

50

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Cheung

1999

99146391

General predictors:

1) BW

2) GA

3) Apgar score

CNS predictors:

1) intracranial/ intraventricular 

hemorrhage

Cardiovascular or pulmonary 

predictors:

1) days of ventilation

2) days of O2 use

Other predictors:

1) frequency of apnea

2) mean desaturation of 

apnea

3) mean frequency of apnea

4) Blisten index 

(socioeconomic status)

ND CNS outcomes:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Seizure disorder

Neurodevelopmental disability

Ophthalmology outcomes:

Blindness

Audiology outcomes:

Hearing disorders

Growth outcomes:

Weight > 2 SD below the mean

Height > 2 SD below the mean

HC > 2 SD below the mean

Bayley scores

Stanford-Binet Intelligence Scale

Peabody Developmental Motor Scale

Neurodevelopmental disability: "children

with 1 or more of a) cerebral palsy b) 

legal blindness c) hearing loss d) 

convulsive disorder e) cognitive delay

Duvanel

1999

99207097

General:

1) Hypoglycemia:

2) Severity of hypoglycemia 

(0-11 mg/dl, 11-29 mg/dl, 

29-47 mg/dl), and

3) Frequencies of 

hypoglycemic episodes 

Blood glucose level in the first 24 

hours of less than 47 mg/dl by

reagents sticks, or confirmed by 

glucose analyzer for stick 

measurements less than 36mg/dl. 

About the frequency of episodes: no 

Precise information on the frequency

Of performance of glucose 

measurements.

CNS:

Scores in psychometric tests done for 

neurodevelopmental assessment at:

ÿ 6 moths

ÿ 12 moths

ÿ 18 months

ÿ 3.5 yrs

ÿ 5 yrs.

Growth:

Head circumference at 

ÿ 6, 12, 18 months, 3.5 yrs, 5 yrs

ÿ Growth rates for weight, length, 

and HC for time intervals:

ÿ 6-18 months

ÿ 6-3.5 yrs

ÿ 6-5 yrs

Griffith’s test (6 items): at 6, 12, 18 mo

 McCarthy test (6 items) : 3.5 yrs, 5 yrs
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

51

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Pennefather, 

1999

20002011

Pennefather, 

2000

20217908

* This study is 

also in eye 

table

Genera Predictor: GA

CNS:

1) IVH

2) Periventricular leukomalacia

3) Ventriculomegaly/Ventricular 

Dilation

Ophthalmology: 

1) ROP

2) Refractive error

Other: Family Hxg strabismus, 

Developmental disability, CP

ND CNS:

Cerebral palsy

Ophthalmology:

Visual impairment (cortical)(CVI)

Cicatricial ROP

Strabismus

Retrospective review of patient records

Visual acuity, Visual fields

Ambalavanan

2000

21031370

General: BW, GA, Antenatal 

steroids, Apgar score

Other: Race, Gender Multiple 

gestation, Maternal education, 

Maternal age

CNS:

Intracranial hemorrhage

Periventricular/Ventricular 

Dilation

Bronchopulmonary dysplasia

GI: Necrotizing “entrocolitis” 

Interinal perforation, 

Chorioamnionitis

Multiple gestation

Maternal education

Maternal age

Extensive list of the 21 predictor 

variables

CNS:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

PHH

Neurologic exam

Major handicap

Ophthalmology:

Visual impairment

Blindness

Audiology:

Hearing disorders

Deafness

Bayley Scales of Infant Development

Major handicap-presence of one or any 

poor outcome (i.e. CP, deadness, 

blindness). Mental retardation (MDI or 

PDI <70), PHH requiring sheet
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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52

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Cioni

2000

20150341

CNS 

intracranial hemorrhages, 

white matter disorder, 

Ventriculomegaly

MRI findings Total MRI score (the 

higher the worse, range 7-21) made 

by summation of subscores of 

following categories: Size of Lateral 

ventricles, white matter abnormal 

signal intensity, white matter 

reduction, cysts, size of subarachnoid 

space, corpus callosum, cortical gray 

matter; MRI score of visual cortex 

and optic radiations 

CNS:

CP

Ophthalmology: 

Visual assessment 

Developmental 

Neurological examination: 

Normal

Mildly abnormal (mild retardation and/or 

mild abnormal neurological signs, 

but not CP.

CP with relatively normal head and 

trunk control.

CP without head and trunk control.

Visual assessment: 

Grating acuity: assessed with binocular 

Teller acuity card procedure (cycles 

per second)

Visual Field (kinetic perimetry)

Horizontal optokinetic nystagmus (OKN)

Oculomotor behaviour (following and 

fixation) and strabismus.

Developmental Assessment:

Griffith’s developmental scales (global 

and each subscale: locomotor, 

personal-social, hearing-speech, handeye co-ordination, and performance)

Scores ≥85 = normal

Borderline 84-71

Abnormal ≤70
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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53

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Hack

2000

20358826

General:

 1) Birth weight

 2)GA

 3) SGA/IUGR

 4) Antenatal steroids

 5) Jaundice

CNS:

1) Intracranial/Intraventricular 

Hemorrhage

2) Periventricular leukomalacia

3) Ventriculomegaly/ ventricular 

dilation

Cardiovascular/Pulmonary: 

Chronic lung disease

Gastrointestinal: Necrotizing 

“entroclitis”

Other:

 1) Infectious Disease

 2) Dexamethasone

 3) Perinatal factors 

(chorioamnionotis)

 4) Multiple birth

 5) C-section

 6) Social risk

 7) Male sex

ND CNS:

Cerebral palsy

Motor delay

Cognitive delay MDI score<70

Post hemorrhagic Hydrocephalus

Ophthalmology: 

Blindness

Audiology:

Deafness

Neurologic abnormality - includes: 

CP, hypotonia, hypertonia 

Shunt-dependent hydrocephalus 

1)

Jankov

2000

20188680

Cardiovascular predictors:

1) CPR

Other predictors:

1) Apgar scores

2) Use of CPR in delivery room

3) Assignment of Apgar scores in 

the delivery room

CNS outcomes:

Cerebral palsy

Cognitive delay

Mental retardation

Adverse outcome

Ophthalmology outcome:

Blindness

Audiology outcome:

Hearing disorders

Adverse outcome defined as:

1) CP causing non-ambulation 

beyond 2 years or spastic 

quadriparesis

2) Intellectual delay = below 2 SD

3) Hearing loss requiring aids

4) Legal blindness (<20/200)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

54

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Kurkinen-Raty, 

2000

20284814

*sample from 

the same big 

population as 

98197235

General predictors:

Birth weight

GA

Antenatal steroids

Cord pH

Bronchopulmonary dysphasia 

(BPD)

Other predictors: 

Indicated preterm delivery

Spontaneous preterm delivery

BPD diagnoses were based on 

radiologic finding

CNS: 

Motor delay

Cerebral palsy

Ophthalmology

Visual impairment

Audiology

Hearing disorder

Pulmonary

Chronic lung disease (CLD) at 1 year

Growth:

Wt, Ht, HC

Motor delay = abnormalities of tone or 

reflexes but functionally normal or 

borderline

CP = spastic diplegia or hemiplegia or 

spastictetraplegia

Diagnosis of CLD was made if infants 

required oxygen, continuous 

bronchodilator, or steroid tx because 

of respiratory signs and symptoms.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

55

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Marlow

2000

20150342

General: 1) Birth weight 

2) Apgar score 3) CRIB scores

CNS:

1) Maximum bilirubin level

2) Abnormal cerebral US scan

Audiology:

1) Sensorineural hearing loss

Cardiovascular/Pulomonary:

1) Duration of intubation, 

respiratory support, oxygen, 

pH<7.2, base excess 

2) Dopamine excess

3) Furosemide

4) Indomethacin use

Other:

3) Netilmicin 6) Vancomycin

7) Positive blood cultures

8) Bilirubin >200 ?mol/l

9) Bilirubin>GA x 10

10) Creatinine >60 mmol/l

11) Netilmicin 12) Vancomycin

Combination of the above:

1) Bili.200 + acidosis

2) Bili> 200 + sepsis

3) Bili >200+ netilmicin

4) Bili> 200+ vancomycin

5) Bili>200+ furosemide

6) Peak bil+ acidosis

7) Peak bili+ sepsis

8) Peak bili+ netilmicin

9) Peak bili+ furosemide

10) Creatinine>60+ netilmicin 

or vancomycin or furosemide

11) Netilmicin+furosemide

12) Vancomycin+ furosemide

Not further specified In case control component:

Audiology:

Sensorineural hearing loss (SNHL) of 

50 dB within 9 months from birth

In Longitudinal component:

CNS:

Cerebral palsy at 12 months of age in 

the 2 groups (SNHL and control 

group)

Cases of SNHL were identified if the 

hearing loss had been identified within 3 

months of discharge home, (within 9 mo 

from birth); after excluding cases with 

conductive hearing loss, possible 

congenital cause, or had neonatal 

bacterial meningitis
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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56

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Victorian Infant 

Collaborative 

study Group, 

2000

20307288

*some 

subjects were 

overlapped 

with Doyle, 

2001

Other: DexamethasonePostnatal ND CNS:

Cerebral palsy

Cognitive delay

Ophthalmology: Blindness

Audiology: Deafness

Wechsler PPSI-R

Wood

2000

20373840

General:

1) GA

2) Gender

Other: Perinatal Factors‡

Multiple gestation

ND CNS: 

Motor delay

Cognitive delay

Seizure disorder

Overall development

Ophthalmology:

Visual impairment

Blindness

Audiology:

Hearing disorders

Deafness

Speech

Communication disorder

Other:

Severely disabled

Other disability

No disability

Disability of hearing, vision, or 

communication

Bayley scales 

Severe disability = need of physical 

assistance to perform daily activities. 

If disability did not fit into this category = 

“other disability”
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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57

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Doyle

2001

21326609

Victorian Infant 

Collaborative 

study Group, 

1997

97290716

*some 

subjects were 

overlapped with 

20307288 

(stated in text)

*possibly 

overlapped with 

98026322

General predictors:

1) GA

2) SGA/IUGR

3) antenatal steroids

4) gender (female)

5) postnatal age

CNS predictors:

1) intracranial/ intraventricular 

hemorrhage

2) periventricular 

leukomalacia

Cardiovascular or pulmonary 

predictors:

1) bronchopulmonary 

dysplasia

Other predictors:

1) dexamethasone

2) perinatal factors

a) multiple birth

b) cesarian section

3) socioeconomic variables

i) Asian mother

ii) higher SEC

iii) no Englishspeaking at home

4) surgery in primary hospital

5) patient with no adverse 

events

1) SGA/IUGR - BW ratio <0.8

2) intracranial/ intraventricular 

hemorrhage - Papille system

3) periventricular leukomalacia -

cystic lesions in PVWM dx < 

discharge

4) bronchopulmonary dysplasia -

ROS + O2 Rx after 28 days age

5) dexamethasone - postnatal 

steroid use

CNS:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Ophthalmology outcomes

Blindness

Audiology outcomes:

Hearing disorders

Deafness

Other outcomes:

Survival without major disability at 5 

 years age

Survival with major neurosensory 

 disability at 5 years age

1) motor delay, cognitive delay -

WPPSI-R and alternative IQ tests

2) cerebral palsy - not walking or 

walking with difficulty

3) mental retardation - IQ < 2 SD 

below mean for NBW group
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Gaillard

2001

21221175

In retrospective case-control 

component:

General:

1) shorter length of ventilation 

beyond 27 (but not 50) 

postnatal ds vs more 

prolonged ventilation 

beyond 49 ds

2) Number of days “off”” 

ventilator in the groups of 

27-49 postnatal ds 

ventilation and the group of 

>49ds ventilation

In retrospective cohort with 

historical control group 

component:

GeneraL:

1) Birth in a period where 

Antenatal steroids and 

Surfactant were more 

routinely used vs birth in 

pre-surfactant pre-antenatal 

steroid period

Not further specified CNS:

Neurodevelopmental outcome:

1) Normal

2) Mild disability

3) Moderate disability

4) Severe disability

Normal neurodevelopmentally: no 

clinically apparent 

neurodevelopmental abnormality 

causing functional disability

Mild disability: e.g. myopia, language 

delay, mild hearing loss, 

hyperactivity or motor clumsiness.

Moderate disability: for example: spastic 

diplegia, hemiplegia or moderate 

learning disability (Developmental 

Quotient: 50-69)

Severe disability: e.g. spastic 

quadriplegia, blindness, deafness (loss 

of 70 decibel or more), uncontrolled 

epilepsy, or severe learning disability 

(developmental quotient <50). Infants 

with multiple disabilities.

( 3 yrs CA)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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59

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Roth

2001

21262686

CNS:

1) intracranial/Intraventricular 

hemorrhage

2) white matter disorder

3) Periventricular leukomalacia

4) Ventriculomegaly/ventricular 

dilation

5) Ultrasound methodology: linear 

array vs mechanical sector

ND CNS:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

School problems

Learning disabilities

Ophthalmology: 

Visual impairment

Blindness

Audiology:

Hearing disorder

Deafness

Outcome categories:

1) No neurodevelopmental impairment

2) Detectable impairment with

 disability (included neuromotor 

 impairment with functional consequences, high tore hearing loss with 

 need for aid, IQ 70-79, informal 

 “help” in mainstream school)

3) Impairment leading to disability 

(included neuromotor impairment 

leading to disability sensory neural 

hearing loss, requiring aids, blindness 

or registered partial sight, IQ<70 or 

requirement for formal extra 

educational provision

Saigal

2001

21376729

* Important 

paper

Birth weight

GA

ELBW=500-1000 g CNS:

Motor delay 

Cognitive delay

Other: neurosensory impairment

Ophthalmology:

Visual impairment 

Growth:

1) height 

2) weight 

3) head circumferences

4) BMI (wt/ht2)

Other:

1) Health status and problems ; 

current and past

2) Extra health care expenses

3) Utilization and health care 

resources

Reported previously in the authors’ 

other paper

Growth reference population was using 

the age- and gender- specific 

reference data provided by the NCHS 

growth chart
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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60

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Schmidt

2001

21298249

1) Prophylactic indomethacin 

administration : 0.1 mg/kg 

Q24 hrs X 3 days (vs NS 

placebo) in VLBW infants, 

during first 6 hrs of life

Nor further specified Primary outcomes at 18 months of

age:

1) Composite outcome: death or 

impairment

2) Death before 18 mo corrected 

age

3) Cerebral palsy

4) Cognitive delay (MDI<70)

5) Hearing loss requiring 

amplification

6) Bilateral blindness

Secondary long term outcomes 

outcomes:

1) Hydrocephalus, necessitating 

the placement of shunt

2) Seizure disorders

3) Microcephaly (HC<3 d %)

1) Death before a corrected age of 18 

months or documentation in survivors of 

one of the following: CP, Cognitive 

delay, Hearing loss requiring 

amplification, B/L blindness

2) Cerebral palsy diagnosed if had 

nonprogressive motor impairment with 

abnormal muscle tone and decreased 

range or control of movements.

3) Cognitive delay: as MDI less than 

70 (2SD below the mean of 100) on the 

Bayley scale between 85-114: classified 

as normal, Scores below 70: marked 

cognitive delay.

4) Documentation of composite 

primary outcome: required 

documentation that the infant had died 

or had survived with one of the 4 types 

of impairment. A single missing 

component of the f/up assessment 

would result in designation of missing 

for primary outcome. A priori criteria for 

definitions of presence or absence of 

component of the primary outcome.

5) In cases it was difficult to obtain 

Audiologic test results, deafness 

requiring amplification was assumed to 

be absent if no such indication was 

present during the Bayley test. (n=27 )

6) Blindness: a corrected visual Acuity

of less than 20/200. F/up evaluation

around 18 mo: allowed range 18-21 mo.

(Home visits were permitted when 

necessary)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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61

Author, Year Associations found Potential Biases Comments

Akerman 

1992

93255928

Physical and Emotional Problems at 4yrs:

Psychomotor retardation-------- 11.8%

Impaired hearing------------------2.9%

Impaired vision--------------------2.9%

Delay in speech/language--------11.8%

Emotional Problems---------------2.9%

No physical or psychological problems--------------------------67.7%

All except 3 infants with physical and emotional problems were either premature

or weighed less than 2500 gms at birth.

Of the 22 infants with physical or psychomotor impairment, 17 were 

males

No infant weighed less than 

 1250 g

Population homogeneous middle 

class with access to medical 

care

No data on funding source

Thompson 

1993

93234177

Two years CA neurodevelopmental outcome and Griffith’s scores for a cohort of 

South African infants with BW < 1250 g, n = 96. Mechanical ventilation not 

routinely used when BW < 900g.

Percent with outcome

Normal 75%

CP 6%

DQ < 70 and CP 3%

DQ < 70, no CP 1%

DQ 70-79 and CP 0

DQ 70-79, no CP 15%

Hyperactive 3%

“Squint” 0

Developmental delay 0

Scores on Griffith’sscales for most items fell significantly (P < 0.001) between one 

and two years of CA.

Overall major handicap rate rose between years 1 and 2 CA from 14% to 22%

(None) Study was private funded
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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62

Author, Year Associations found Potential Biases Comments

Rademaker 

1994

95003452

3.6% of the Preemie population (= 32 weeks) have unilateral intracranial 

parenchymal lesion.

Not all unilateral parenchymal lesions are the same. Size of the lesion, location

 of the lesion, and whether the lesion communicates with the ventricle at any 

time all have important role in prediction of neurodevelopmental outcome. For 

example, if the initial lesion is triangular/fan-shaped and does not 

communicate with the ventricle at any time and is located in the fronto-parietal 

area, overall prognosis is favorable. But if the lesion is globular-shaped, 

continuous with the ventricle and extends beyond the trigone into the occipital 

periventricular white matter, risk for death and developing moderate to severe 

hemiplegia is significantly increased.

Small sample size No data on funding source

Cases series
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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63

Author, Year Associations found Potential Biases Comments

Vonderveid

1994

94297368

Of all these 22 predictors/variables evaluated for CNS outcomes :

• PVL was associated with more than 5-fold increase in the risk of CP (OR: 

5.8; 95% CI: 3.8-8.8)

• Acidosis during hospitalization was associated with more than 1.5-fold 

increase in the risk of CP (OR: 1.6; 95% CI: 1.1-2.4)

Overall in this NICU cohort: there were: 443/634 (70%) LBW and 191/634 (30%) 

were VLBW

Overall CNS outcomes at 2 yrs:

1) Functionally normal were:

• 52% of all prematures

• 25% of VLBWs

• 63% of LBWs

2) 62/634 (10%) children had one or more disabilities

• 46/62 (74%) had CP of severity score 2-4

• 2 had peripheral motor disability 

• 9 had DQ< 80 (without motor or sensory disability) 

Ophthalmology outcome:

1) 8 were blind due to ROP (3 also had CP)

Audiology outcome:

1) 1 was deaf (was also blind and had CP)

A definite handicap was considered for:

• 21/62 (34%) disabled children 

• (21/634=3%) (according to WHO definitions)

• Cannot exclude 

Diagnosis bias as no information 

is given on blinding of personnel 

doing the outcome assessment 

on PMHx of the child.

• Cannot exclude false

Association found due to high

number of predictors analyzed

for the number of CP events (22

predictors for 46 CP cases)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

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Author, Year Associations found Potential Biases Comments

Kraybill

1995

95264242

Predictor evaluation for Pulmonary, Growth and Neurodevelopmental 

outcomes at 1 yr.

Single dose Surfactant tx at birth was not associated with the pulmonary, growth, 

neurodevelopmental and neurosensory status of VLBW premature infants at 1 yr 

of corrected age Placebo group vs Surfactant group, at 1 yr of age:

1) Overall survival at 1 yr: 160/193 (83%) vs 163/192 (85%)

Pulmonary:

1) Oxygen via NC: 4/122 (3%) vs 2/136 (1.5%)

2) Oxygen via CPAP: 0/122 vs 1/136 

3) CLD: 8/122 (6.5%) vs 10/136 (7%)

Growth:

1) Distribution of pts in both groups across different percentiles:

Ht/age, Weight/age and HC/age: were not s/s different across the two groups.

CNS:

1) Mean MDI score: 85 ± 20 vs 88 ±22 (not ss))

2) MDI scores< 2SDs : 11/118 vs 23/133

3) Mean PDI score: 89±22 vs 91 ±23 (not ss)

4) PDI scores < 2 SDs: 11/118 vs 8/133

5) No impairment: 69/119 (58%) vs 78/134 (58%) 

6) Impairment present (total ): 50/119 (42%) vs 56/134 (42%)

7) Severe impairment: 29/119 (24%) vs 37/ 134 (28%)

8) Mild/Moderate impairment: 21/119 (18%) vs 19/134 (14%) 

9) Types of impairment:

MDI<69: 21/119 (18%) vs 27/134 (20%)

 MDI: 69-84: 19/119 (16%) vs 20/134 (15%)

 Moderate/severe CP: 10/119 (8%) vs 9/134 (7%)

 Mild CP: 10/119 (8%) vs 12/ 134 (9%)

Audiology:

1) Bilateral sensorineural deafness: 0% vs 0%

2) Deafness not requiring amplification 1/119 (1%) vs 2/134 (1%)

Ophthalmology:

1) Bilateral blindness: 4/119 (3%) vs 2/134 (1%)

2) Visual defect: 9/119 (8%) vs 9/134 (7%)

Assessment from 28ds-12 mo:
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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65

Author, Year Associations found Potential Biases Comments

Kraybill

1995

95264242

(continued)

• No ROP: 50/132 (38%) vs 57/143 (40%)

• Present ROP overall: 82/132 (62%) vs 86/143 (60%) 

• Mild/Moderate ROP: 79/132 (60%) vs 84/143 (59%) 

• Severe ROP: 3/132 (5%) vs 2/143 (2%) 

• Treatment for ROP overall:7/132 (5%) vs 10/ 143 (7%) 

Surgery: 4/132 (3%) vs 3/143 (2%) 

 Cryotherapy: 4/132 (3%) vs 8/143 (6%) 

In the NCMH cohort there was no difference in impairments (present or absent), 

the severity of impairments and the types of impairments at the 1yr of age 

assessment of this cohort)

Predictor evaluation for Pulmonary, Growth and Neurodevelopmental 

outcomes at 2 yr.

Single dose of Surfactant tx at birth was not associated with the pulmonary, 

growth, neurodevelopmental and neurosensory status of VLBW premature 

infants at 2 yrs of corrected age24/52 (46%)

Placebo group vs Surfactant group, at 2 yr of age:

• Overall survival at NCMH only at 2 yrs: 68/60 (13%) vs 67/83 (81%)

Pulmonary:

1) Hospitalized for respiratory illness: 9/84 (82%) vs 9/52 (17%)

2) Bronchodilator regular use: 10/61 (16%) vs 6/57 (11%)

3) Tracheostomy: 2/61 (3%) vs 0/57

Growth:

1) Distribution of pts in both groups across different percentiles:

Ht/age, Weight/age and HC/age were: not s/s different across the two 

groups

CNS:

1) Mean MDI score: 89 ±21 vs 90 ±19

2) MDI scores< 2SDs: 5/58 (9%) vs 2/48 (4%) (NS)

3) Mean PDI score: 89 ±18 vs 88 ±16

4) PDI scores < 2 SDs: 4/58 (8%) vs 3/48 (7%)

5) No impairment: 32/60 (53%) vs 24/52 (46%)

6) Impairment present (total): 28/60 (47%) vs 28/52 (54%) (NS)

7) Severe impairment: 11/60 (18%) vs 7/52 (13%) 

8) Mild/Moderate impairment: 17/60 (28%) vs 21/52 (40%)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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66

Author, Year Associations found Potential Biases Comments

Kraybill

1995

95264242

Continued

9) Types of impairment:

MDI<69: 8/60 (13%) vs 2/52 (4%) 

MDI: 69-84: 14/60 (23%) vs 18/52 (35%) (NS) 

 Moderate/severe CP: 6/60 (10%) vs 5/52 (10%) (NS) 

Mild CP: 2/60 (3%) vs 3/52 (6%) (NS) 

Audiology: 

1) Bilateral sensorineural deafness: 0 vs 0

2) Deafness not requiring amplification: 0 vs 0

Ophthalmology:

1) Bilateral blindness: 0 vs 3/52 (6%)

2) Visual defect: 8/60 (13%) vs 2/52 (4%) (not ss)

Others:

1) Any surgery (between 1-2 yrs): 10% vs 9 %

Administration of single dose surfactant at birth in premature VLBW infants, with 

BW: 700-1350 g, results in improved survival rates up to 28 ds, without BPD and 

is not associated with adverse physical or neurodevelopmental outcomes at 1 yr 

or 2 yr corrected age.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

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67

Author, Year Associations found Potential Biases Comments

Speechley

1995

96356544

General Health outcome:

Among boys around 12 yrs of age: NICU graduates as opposed to normal boys:

1) Are living with more chronic health problems

2) Are more likely to have a physical impairment

3) And have been hospitalized more often.

Among girls around 12 yrs of age: NICU graduates as compared to normal girls: 

No statistically significant differences in their physical health outcome. Among 

NICU graduates, boys were not different from girls in their long-term physical 

health outcomes.

Emotional and Social well being outcomes:

Among girls around 12 yrs of age: NICU graduates as opposed to normal girls:

1) Had significantly lower social competence

2) Lower social support

3) And Lower self-esteem.

Among boys around 12 yrs of age: NICU graduates as compared to normal boys:

1) They had no difference in their emotional or social well being. There was no 

interaction between family’s socioeconomic status and long term outcomes 

among NICU graduates.

Analytically:

The physical health outcomes at 12 yrs were 

(Boys NICU grads vs Boys NNN grads/ Girls NICU grads vs Girls NNN grads)

• Chronic physical health (mother’s report): 2.8 vs 1.8 (p<0.005)/ 2.4 vs 1.3

• Lifetime hospitalizations (mother’s report): 2.5 vs 1.6 (p<0.005)/ 1.7 vs 0.4

• Physical impairments (mother’s report): 0.29 vs 0.10 (p<0.005)/ 0.22 vs 0.06

• Perception of child’s heath (child’s report): 21.6 vs 22.2/ 21.1 vs 21.9

• Perception of child’s health (mother’s report): 16.9 vs 17.7/ 16.8vs 18.0

Emotional and social well being at 12 yrs:

(Boys NICU grads vs Boys NNN grads, Girls NICU grads vs Girls NNN grads)

• Internalizing problems (child’s report):15.3 vs 15.5/ 18.2 vs 14.8 

• Externalizing problems (child’s report): 15.9 vs 16.0 / 14.3 vs 13.5

• Social competence (child’s report): 109.1 vs 113.9 / 101.7 vs 115.7 (p<0.005

• Social support (child’s report): 81.6 vs 83.2/ 79.9 vs 86.1 (p<0.005)

• Self esteem (child’s report): 31.9 vs 32.4/ 29.8 vs 32.5 (p<0.005)

• School performance (mother’s report): 4.5 vs 4.6/ 4.8 vs 5.3

1) There is an inconsistency in 

mother’s appreciation of their 

child’s physical health: mothers of 

NICU graduate boys reported that 

their children had more physical 

impairments than NNN boy 

graduates; however, their overall 

perception of their child’s health 

status was not any different from 

NNN boys graduates.

2) Some of the outcomes

collected are prone to recollection 

bias (e.g., frequency of lifetime 

hospitalizations).

1) In this NICU cohort, only 36%

of infants had BW<2500 g and only 

5% had BW < 1500 gs, reflecting 

more NICU populations in the 

1970s and early 1980s than the 

current ones. 

2) It is unclear whether

statistically significant differences

in psychometric scales, with 10-36 

items each, reflect clinically 

significant differences in the 

emotional and social well wellbeing 

of these children. 

3) Conversely, given the fact of 

many negative findings, post hoc 

power analyses demonstrated that 

the study had an 80% power to 

detect a 40% difference between 

the 2 groups. (considering 20% as 

small effect and 50% as medium 

effect)

4) The fact that girl NICU 

graduates had a more substantial 

psychological effect than boys may 

reflect that girls are further into 

adolescence than the boys, 

experiencing the sequelae earlier. 

Thus in order to determine whether 

the differences observed are a 

temporary effect/related to 

adolescence, this cohort had to be 

followed further into their teenage 

years
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

68

Author, Year Associations found Potential Biases Comments

Hack

1996

97060805

At 8 year age, 10% of VLBW (24/249) had major neurosensory abnormality vs.

0% of Normal Birth Weight. 

At 8 years age, VLBW vs. Normal Birth weight were significantly less for each 

of the growth outcomes: weight, height, and head circumference (p<0.001)

Significantly greater % of former VLBW infants with (22%) vs. without (7%) 

major neurosensory abnormal had significantly greater subnormal growth at 8 

yr (OR 3.91, 95% CI 1.18-12.88). VLBW with major neurosensory abnormal 

had no catch-up growth after 20 months age. VLBW +SGA had increased 

odds of subnormal growth at 8 years (OR 3.89, 95%CI 1.35-11.23) 

(None) No data on funding source

ELBW: Lost to follow-up 

(22), families refused (17), 

families moved out of 

state (20)

Hack

1996

97066007

 MR (MDI<84) CP Blind Deaf Major Neurosensory abnormal

 +MDI<80

1982-1988 52% 10% 10% - 49%

1990-1992 34% 10% 2% 6% 35%

20-month Neurodevelopmental outcomes did not change appreciably between 

the 2 eras. 

20% of infants had subnormal cognitive function (MDI<70) and 10% had CP 

during 1990-1992 period. One third of infants with BW 500-750 gram had 

major neurosensory abnormalities and / or MDI<80. 

(None) No data on funding source

Northern 

Neonatal 

Nursing Initative 

Trial Group

1996

96304894

No significant differences by Griffith’s Developmental quotients, incidence of 

CP, seizures, hearing disorders. Initial demographics available in an earlier 

study.

(None) Study was government and 

privately funded
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

69

Author, Year Associations found Potential Biases Comments

Sethi

1996

96334245

Single evaluation at 2 years age. Follow-up information available for 99% of 

cohort.

Normal 70%

Major impairment 11%

Minor impairment 19%

Cerebral palsy 8.7%

Blindness 2%

Results are from a single district 

general hospital

No accounting for confounders: 

IVH, antenatal steroids, etc.

Very little information provided to 

characterize groups BW 

distribution, degree of illness, 

IVH, BPD, etc.

Inadequate information about 

population and about 

determination of cognitive 

function

No data on funding source 

93 infants; follow-up 

available for 92; 20 infants

had follow-up data from 

local medical care center 

rather than clinic visits

Wilkinson

1996

97087405

Among 10 surviving infants GA<35 wk/ BW<1500 gm who had severe cystic PVL, 

all (100%) had severe neurodevelopmental outcome (CNS [spastic 

quadriplegia, abnl neuro exam, seizures], impaired vision and hearing) at mean 

27.3 mo age. 

10/12 examined (8 by single 

neurologist/ 2 by pediatrician 

and neurologist)

9/10 eye examined in NICU ? 7/10 

followed as outpatients

Not a complete population 

sample of all GA<35 weeks or 

BW<1500 g with complete 

scanning data

Small sample size

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

70

Author, Year Associations found Potential Biases Comments

DeReginer 

1997

98041177

Chronic lung disease 

Any adverse outcome:

 2/54 

 12/54 P<0.001

 18/56

Sensorineural hearing loss:

 0/54 

 0/54 P<0.05

 3/56

Low MDI<2 SD from mean:

 0/54 

 4/54 P<0.05

 5/56

Low PDI<2 SD from mean:

 1/54 

 4/54 P<0.05

 7/56

Weight Z-score:

 No numbers given <0.05

Chronic lung disease and cerebral palsy, unilateral blindness, length Z-score,

head circumference Z-score are not significant.

Matching scheme used is likely to 

be ineffective

Large proportion of study 

population excluded by their 

matching strategy: subjects 

excluded were: 329/387=85% 

with no chronic lung disease; 

53/111=47.7% with mild 

chronic lung disease; 

122/180=68% with severe 

chronic lung disease

No data on funding source

Dezoete

1997

97359687

Outcome of category I & II:

 SGA: No difference between SGA and AGA infants

 IVA gr. III, IV: signify more cat I & II outcome 

 with gr III-IV IVA vs I+II P= 0.01

Category IV:

 CLD: Children with CLD more likely to be normal 

 (category IV) P<0.01

Entry criteria of infants that 

admitted to NICU; don't know 

standards of resuscitation in all 

276 centers and it expertise of 

resuscitators creates a different 

kind of population.

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

71

Author, Year Associations found Potential Biases Comments

O’Shea

1997

98049056

*overlapped 

sample with 

98190123

Major neurosensory impairment:

 Grade 3 LVH or PVE: 6.21(2.56, 15.101)

CP:

 Total: (N=216) 14% (17/129 survivors)

Blindness:

 Total: (N=126) 4% (5/129 survivors)

MDI<68

 Total: (N=216) 14% (17/129 survivors)

(None) Study was government funded

Piecuch

1997 

97456215

Neurologic abnormal, neurosensory abnormal, cognitive abnormal

 BW No association

Neurologic:

 GA Negative association 

Neurologic/neurosensory:

 ICH/PVL Significant association with abnormal outcome

Cognitive:

CLD Significant association with poor outcome

Social risk Strong association

No association was found between outcome and birth weight. 

(None) No data on funding source

Piecuch

1997 

98012134

Mean age at follow-up was 32 months. Bayley exams were done at 18 months.

Neurologic abnormalities and CP did not differ significantly across the gestational 

ages of 24 to 26 weeks. Between 67% and 89% were normal in each 

gestational age group.

Significant differences (P = 0.036) related to gestational age were found in 18 

month Bayley exam scores when group as norma l borderline or deficient

 Normal Deficient

24 wk 28% 39%

25 wk 47% 30%

26 wk 71% 11%

Significant differences (P = 0.008) related to gestational age were found in the 

combined end point of CP or an abnormal Bayley exam score:

 Neither One Both

24 wk 28% 39% 33%

25 wk 47% 23% 30%

26 wk 63% 34% 3%

All inborn infants No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

72

Author, Year Associations found Potential Biases Comments

Singer

1997

98049057

Singer

2001

21163669

Evaluation at 36 months corrected age. VLBW, VLBW with BPD, full term (FT).

 Bayley MDI % with MDI below 70

VLBW 90 + 16 (38-126) 11%

VLBW w/ BPD 84 + 24 (10-116) 21%

FT 96 + 12 (57-127) 4%

P = 0.001 for VLBW vs. VLBW w/ BPD

 Bayley PDI % with PDI below 70

VLBW 98 + 20 (33-122) 9%

VLBW w/ BPD 84 + 29 (8-127) 9%

FT 103 + 15 (58-128) 1%

 P = 0.001 for VLBW vs. VLBW w/ BPD

At 3 years BPD predicted poorer motor outcome but not poorer mental outcome.

Receptive DQ: BPD < VLBW < Term, p < 05

Receptive DQ < 85: BPD 49%, VLBW 34%, Term 30%,

BPD < VLBW + Term p < .05

Expressive DQ: BPD < VLBW + Term, p < .05

Expressive DQ<85: BPD 44%, VLBW 25%, Term 25%

BPD < VLBW + Term p < .05

Communication DQ: BPD < VLBW + Term, p < .05

Communication DQ < 85: BPD 43%, VLBW 31%, Term 28%, NS

Rank order listing of risk factors in order of magnitude of effect and the number of 

communication DQ lowered by the risk factor: PDA lowered DQ by 13 points, 

Minority race by 6 points, lower socioeconomic status by 5 points, and higher 

neurologic risk by 5 points. p .001

Bayley Scales MDI:

BPD 83.7 ± 24, VLBW 90 ±16, Term 96.4 ± 12, BPD < VLBW < Term, p< 0.05

Bayley Scales PDI:

BPD 84.1 28, VLBW 97.4 19, Term 102.8 14

BPD < VLBW + Term, p< .05

ROP: BPD 43%, VLBW 4%, p= .001

Seizures: BPD 7%, 

Neurologic score: BPD 1.3 ± 2, VLBW 58 ± 1, p < .001

Single region, but at least it is a 

region

Unclear if examiners were blinded 

to group status

Study was government funded
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

73

Author, Year Associations found Potential Biases Comments

Victorian Infant 

Collaborative 

study Group, 

1997

98026322

*This study is 

also in CNS 

table

Birth weight < 1000g; assessed at 2 years corrected age.

Cohort n DQ < -3 SD DQ –3 to –2 SD DQ –2 to –1 SD DQ> -1 SD

‘91-’92 237 5.9% 6.3% 13.9% 73.4%

‘85-’87 211 6.2% 4.3% 14.2% 75.4%

Cohort n Mild CP Mod. CP Severe CP Any CP Blindness Deaf

‘91-’92 237 3.8% 1.7% 3.8% 9.3% 2.1% 0.8%

‘85-’87 211 NS NS NS 6.6% 4.3% 0.5%

Cohort No disability Mild Disability Moderate disability Severe disability

‘91-92 71.3% 14.8% 7.2% 6.8%

n = 237

‘85-’87 71.6% 15.6% 6.2% 6.6%

n = 211

Incomplete reporting of 

demographic data, 

methods and results.

Study was government 

funded

Victorian Infant 

Collaborative 

study Group, 

1997 

97466059

Arch Dis Child

All children born outside the level III perinatal centers. Assessment at 2 years 

corrected age. 

 1985-1987 1991-1992

 n 19 16

Cerebral Palsy 19.1% 12.5%

Cognitive delay 19.1% 18.8%

Blind 5.6% 6.2%

Deaf 0 0

Sensorineural disability

Mild 15.8% 6.2%

Moderate 0 0

 Severe 5.3% 12.5%

Incomplete reporting of 

demographic data, 

methods and results.

Study was government 

funded
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

74

Author, Year Associations found Potential Biases Comments

Cheung

1998

99059896

Mean MDI 81 ± 21, PDI 64 ± 22

Normal development 31%

Neurodevelopmental delay 20%

Disabled 50%

Severe mental retardation 10%

Spastic diplegic CP 30%

Hemiplegic CP 10%

<3

rd %ile for weight 20%

<3rd%ile for height 40%

<3rd%ile HC 30%

BPD 80%

Need bronchodilators for CLD 10%

Recurrent wheezing but did not need meds 40%

Grade 4 IVH 20%

Grade 3 IVH 20%

VP shunt 30%

PVL 10%

Sensorineural hearing loss 10%

Very small sample size

Descriptive study with no control 

group for comparison

No data on funding source

Finnström

1998

99041345

CP in 23-24 wks: 14%, in 25-26 wks 10%, =27 wks 3%, p<0.02

CP 25-26 wks AGA: 8%, SGA 24%

Major handicap by GA:

23-24 wks: 14%

25-26 wks: 9%

=27 wks: 3%

Major handicap by predictors:

Grade = 3 IVH and/or PVL: 29%, OR 5.6 (95%CI 2.4-12.9)

Stage = 3 ROP 19%, OR 2.8 (1.1-7.6)

Oxygen-dependent at 36 wks: 11%, OR 2 (0.9-4.1)

PDA requiring treatment: 10%, OR 1.2 (0.5-2.8)

Apgar score 0-3 at 1 min: 15%, OR 1.7 (0.7-4.0)

Mechanical ventilation: 7%, OR 1.3 (0.4-4.5)

After adjusting for GA, significant increased risk of handicap in infants with Grade 

= 3 IVH/PVL and Stage = 3 ROP

The mean height, weight and head circumferences were significantly lower 

than reference values.

Exams done by infants’ own 

pediatrician who is not 

blinded. Also they were not 

specifically trained in the 

evaluation so that results may 

be inconsistent. No control 

group.

Scheffzek’s categories not well 

defined.

Infants were in the era of limited 

use of antenatal steroids and 

surfactant so that they may 

have been much sicker.

How GA was determined not 

reported.

No data on funding source

Possible that because of 

national recommendation 

that mothers should not be 

treated actively on fetal 

indications before 

completion of 25 weeks 

that only the fittest survive 

and this may 

underestimate Incidence 

of CP in this study.

{Died by the follow-up 

exam (1)

Left the country (6)

Incomplete identification 

Number (1)}
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

75

Author, Year Associations found Potential Biases Comments

Gregoire

1998

98232532

Neurodevelopmental Outcome at 18 Months

Control BPD-1 BPD-2

N 76 48 93

Developmental 

quotient (DQ) 97.4 (15.6) 97.9 (11.6) 90.7 *(19.3)

DQ when no grade 4

IVH or PVL 97.4 (15.6) 99.9 (9.1) 93.0 *(19.3)

Percent w/ 

DQ < 93 25% 29% 46%*

Percent w/

DQ < 82 13% 13% 24%

Total CP 14% 17% 17%

Severe CP 13% 13% 17%

Total disabilities 29% 31% 50%**

BPD-1: supplemental O2 at 28 days but not at 36 weeks PCA.

BPD-2: supplemental O2 at 36 weeks PCA.

*P < 0.05 for comparison between BPD-1 vs. BPD-2.

** P < 0.05 for control group vs. BPD-2 and for BPD-1 vs. BPD-2.

Exam of SGA infants in BPD-2 

group

Higher receipts of postnatal 

steroids in BPD-2 groups 

Higher rate of severe IVH in BPD2 groups

Study was private and hospital 

funded

Kurkinen-Raty 

1998

98387235

(All+Lung)

*sample from 

the same big 

population as 

20284814

Retrospective controlled cohort study of early PROM between 17 and 30 weeks 

of gestation. Assessments at one year corrected age. N = 55 for early PROM 

and 56 for control.

Outcome Early PROM Control OR (CI)

Cerebral palsy 18% 16% 1.2 (0.4, 3.1)

Delayed motor

Development 9% 16% 0.5 (0.2, 1.7)

Visual disability 4% 4% 1.0 (0.1, 7.5)

Hearing loss 7% 9% 0.8 (0.2, 3.2)

Good nuerosensory

development 67% 61% 1.2 (0.6, 2.2)

Early PROM seems to be a major obstetric and neonatal problem with pulmonary 

ramifications extending beyond the neonatal period. However, most of these 

infants can be saved.

(None) No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

76

Author, Year Associations found Potential Biases Comments

Lee

1998

98442293

Growth, CNS and 

Audiology, and 

ophthalmology outcomes

for prematures<1250 g with 

candidemia/candida 

meningitis 

Growth:

1) No difference in Growth 

retardation: 

CNS:

1) No difference in MDIs of 

survivors

2) Lower PDIs in survivors

3) No difference in overall 

Neurodevelopmental 

disabilities (NDDs)

4) Cerebral palsy

Ophthalmology:

1) Vision loss

Audiology:

1) Hearing loss

(All the children with NDDs 

had Cerebral palsy with or 

without visual or hearing 

deficit)

Prematures<1250 g with 

candidemia/candida 

meningitis had: Higher 

Combined mortality and 

NDDs

Cases

7/14 survivors(50%)

83 ±20

71 ±21

4/14 (29%)

4/14 (29%)

2/14 (14%)

2/14 (14%)

60% 

(OR=3.9; 1.2-12.6)

Controls

11/21 survivors (50%)

90 ±20 (p>0.05)

87±18 (p<0.05)

3/21 (14%) (p>0.05)

3/21 (14%)

1/21 (5%)

1/21 (5%)

28% (p< 0.05)

1) Cannot exclude missed 

association due to the small 

number of patients analyzed 

n both groups
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

77

Author, Year Associations found Potential Biases Comments

Lefebvre

1998

98387703

Assessed at 18 months corrected age. Divided into low, moderate and high-risk

group based on Neurobiologic risk score (NBRS). Tested with Griffith’s

Developmental Scales.

 Griffith’s Developmental Score Category

Risk Group n Severe impairment, <80 All < 80

Low 50 0% 12%

Moderate 37 22% 24%

High 34 50% 71%

Significance: for severe or any delay the NBRS was predictive, P < 0.0001

Risk Group n Severe CP (+) Any CP

Low 50 0% 4%

Moderate 37 13% 19%

High 34 26% 41%

Significance: NBRS predictive of CP, severe CP, P < 0.0009, any CP P < 0.0001

(None) Study was privately funded

Millet

1998

98212544

Motor deficits:

 Diffuse brain damage (N=26); 14

Moderate CP:

 Diffuse brain damage (N=26); 6

Visual impairment:

 Diffuse brain damage (N=26); 12

Sensorineural hearing loss:

 Diffuse brain damage (N=26); 2

Cognitive impairment:

 Diffuse brain damage (N=26); 16

Epilepsy(in..? spasm) :

 Diffuse brain damage (N=26); 2

This paper has serious flaw s

There is little demographic 

information and 

sparse reporting of CNS 

outcome. No 

statistical testing is report

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

78

Author, Year Associations found Potential Biases Comments

Piecuch

1998

98446413

Neural/Neurosensory outcome

1) Neurologic and cognitive outcomes were relatively stable over the 3 time 

periods (1989-1991, 1984-1986, 1979-1981) for infants of 1000-1499 g BW.

2) > 90% of the infants born in each time period were neurologically normal. 

3) There was a non-statistically significant trend towards an increased number 

of infants with neurologic abnormalities in the more recent period.

4) The incidence of CP was stable over the 3 time periods.

Born in a recent period vs Born in a midpoint period vs Born in an Early period

• Normal: 168/186 (90%) vs 143/155 (92%) vs 102/109 (94%)

• Suspect: 10/186 (5%) vs 3/155 (2%) vs 1/109 (1%)

• Abnormal: 8/186 (4%) vs 9/155 (6%) vs 6/109 (5%)

More than 80% of infants in each group had normal cognitive outcome.

Cognitive outcome:

• Average/Above average: 152/182 (83%) vs 122/150 (81%) vs 86/102 (84%)

• 1-2 SD< mean: 23/182 (13%) vs 19/150 (13%) vs 12/102 (12%)

• > 2 SDs< mean: 7/182 (4%) vs 9/150 (6%) vs 4/102 (4%)

5) MDI scores declined slightly over time. But, mean PDI scores and MDI 

scores were not “clinically” significant across the 3 periods. More recent periods 

the infants born were smaller, younger, and had longer CLD

Mean PDI: 96.6 vs 98.5 vs 96.9; Mean MDI: 101.0 vs 103.4 vs 106.9

In all the infants from the 3 time periods: General Predictors evaluation:

Univariate analyses of predictors showed different relationships between outcome 

depending on inborn or outborn, with inborn having better neurologic and 

cognitive outcome. Predictors associated with with poor neurologic/neurosensory 

(suspect and abnormal) or poor cognitive outcome (p< 0.02) were: Place of birth 

(outborns vs inborns); GA; male gender; ICH; CLD. When infants of suspect or 

abnormal neurologic outcome and infants of abnormal neurosensory outcome 

were grouped together and compared with infants of normal 

neurologic/neurosensory outcome (multivariate): For inborns: ICH, GA were 

predictors of poor outcome; For outborns:ICH, CLD were predictors of poor 

outcome. When infants of mild and moderate to severe cognitive deficits were 

grouped together and compared with infants of normal cognitive outcome 

(multivariate): For inborns: males had poorer outcome; For outborns: CLD was 

associated with poorer outcome

Concern about generalizability of 

findings in other populations with 

higher socieconomic status and 

higher maternal education.

(For 50% of infants families were 

on public assistance and had 

maternal education of <12 yrs)

Predictors were assessed for 

their association with the 

outcomes; but the outcomes were 

measured with different scales for 

the different age groups (Bayley, 

Stanford-Binet, McCarthy, 

Wechler Intelligence scale) and 

the mean age at assessment 

were different in the 3 periods

Severe cognitive delay may be 

apparent at 26 mo CA (the mean 

age of assessment of the youngest 

group in the study). However, subtle 

or late appearing cognitive 

problems may not have yet been 

diagnosed. Thus, the study had a 

limitation in detecting borderline 

cognitive or academic problems.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

79

Author, Year Associations found Potential Biases Comments

Sajaniemi

1998

99041674

The neurological outcome of preterm infants was:

For Cerebral palsy: Free from major disabilities MDI

1) All prematures: 17.5% 82.5% 103

2) Prematures < 1000 gs: 23.5% 23.5% 98

3) Prematures > 1000 gs: 13.5% 85.6% 107

The developmental outcome: Preterm infants had significantly lower MDI scores 

when compared to full terms (Full terms 124 )

When temperament was considered: the premature children were significantly 

less active; more adaptive; less intensive; more positive in mood and had lower 

sensory threshold than the healthy control term children. When behavior was 

assessed (Infant’s Behavior Records): the preterms were significantly less goal 

directed; less attentive and; had lower in endurance than the controls.

When Bayley neurodevelomental was assessed:

1) The preterms performed significantly less well than the controls.

2) Low Bayley scores correlated with temperament scores of high rythmicity, 

positive mood, low persistence and high threshold

3) Low Bayley scores correlated with IBR scores

4) No strong relationship between temperament characteristics and cognitive 

performance. Preterm infants had significantly lower MDI compared to full terms:

• Preterm infants were different in 5/9 items of temperament profile compared 

to full terms: less active (p<0.008), more adaptive (p<0.02), less intense (p<0.01), 

more positive in mood (p<0.0004), lower in threshold to respond (p<0.0003)

• Preterm infants were different in 3/5 items in IBR profile, when compared to 

full terms: less goal directed, less attentive, lower in endurance

Predictors evaluation:

• From the perinatal risk factors: pre-eclampsia, SGA, PVL and IVH were not

associated with developmental outcome or temperament profiles.

• PVL, IVH were associated with shorter attention span (1/5 items in IBR 

profile); when preterms compared to full terms.

• Duration of NICU stay was not associated with Bayley score

• Duration of ventilation was not associated with Bayley score

• Duration of ventilation and days in NICU were associated with the 5 items of 

IBR profile; Duration of ventilation was associated with 1/9 items of temperament 

profile

• Post hoc multiple 

comparisons were done 

between preterms and full 

terms for the multiple 

individual items of the tests 

used.

• Cannot exclude selection 

bias

• No matching between 

groups cannot exclude the 

presence of confounders.

• Interactions between 

predictors may have masked 

some real associations; 

possible interactions were 

not formally tested 

• Cannot exclude diagnosis 

bias, as no information is 

given on the blinding of the 

personnel doing the outcome 

evaluation of the child’s 

PMHx.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

80

Author, Year Associations found Potential Biases Comments

Scherjon

1998

98429216

Predictors for Neurodevelopmental outcomes (Univariate analysis)

Adverse neurodevelopmental outcome at 3 years, measured with the Hempel 

test, was related to:

1) neonatal cranial ultrasound abnormalities of neonatal periventricular 

echodensities- as a sign of cerebral ischemia or intracranial haemorrhages (p< 

0.0001)

2) low head circumference at 3 years. (when compared to normal and 

moderate abnormal findings) (p< 0.0001)

Hempel test was not related to the umbilical/cerebral artery pulsatility index 

(raised vs normal) (p=0.23)

Fetal growth retardation (IUGR) or gestational age was not related to behavioral 

aspects, language and speech skills using a parental questionnaire.

Abnormal neurosonographic findings had an influence on Hempel outcome, only 

if these findings occurred in combination with a normal U/C ratio.

However, abnormal neurosonographic findings with raised U/C ratio were not 

associated with a poor Hempel outcome. (Raised U/C ratio reflects a more 

favorable adaptation to prematurity related risks, preventing the infant from having 

severe intracranial pathology)

Predictors for Growth outcomes at 3 yrs (Univariate model)

In preterm infants born 26-33 wks, lower median HC at 3 yrs was associated with

1) fetal Doppler findings of raised Umbilical/cerebral artery pulsatility index 

(U./C ratio) (vs Normal U/C ratio) (p=0.01)

Weight or height at 3 yrs was not associated with this predictor.

Predictors for Growth and Neurodevelopmental outcome (multivariate)

1) Cranial U/S findings of IVH and ED were associated 

a) with Hempel outcome (p<0.001), and

b) with HC at 3 yrs. (p=0.01) 

(it is not clear if it refers to moderate or abnormal U/S classification, or both)

2) U/C ratio, fetal growth ratio and GA were not associated with Hempel 

outcome

Cannot exclude possible 

confounders between compared 

groups.

The methods used for evaluation of 

qualitative behavioral and 

language differences at the age 

of 3 years between infants with 

and without placental 

insufficiency, possibly was not 

sensitive enough.

There was blinding for the Hempel 

outcome assessment on the 

patients PMH or cranial U/S 

findings.

The focus of this study was on 

motor development and quality of 

motor function. However, as there 

is weak association between 

neurodevelopmental outcome at 

3 yrs and at school age yrs, it 

remains to reevaluate these 

children for their cognitive 

function at school age.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

81

Author, Year Associations found Potential Biases Comments

Cheung

1999

99146391

Mental score:

 Days of ventilation: (N=64) <0.0001 

Motor Score:

 Days of ventilation: (N=164) <0.004

Mental Score:

 Grade of IVH: (N=164) 0.003

Motor Score:

 Grade of IVH: (N=164) <0.0001

Mental Score:

 Infants <1250g with gr. 3 or 4 IVH: (N=50) <0.001 

Motor Score:

 Infants <1250g with gr. 3 or 4 IVH: (N=50) <0.001

(None) No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

82

Author, Year Associations found Potential Biases Comments

Duvanel

1999

99207097

There was no association of hypoglycemia with scores in Griffith’s test at 6, 12, 

18 months and in the McCarthy’s test at 5 years.

There was association of hypoglycemia with significantly lower scores in 2 items 

of the McCarthy’s test (the perceptive index and the motricity index score) at 

3.5 years

Repeated episodes of hypoglycemia were associated with significantly decreased 

scores for 2/ 6 items in the McCarthy’s test (perceptive performance and 

motricity scale index) only at 3.5 years. (p< 0.05)

 Hypoglycemic Euglycemic group 

One episode of hypoglycemia:

 Mean MDI perception score at 3.5 yrs: 44.00 50.33 (p<0.01)

 >6 episodes of hypoglycemia

MDI perception score at 3.5 yrs 44.89 50.33 (p<0.05)

 >7 episodes of hypoglycemia:

• MDI perception score at 3.5 yrs 42.64 50.33 

(P<0.01)

• Motricity index score at 3.5 yrs 43.00 52.53 

(p<0.05)

Moderate hypoglycemia (11-29 mg/dl) was associated with significantly lower 

score in 2/6 items (perceptive performance and motricity scale index) in the 

McCarthy’s test only at 3.5 years. (p< 0.005)

No data on the association between the severity of hypoglycemia and the 

outcomes at 6, 12, 18 months and 5 years. (No complete data reporting)

Infants with recurrent mild hypoglycemia had lower neurodevelopmental 

scores than the group with 1 unique severe episode of hypoglycemia. (Multiple 

subgroup comparisons, between subgroups of the independent variable and 

subgroups of the dependent variable)

Hypoglycemia was not associated with growth rates for Weight, length, and 

HC at intervals 6-18 months, 6 mo-3.5 yrs, or 6mo -5 yrs.

Hypoglycemia was associated with significantly reduced HC at 12, 18 mo and 

5 yrs. (p<0.05)

1) Selection bias 

2) Information bias (in the 

measurement of the 

independent 

variable/glucose levels)

3) Confounders between the 2 

groups

4) Multiple subgroup 

comparisons. Hypothesis 

generating analyses.

Selected Population/Potential

Selection bias: 

Apparently a highrisk population was studied as the

frequency of hypoglycemia

identified was much higher than 

usually anticipated.

Methods: 

Not clear for which

parameters the matching between

the 2 groups was done. Did not 

describe the flow of patients

(Enrolled, excluded, lost to follow

up, eligible for the analysis)

Statistical analysis:

No predefined in the Method 

section of primary and secondary 

outcomes to be studied.

Many exploratory, hypothesis 

generating, subgroup analyses, 

which were not predefined in the 

Method sections.

Information bias:

Not consistent measurement of the 

predictor (glucose level) across 

different categories of 

hypoglycemia. Dextrosticks if 

glucose> 36mg/dl vs glucose 

analyzer if glucose<36 mg/dl)
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

83

Author, Year Associations found Potential Biases Comments

Pennefather, 

1999

20002011

Pennefather, 

2000

20217908

* This study is 

also in eye 

table

Strabismus in 70/558 (12.5%) infants GA<32 week .

The incidence of strabismus increased with decreasing GA (p=0.0004), 

increasing severity of ROP (p=0.0001), and decreasing general 

developmental quotient (GMDS) (p<0.0001).

Stabismus present in 28 (52%) of patients with CP (P< 0.001)

OR (95% CI) of Strabismus if following predictor was present:

Cicatricial ROP: 4.94 (1.1-22.12), p0.037

Fam Hx of Strabismus: 4.15 (2.19-7.88), p<0.00005

Refractive Error: 2.71 (1.3-5.66), p=0.008

GMDS 78-100: 3.34 (1.46-7.64), p =0.004

GMDS <77: 46.2 (17.1-125), p<0.00005

This study confirms findings of other studies that strabismus is increased in 

premature infants with decreasing GA and is increased with increasing 

severity of ROP and CP. Independent factors related to strabismus are 

cicatricial ROP, refractive error, family hx of strabismus, and developmental 

delay (especially delayed hand-eye coordination)

Prospective evaluation but 

retrospective collection of 

neonatal data; therefore, 

probable incomplete collection 

of variable reason for present 

and absent data

No demographic data was report 

(the cohort was described 

elsewhere)

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

84

Author, Year Associations found Potential Biases Comments

Ambalavanan

2000

21031370

ELBW:

MDI<68 : 12%

PDI<68: 20%

Major handicap: 28%

CP:28%

MR 16%

Post-hemorrhagic hydrocephalus: 5%

Deaf 1.4%

Blindness 1%

Predictors of major handicap (Low MDI and/or PDI): Grade of IVH, PVL, absence 

of chorio (in this population, not in most others), NEC>II; race; multiple 

gestation, BPD, maternal education

For ELBW infants without IVH, the prevalence of major handicap, low MDI, and 

Low PDI was 25%, 17%, 16%, respectively.

For ELBW infants with grade III IVH, the prevalence of major handicap, low MDI, 

and Low PDI was 33%, 29%, 24% respectively.

For ELBW infants with grade IV IVH, the prevalence of major handicap, low MDI, 

and Low PDI was 69%, 44%, 63% respectively.

This study identifies major determinants of adverse neurodevelopmental outcome 

(i.e. major handicaps, low MDI, low PDI) of ELBW (<1 kg) infants born 1990-

1994. Grade of IVH is strong predictor of adverse outcome. But note large % of 

ELBW without IVH who had major handicap, low MDI, and Low PDI. BPD was 

a significant determinant of low MDI and PDI. Mat education level was 

significant determinant of neurodevelopmental outcome. NEC, race, multiple 

gestation, PVL independently contributed to poor outcome in ELBW infant. 

Lower BW predicted low PDI.

Retrospective, relatively small 

samples size (218).

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

85

Author, Year Associations found Potential Biases Comments

Cioni

2000

20150341

Multivariate analysis found that periventricular leukomalacia in premature 

infants is highly, significantly correlated with visual impairment and abnormal 

neurodevelopment at 1 and 3 years age. The degree of visual impairment 

correlated well with degree of neurodevelopmental abnormality at 1 and 3 

years age. Strong association between visual impairment and involvement of 

optic radiation on MRI. 

28 of 29 infants had abnormal neurological examination at follow-up (6 mild 

abnormal; 22 had CP).

23/29 premature infants with PVL abnormality on MRI had at least one 

abnormality of visual function, and 50% had multiple visual function 

abnormalities. 

8/29 severe ‘fixation and following’ disorders

19/29 had strabismus

abnormal grating visual acuity 13/29

reduced visual field 9/29

OKN abnormalities 17/29

(None) Study was government 

funded

Visual function plays a 

strong role in early global 

development. But the 

presence of exceptions to 

these results also illustrate 

the complex, multifactorial 

nature of neurodevelopmental outcome. 

This study also illustrates 

the importance of a 

comprehensive assessment 

that includes various 

aspects of visual function. 

No single visual 

assessment will detect all 

visual abnormalities. 
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

86

Author, Year Associations found Potential Biases Comments

Hack

2000

20358826

MDI Score < 70:

 CLD: 55% (49/89); 2.18 (1.20-3.94)

MDI Score<70 (multi stepwise logistic regression) 

 Male sex: 2.73 (1.52-4.92)

 Social risk: 1.48 (1.09-2.00)

 CLD: 2.18 (1.20-3.94)

OR adjusted for sex, social risk & BW:

 Gr III-IV IVH: 

 50% (16/32); 8.55 (3.52-20.76)

 50% (8/16); 4.45 (1.54-12.84)

 50% (17/34); 5.48 (2.41-12.47)

 CLD: 30% (27/89); 3.09 (1.51-6.35)

 Sepsis: 14% (13/93); 3.47 (1.16-10.36)

 Jaundice: 26% (6/23); 5.15 (1.63-16.22)

Mult. Stepwise Logistic regression:

 Male sex: 2.79 (1.02-7.62)

 Sepsis: 3.15 (1.05-9.48)

 Jaundice: 4.80 (1.46-15.73)

Predictors of neurologic abnormality were a severely abnormal finding on cerebral 

ultrasound (OR, 8,09; 95% CI 3.69-17.71) and chronic lung disease (OR 2.46; 

95% CI 1.12-5.40); predictors of deafness were male sex (OR 2.79 95% CI 1.02-

7.62), sepsis (OR 3.15 95 % CI 1.05-9.48), and jaundice (maximal bilirubin level 

>171)

The authors concluded 

that there is an urgent 

need for research into the 

etiology and prevention of 

neonatal morbidity.
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

87

Author, Year Associations found Potential Biases Comments

Jankov

2000

20188680

Infants CPR in delivery room

-9 survived to discharge

 8/9 were free of severe neurologic disability

1/9 was legally blind

DR resuscitation beyond PPVin <750 gms was associated with high mortalilty 

but without unnecessary prolongation of life

Persistent Apgar score <5 and delayed onset of respirations beyond 5 mins in 

CPR recipients were associated with death or severe disability.

Did not find a high rate of severe neurodevelopmental disability in CPR recipients

Incomplete disclosure of data as 

it relates to 

the subgroups

Small sample size

Opposite results to other studies 

might be 

explained by decisions in many 

cases not to 

resuscitate infants that are 

extremely high risk 

which would be resuscitated in 

other centers

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

88

Author, Year Associations found Potential Biases Comments

Kurkinen-Raty, 

2000

20284814

*sample from 

the same big 

population as 

98197235

CLD at 1 year age: 

Indicated PT delivery: (81) 12/81 (15%)

Spontaneous PT delivery: (94) 3/94 (3%)

RR 4.6 (1.4, 1.6)

Growth: 

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94) 

Weight RR =0.03 (-5.3, 0.3)

L RR = 0.002

HC RR = 0.03

CP:

Indicated PT delivery: (81) 5/81 (6%)

Spontaneous PT delivery: (94) 10/94 (11%)

RR=0.6 (0.25-1.6)

Delayed motor:

Indicated PT delivery: (81) 8/81 (6%)

Spontaneous PT delivery: (94) 8/94 (9%)

RR 1.2 (0.5-3.0)

Visual disability:

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94)

RR =1.9 (0.5, 7.8)

Hearing loss:

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94)

RR =1.9 (0.5, 7.8)

This study demonstrated that premature infants who were born due to ‘indicated 

maternal/fetal reasons’ vs. spontaneous preterm delivered infants had worse 

pulmonary outcome a 1 yr age. More infants in ‘indicated’ group were SGA and 

were significantly smaller than control group at 1 yr in Wt, HT, and HC. There 

was no difference between groups in neurosensory outcomes.

Outcome not well defined

Difficult to know if lack of 

difference between 

groups is due to sample size or 

event rate. 

No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

89

Author, Year Associations found Potential Biases Comments

Marlow

2000

20150342

Pulmonary and Other predictors evaluation for Audiology outcome.

Children with sensorineural hearing loss [15] as compared to control group[30] 

had longer periods of:

1) Intubation, (14 ds vs 2 ds)

2) Ventilation (34 ds vs 6 ds)

3) Oxygen therapy (57 ds vs 10 ds) 

4) Acidosis (12 ds vs 0.5 ds), and 

5) More treatments with dopamine (33% vs 7%)or

6) Furosemide (87% vs 53%)

7) Neither P/T of aminoglycosides 

8) nor duration of jaundice 

9) or level of bilirubin varied between the 2 groups. 

SNHL was more likely when :

1) netilmicin use coexisted with the peak of bilirubin (87% vs 14%)_

2) when acidosis occurred when bilirubin was over 200 ?mol/l, (31% vs 4%)

3) when furosemide was used in the face of high creatinine levels (64% vs 

27%)

4) when furosemide was used with netilmicin (67% vs 37%)

CNS outcome at 12 mo:

At 12 months of age evidence of cerebral palsy was present in 7/15 (47%) of 

children with SNHL vs 2/30 (7%) of children without SNHL.(p=0.022)

1) Very small sample size 

(cases with SNHL only 15)

2) Analyzed too many 

predictors and 

combination thereof, for 

very few outcomes. Very 

wide confidence intervals; 

and even those predictors 

found to be associated 

with the SNHL this may 

have been due to chance.

3) The association found 

between SNHL and 

cerebral palsy was not

based on an adjusted 

analyses for possible 

confounders; 

4) The 2 groups were different 

in many factors that were 

associated with both SNHL 

and CP

Not reported source of funding
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

90

Author, Year Associations found Potential Biases Comments

Victorian Infant 

Collaborative 

study Group, 

2000

20307288

*some 

subjects were 

overlapped 

with Doyle, 

2001

 Cortocosteroids No Cortocosteroids P-value

 n 98 195 Cerebral 

Palsy 22.7% 3.6% <0.0001

Blindness 5.2% 0.5% <0.02

Deafness 1% 1.5% ns.

IQ scores <0.0001

 =-1SD 46.4% 68.2%

 -2 SD to <-1 SD 27.8% 24.1%

 -3 SD to <-2 SD 13.4% 4.6%

 < -3 SD 12.4 3.1 

Sensorineural disability <0.0001

Mild 26.8% 23.6%

Moderate 18.6% 6.7%

Severe 13.4% 3.6%

Subgroup case-control study: cases (subjects with cortocosteroids treatment) 

and controls (subjects w/o with cortocosteroids treatment) were well matched 

in most perinatal variable

 Cortocosteroids No Cortocosteroids P-value

 n 60 60 Cerebral 

Palsy 21.7% 5.0% <0.002

Blindness 1.7% 1.7% ns. 

Deafness 1.7% 3.3% ns.

IQ scores, SDS -1.26 -0.86 <0.05 

Sensorineural disability 

Mild 26.7% 26.7%

Moderate 21.7% 6.7%

Severe 10% 8.3%

(None) No data on funding source
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

91

Author, Year Associations found Potential Biases Comments

Wood

2000

20373840

Infants 22-25 weeks GA developmentally assessed at median 30 months

• 138/283 had disability 49% (64 met criteria for severe disability)

• 49% no disability

• 53/283 severely delayed 19% (Bayley below 3 SD)

• 32/283 2-3 below SD 11%

• 28 severe neuromotor disability 10%

• 7 blind or perceived light only 2%

• 8 hearing loss that was uncorrectable or required hearing aids 3%

 Survived without overall disability

 22 wks--------------0.7 %

 23 wks--------------5%

 24 wks--------------12%

 25 wks--------------23%

Severe disability at 30 months

 22 -------------------0.7%

 23 --------------------3%

 24---------------------6%

 25---------------------9%

• no relation between morbidity pattern and either gestational age &multiple 

birth 

• boys were likely to be disabled than girls

(None) Severe disability common children 

born extremely prema ture
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

92

Author, Year Associations found Potential Biases Comments

Doyle

2001

21326609

Victorian Infant 

Collaborative 

study Group, 

1997

97290716

J Paediatr Child 

Health

*some 

subjects were 

overlapped 

with 20307288 

(stated in text)

*possibly 

overlapped 

with 98026322

Evaluation at 5 years corrected age:

CP : 23-27 wk survivors (11.3%) 25/221 Blindness : 23-27 wk (1.8%) 4/221

 FT controls (0%) FT control 0%

Deafness : 23-27 wk (0.9%) 2/221

FT control 0%

IQ <-2 SD: 23-27 wk (15.4%) 34/221

 Major neurosensory disability 

23 –27 wk (19.6%) 44/225 FT control (4.1%) 10/245

Major disability among survivors

 23 wk GA: 2/5 (40%) 24 wk GA: 7/21 (33%)

 25 wk GA: 13/51 (25%) 26 wk GA: 17/71 (24%)

 27 wk GA: 5/79 (6%) Overall 23-27 wk: 19%

OR for survival with major disability at 5 years:

OR each 1 wk increase in GA = 0.59 (95% CI 0.43, 0.8)

Prognostic factors with major disability at 5 years: IVH, cystic PVL, surgery 

during primary hospitalization, postnatal steroid treatment.

Rates of survival free of major disability for surviving PT infants: 

None 96/103 =93% One 59/71 =83 % 

Two 23/43 =53 % Three 3/9 =33%

Four 0/1 = 0

Evaluation at 2 years corrected age. Data shown are for births in 1991-1992.

Gestational age Sensorineural disability (% of survivors)

 n Severe Moderate Mild None

23 weeks 5 29% 20% 40% 20%

24 weeks 21 14.3% 19% 33.3% 33.3%

25 weeks 51 5.9% 21.6% 25% 47%

26 weeks 68 8.8% 11.8% 20.6% 58.8%

27 weeks 74 1.4% 10.8% 23% 64.9%

Overall 219 6.4% 14.6% 24.2% 54.8%

Decrease in disability with increase in gestational age was significant, p = 0.014.

Also showed significant fall in severe disability with increase in gestational age, 

Odds ratio = 0.58 (0.36-0.94)

Comparison of cohorts born in 1985-1987 vs. 1991: 1992 did not demonstrate 

any difference between cohorts.

Perinatal data lacking on some 

infants, 

Especially outborn (in level II or I)

Different methods of testing IQ

Different times of assessing 

Neurodevelopmental outcome

Some children not evaluated at 5 

years 

(evaluated at 2 years)

210/401 preterm infants were 

assessed at 

both 2 and 5 years

The classification of disability or 

no disability 

was the same at both 2 and 5 

years (90.5% 

agreement; k=0.691)

Inadequate discussion of study 

population, 

Demographic 

Also various surrogate data

Study was government 

funded
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

93

Author, Year Associations found Potential Biases Comments

Gaillard

2001

21221175

Predictors for Neurodevelopmental outcome:

1) Shorter length of ventilation (beyond 27(but not 50) postnatal days) was 

associated with better neurodevelopmental outcome :

 59% (33/56) neurodevelopmentally normal or only mildly disabled 

survivors vs 25% (7/28) with more prolonged ventilation( > 49 ds )

Ventilated beyond 27 (but not 50)ds vs Ventilated beyond 49 ds

Total: 56 vs 28

Survived: 48/56 (86%) vs 14/28 (50%

Normal neurodevelopmentally: 26/48 (54%) vs 5/14 (36%)

Mild disability: 7/48 (15%) vs 2/14 (14%)

Moderate disability: 11/48 (23%) vs 4/14 (29%)

Severe disability: 4/48 (8%) 3/14 (21%)

2) Number of days “off”” ventilator was not associated with the 

neurodevelopmental outcome at 3 yrs neither in the groups of 27-49 

postnatal ds ventilation nor in the group of >49ds ventilati on ( but had only 

1,4 and 9 survivors in the 3 subgroups respectively)

Ventilated beyond 27 (but not 50)ds and O ds “off” ventilator vs 1-7 ds “off” 

ventilator vs > 7 ds off ventilator

Total: 18 vs 17 vs 21

Survived: 13 (72%) vs 15 (88%) vs 20 (95%)

Neurodevelopmentally normal: 8 (44%) vs 7 (41%) vs 11 (52%)

Mild disability: 2 (11%) vs 2 (12%) vs 3 (14%)

Moderate disability: 3 (17%) vs 4 (24%) vs 4 (19%)

Severe disability: 0 vs 2 (12%) vs 2 (10%)

(In the second component: comparison of the retrospective cohort with

the historical control)

3) Birth in a period where antenatal steroids and exogenous surfactant was 

more routinely used was associated with better neurodevelopmental 

outcome (69% vs 40% and 45% respectively in the 2 historical control 

cohorts) 

In First component:

Retrospective cases control 

design:

1) the 2 groups were 

unmatched for possible 

confounders, thus cannot exclude 

false associations

2) Cannot exclude selection

Bias as only 62 survivors were 

analyzed from the 84 initially 

included in the 2 groups

In the Second component:

3) Problems of confounders 

due to historical control 

group could be even greater

ND
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

94

Author, Year Associations found Potential Biases Comments

Roth

2001

21262686

Neurodevelopment Impairment:

Liner arrayall impairments 58 (28%)

Disabling impairment 24 (12%)

Mech sector 

all impairments 207 (36%)

Disabling impairment 80 (14%)

Groups outcome into large 

categories of 

Disability unable to specify motor 

vs cognitive 

Vs hearing vs vision
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

95

Author, Year Associations found Potential Biases Comments

Saigal

2001

21376729

* Important 

paper

Neurosensory Impairment:: ELBW 28%, FT Controls 2%, p= 0.001

Growth: Weight: diff. between ELBW and FT (mean z scores ) –5.78 (p<0.0001)

Visual Problems: ELBW 57%, FT Controls 21%, p=<0.001 (OR 5.1, CI 2.89-

9.05)

Current Health Problems (multiple/patient): ≥3 Health Problems: ELBW 35%, FT 

Controls 7%, p<0.0001

Past Health Problems:

 Seizures: ELBW 11%, FT Controls 2%, p<0.005

 Asthma: ELBW 25%, FT Controls 14%, p=0.05

 Recurrent bronchiolitis/pneumonia: ELBW 14%, FT Controls 3%, p=0.005

Current (at 12-16 yr age) Functional Limitation (Table 4 page 411) 

(multiple/patient)

 Visual difficulty: ELBW 57%, FT Controls 21%, p<0.001

 Hearing Difficulty: ELBW 7%, FT Controls 5%, ns.

 Emotional problems: ELBW 4%, FT Controls 1%, ns

 Mental problems: ELBW 4%, FT Controls 1%, ns.

 Clumsiness: ELBW 25%, FT Controls 1%, p<0.001

 Developmental Delay: ELBW 26%, FT Controls 1%, p<0.001

 Learning Disability: ELBW 34%, FT Controls 10%, p<0.001

 Hyperactivity: ELBW 9%, FT Controls 2%, p=0.04

 Reduced self-abilities: ELBW 5%, FT Controls 0%, p=0.02

Limitation in school or in normal activity: ELBW 31%, FT Controls 9%, 

p<0.002

Any functional limitation: ELBW 81%, FT Controls 42%, p<0.001

Functional limitation/child [Mean (SD)]: ELBW 2.0 (1.8), FT Controls 0.6 

(0.8), p<0.001

Utilization of Health Care Resources:

Pediatrician: ELBW 34%, FT Controls 14%, p<0.0002

Ophthalmologist: ELBW 62%, FT Controls 34%, p<0.0001

Ear/nose/throat: ELBW 14%, FT Controls 6%, p<0.05

Occupational therapist: ELBW 7%, FT Controls 1%, p=0.002

Speech therapist: ELBW 8%, FT Controls 0%, p<0.002

Special Education: ELBW 48%, FT Controls 10%, p<0.0001

Prescription Glasses: ELBW 36%, FT Controls 10%, p<0.001

Didn’t specify exclusion criteria 

but these are implied based on 

clear industry criteria 

Limits to generalizability: 

1) different era of natural care 

2) white race 

3) access to universal health care 

in Canada 

Study was private funded
Evidence Table 1. Studies Evaluating Association of LBW and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

96

Author, Year Associations found Potential Biases Comments

Schmidt

2001

21298249

1) There was no difference in primary outcomes between the 2 groups at 18 

months of age.

2) Among the 574 infants who were assigned to prophylaxis with indomethacin, 

271 (47%) died or survived with impairment as compared with 261 of 569 infants 

(46%) assigned to placebo (OR: 1.1; 95% Confidence intervals; 0.8-1.4)

3) In VLBW infants, prophylaxis with indomethacine does not improve the rate 

of survival without neurosensory impairments at 18 months of age

4) There was no difference in any of the secondary outcomes between the 2 

groups , at 18 months of age.

Primary: Composite / CNS Outcomes: Indomethacin vs. Placebo

• Death or impairment 271/574(47%) vs. 261/569 (46%)

• Death before 18 mo 121/595 (21%) vs 111/594 (19%)

• Cerbral palsy 58/467 (12%) vs 55/477 (12%)

• Cognitive delay (MDI<70 by Bayley scale 118 /444 (27%) vs 117/457 (26%)

Audiology outcome:

• Hearing loss requiring amplification 10/456 (2%) vs 10/466 (2%)

Ophthalmology outcome:

• Bilateral blindness 9/456 (2%) vs 7/472 (1%)

(Odds ratios adjusted for BW stratum and Center)

Secondary CNS outcomes were not affected by indomethacin administration:

• Hydrocephalus requiring shunt 15/470 (3%) vs 9/480 (2%)

• Seizure disorder 8/470 (2%) vs 7/483 (1%)

• Microcephaly 49/461 (11%) vs 54/475 (11%)

Kaplan Meier estimates of survival in the 2 groups:

• 0 months n=601 vs 601

• 6 months n=479 (80%) vs 490 (82%)

• 12 months n=473 (79%) vs 487 (81%)

• 18 months n=470 (78%) vs 483 (80%)

1) By using the Bayley test at 18 

mo the authors found that 

more than one quarter of all 

surviving infants had moderate 

to severe cognitive delays, 

defined by MDIs< 70. The 

validity of the MDI score at this 

age as a predictor of later 

intellectual functioning remains 

to be determined.

2) At a post hoc calculation the 

study had a 90% power to 

detect a 20% reduction in risk, 

had it existed

3) Authors report that the 

outcome assessments were 

done blindly by investigators 

unaware of treatment groups 

assignments.

4) Authors report that they had 

almost complete 

ascertainment for the primary 

outcome at 2 yrs of age.
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

97

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Casiro

1995

95264245

Location: Canada

Years of Birth: 1988- 1990

Mean GA (range), wk:

 Experiment: 25.8±1.6

Control: 24.8±1.1

Mean BW (range), g:

Experiment: 652±64

Control: : 661±52

Male: 

Experiment: 40%

Control: 40%

Race: White

Experiment: 6%

Control: 14%

Enrolled: 113 (111 controls)

Evaluated: 47 (42 controls)

Number of sites: 13

BW 500-749 g

Informed consent

Mechanical ventilation 

required 

within 24 hr. b/o RDS

A/A PO2 ratio< 0.22

“Exclusion criteria for this

 study were the same as 

those used in an earlier 

trial of synthetic surfactant” 

(Long W, Thompson T, et 

al., 1991)

Died by age of 1 year

Experiment: 

Exosurf (47)

Control: Placebo (42)

Randomized Controlled 

Trial
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

98

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Gerdes

1995

95264241

Location: US

Years of Birth: 3/1989-4/1990

Mean GA (range), wk:

Experiment 1: 27.2±1.7

Experiment 2: 27.2±1.8

Mean BW (range), g:

Experiment 1: 907±121

Experiment 2: : 911±125

Male: 

Experiment 1: 55%

Experiment 2: 56%

Race: 

Experiment 1: White 55%, Black 37%, 

Hispanic 4%, Other 5%

Experiment 2: White 60%, Black 30%, 

Hispanic 5%, Other 5%

Enrolled: 826

Evaluated: 508

Number of sites: 33

Mothers who were expected 

to deliver premature infants 

with BW 700-1100 g

All exclusion prenatal.

1) Proven fetal lung maturity 

2) Known malformation or 

chromosome anomaly

3) Fetal growth retardation

4) Hydrops

5) Purulent amnionitis

6) Maternal heroin addiction

7) Obstetric decision not to 

support fetus

Postnatal exclusions:

1) Major malformation

2) >3 minor anomalies 

3) Hydrops

Experiment 1: One 

doses surfactant (244)

Experiment 2: Three 

doses surfactant (264)

Randomized comparison

 trial (1 year)
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

99

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

O’Shea

1998

98167528 

98190123

*also in CNS 

table

*overlapped 

sample as 

98049056

Location: US

Years of Birth: 1978-89; 1990-94

Mean GA (range), wk:

Born in 1978-1989:

Cases: 28(24-33)

Unmatched controls: 29 (23-39)

Matched controls: 28 (24-34)

Born in 1990-1994: 28.0±2.9

Mean BW (range), g:

Born in 1978-1989:

Cases: 1021 (520-1500)

Unmatched controls: 1150 (580-1490)

Matched controls: 1095 (580-1490)

Born in 1990-1994: 1039±291

Male: 

Born in 1978-1989:

Cases: 54%

Unmatched controls: 50%

Matched controls: 51%

Born in 1990-1994: 51%

Race:

Born in 1978-1989:

Cases: 45% African-American

Unmatched controls: 35% AfricanAmerican

Matched controls: 32% AfricanAmerican

Born in 1990-1994: 56% White

Enrolled: 1978-1989 (1559); 1990-1994 

(1264)

Evaluated: 1978-1989 (80 cases, 240 

controls); 1990-1994 (723)

Number of sites: 2

BW 500-1500g, admitted to 

the 2 intensive care 

nurseries that served the 

17 countries in NW N. 

Carolina. Birth at only 

tertiary OB center in region

Survived to age 1 year 

corrected age

Cases: diagnosis of any 

subtypes of cerebra palsy

Controls: VLBW infants born 

closest in time to the 

respective case, who after 

examination at 1 year of 

age were felt to be free of 

any signs of cerebra palsy

Major congenital anomaly Born in 1978-1989:

Cases: CP (80)

Unmatched controls 

(160)

Matched controls 

(80)

Born in 1990-1994:

VLBW infants: 723

Case-control study (1 

year corrected age)
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part I

100

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

O’Connor

2001

21376723

Location: US

Years of Birth: 1996-1998

Mean GA (range), wk: 29 (27-31)

Mean BW (range), g: 1253 (965-1543)

Male: 39%

Race: ND

Enrolled: 376

Evaluated: 246 (126 controls)

Number of sites: 8

GA < 33 weeks and BW 750-

1805 g

Completed the study to 12 

months’ CA

Serious congenital 

abnormalities, 

major surgery prior to 

enrollment/ 

randomization. PVL/IVH 

> grade II

Maternal Incapacity

Liquid ventilation

Severe asphyxia 

Uncontrolled systemic 

infection at enrollment 

Sample 1: EHM-T fed 

infants (43), 

reference group 

only, not included in 

analyses

At 12 months:

Sample 2: AA+OHA 

(fish/fungal) (120)

Sample 3: AA+DHA 

(egg-TG/fish) (126)

Control: formula-fed 

infants (126) 

Randomized controlled 

trial (12 months)
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

101

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Casiro

1995

95264245

Cardiovascular/Pulmonary: 

Exosurf vs. placebo

ND CNS:

Motor delay

Cerebral palsy

Cognitive delay

Severity impairment

Ophthalmology: ROP

Growth: Height, weight, head 

circumference

Other: Re-hospitalization in 1st year 

of life

Bayley Scales of Infant Development: 

MDI and PDI

The details of ophthalmologic 

examination, 1-year follow-up, health 

status evaluation were described in 

elsewhere (Courtney SE, Long W, et al., 

1995)

Gerdes

1995

95264241

Cardiovascular or Pulmonary: 

Surfactant use

ND CNS:

Cerebral palsy 

Cognitive delay

Mental retardation

Ophthalmology: Visual impairment, 

Blindness

Audiology: Hearing Disorder, 

Deafness

Pulmonary: 

Asthma

e/o CLD

Respiratory support @ 1yr

Growth: Height, Weight, HC

Other: hospital re-admissions, h/o 

surgery

Mental retardation Bayley Scales 

MDI<69
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part II

102

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

O’Shea

1998

98167528 

98190123

*also in CNS 

table

*overlapped 

sample as 

98049056

General predictors:

Birth weight

GA

CNS predictors:

IVH

White matter disorder

Periventricular leukomalacia

Ventriculomegaly/Ventricular 

dilation

Other:

Infectious disease

Perinatal factors

Hemorrhage disease diagnosed by 

Cranial US finding

CNS:

CP

CP including spastic hemiplegia 

(involvement of an arm and leg on the 

same side of the body), spastic diplegia 

(involvement of the both legs with 

minimal to no involvement of the arms); 

and, spastic quadriplegia (involvement 

of all four extremities)

O’Connor

2001

21376723

Other: Nutrition/growth ND CNS:

Motor delay

Cognitive delay 

Other: information processing 

languages

Ophthalmology:

Visual Acuity

Growth:

Weight 

Length 

Head circumferences

Bayley scales – PDI; MDI

Teller visual acuity cards
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

103

Author, Year Associations found Potential Biases Comments

Casiro

1995

95264245

Assessed at one year corrected age.

No significant differences between placebo group and Exosurf group for:

 Bayley MDI (Placebo 79 + 22 vs. Exosurf 87 + 20)

 Bayley PDI ( Placebo 73 + 18 vs. Exosurf 81 + 19)

 Percent of patients with Bayley MDI < 69 (22% vs. 

 21%)

 Percent of patients with Bayley PDI < 69 (29% vs. 

 19%)

No significant differences between placebo and Exosurf groups for:

 No impairment (38% vs. 55%, Placebo vs. Exosurf)

 Any impairment (62% vs. 45%, Placebo vs. 

 Exosurf)

 Serious impairment (41% vs. 32%, Placebo vs. 

 Exosurf)

No significant differences between placebo and Exosurf groups for:

 Bilateral sensorineural deafness: 7% vs. 9%,

 Placebo vs. Exosurf)

 Blindness: (7% vs. 2%, Placebo vs. Exosurf)

No significant difference in height, weight or head circumference.

All patients had RDS requiring mechanical 

ventilation

No data on funding source
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

104

Author, Year Associations found Potential Biases Comments

Gerdes

1995

95264241

Severe ROP:

 1 dose: 47(16) 3 dose: 35(11)

Physical evidence of CLD:

 1 dose: 43(18) 3 dose: 40(15)

Medication for CLD:

 1 dose: 35(14) 3 dose: 30(11)

Medication for chronic neurologic disease:

 1 dose: 12(5) 3 dose: 3(1)

Index<2 SD (%):

 1 dose: 29(15) 3 dose: 30(13)

Impairment present:

 1 dose: 106(44) 3 dose: 92(35)

No impairment:

 1 dose: 123(51) 3 dose: 155(59)

Severity of impairment:

 Mild/moderate:

 1 dose: 40(17) 3 dose: 39(15)

 Serious:

 1 dose: 66(27) 3 dose: 53(20)

Types of impairments:

 MDI<69:

 1 dose: 40(16) 3 dose: 38(14)

 Moderate/severe CP:

 1 dose: 22(9) 3 dose: 16(6)

 Bilateral sensorineural deafness:

 1 dose: 5(2) 3 dose: 10(2)

 Deafness not requiring amplification:

 1 dose: 5(2) 3 dose: 2(1)

 Bilateral blindness: 

 1 dose: 10(4) 3 dose: 4(2)

 Visual defect: 

 1 dose: 24(10) 3 dose: 22(8)

25% loss to follow up, equal in both groups 1 

year follow up does not predict long term 

outcome from all infants

No data on funding source

“Prenatal and postantal 

exclusion criteria were 

identical to those used in an 

earlier prophylactic trial of 

this synthetic surfactant”

Died by 1-year adjusted age 

Lost to follow-up
Evidence Table 2. Randomized Controlled Trials for LBW Infants and Multiple Outcomes: CNS, Eye, Lung, Growth, etc.

Part III

105

Author, Year Associations found Potential Biases Comments

O’Shea

1998

98167528 

98190123

*also in CNS 

table

*overlapped 

sample as 

98049056

 Dexamethasone Placebo P

Definite Cerebral Palsy: 12 3 

Possible CP: 5 2 

Overall CP: 17 5 0.006

Neuro exam severe

Abnormal: 4 2

Mild abnormal: 16 6

Overall abnormal

Neuro exam: 20 8 0.03

Authors analyze associations between prenatal factors and cerebral palsy in 

80 infants with weights 500-1500g who were born in 1978-1989 to a resident 

of northwest region of Carolina. Factors that were strongly associated with 

increased risk of CP were: multiple gestation, chorioamnionitis, maternal 

antibiotics, antepartum vaginal bleeding, and labor lasting less than 4 hours. 

Pre-eclampsia and delivery without labor were associated with decreased risk 

of CP.

(None) Study was government 

funded

O’Connor

2001

21376723

Growth (Wt, Ht, HC) no difference among the 4 pretem groups in terms of 

gm/kg/day for weight ; mm/wk for Ht and HC.

Bayley at 12 months

 MDI range 92.2- 93.4 (no difference among 4 groups)

 PDI range 85.9-87.2 (no difference among 4 groups)

For infants with BW<1250 gm 

 Control group: PDI 81.8 which was sig less than PDI in AA-DHA (fish/fungal) 

(90.6)or AA-DHA (egg) (84.7) groups

Language vocabulary comprehension at 14 mo.

 Comprehension: 97-101.6 (no difference among 4 groups)

 Production: 96.6-98.3 (no difference among 4 groups) 

Results support benefit in PDI of supplementing formulas for premature infants 

with AA+DHA from either fish/fungal or egg/fish source from first enteral 

feeding through 12 months in infants BW<1250 g

(None) No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

106

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Leonard

1990

90204169

Location: US

Years of Birth: 9/1/77- 9/1/82

Median GA (range), wk: 

28.54±1.97

Mean BW (range), g: 1003+155

Male: 43%

Race: ND

Enrolled: 193

Evaluated: 129

Number of sites: 1

BW<1250 g

Head CT between 5-6 days of life 

or head ultrasound days 3 and 

10 after delivery

Died after discharge

Lost to follow-up before 

reaching school age

VLBW infants (129):

Without ICH (84), 

including 72 no 

parenting risk factor 

and 12 having 

parenting risk factor

With ICH (45), 

including 38 no 

parenting risk factor 

and 7 having 

parenting risk factor

Prospective cohort 

(4.5 to 5 years)

Lucas

1992

92122860

Location: UK

Years of Birth: 1982-1985

Mean GA:

 Sample 1: 31.4 ± 0.3

 Sample 2: 31.4 ± 0.2

Mean BW:

 Sample 1: 1420 ± 30

 Sample 2: 1440 ± 20

 Males:

 Sample 1: 42%

 Sample 2: 55%

Race: ND

Enrolled: 313

Evaluated: 300

Number of sites: 5

Premature

BW< 1850 g

ND Sample 1: 

Preterms- no mother’s

milk (mother’s choice 

not to provide breast 

milk to her infant within 

72 hrs from delivery) 

[90]

Sample 2:

Preterms- mother’s 

milk (mother’s choice 

to provide breast milk

to her infant within 72 

hrs from delivery)

matched with sample 1 

for :BW, GA, need for 

ventilation, ds of

NICU stay, other diets

[210]

Prospective 

comparative

longitudinal study 

(7.5-8 yrs)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

107

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Robertson

1994

94181384

Location: Canada

Years of Birth: 1990

Median GA (range), wk: ND

Mean BW (range), g: 500-1500

Male: ND

Race: ND

Enrolled: 241

Evaluated: 163 ? 157

Number of sites: 2

BW 500-1249 g, lived born in 

Alberta to Alberta parents

Corrected rates exclude 

infants with syndromes 

and / or CNS 

malformations

Survived to 1- and 2-

years of corrected age

VLBW infants survived 

to 1 year corrected 

age (163)

? survived to 2 year 

corrected age (157)

Retrospective cohort 

(at 1 year and 2 year 

corrected age)

Spinillo

1994

94257064

*sample 

overlaps with 

Spinillo, 1997

Location: Italy

Years of Birth: 1983-1989

Median GA (range), wk:

Sample 1: 33.4±3.4

Sample 2: 31.6±4.3

Sample 3: 32.7±5.1

Controls: 32.7±4.0

Mean BW (range), g:

Sample 1: 1800±458

Sample 2: 1641±570

Sample 3: 1768±633

Controls: 1748±569

Male: ND

Race: ND

Enrolled: 87

Evaluated: 77 (154 controls)

Number of sites: 1

Cases: LBW infants with diagnosis 

of abnormal antepartum 

bleeding in mother’s pregnancy

Controls: two liveborn LBW infants 

of similar GA and free of 

malformations born immediately 

after each case

ND Cases:

Sample 1: Abruptio 

Placentae (40)

Sample 2: Placenta 

Previa (22)

Sample 3: Unclassified 

reason for 

antepartum bleeding 

(vaginal and cervical 

polyps, excessive 

blood show, and 

cervical lacerations)

Controls (154)

Prospective cohort 

(2 year)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

108

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Chen

1995

96009403

Location: Taiwan

Years of Birth: 2/1990- 12/1991

Mean GA (range), wk: 30 (27-36)

Mean BW (range), g: 1197 (625-

1500)

Male: ND

Race: ND

Enrolled: 74

Evaluated: 17

Number of sites: 1

VLBW preterm infants ND VLBW pretern infants 

(17):

Group 1 - normal 

brain US (12)

Group 2 - abnormal 

brain US (5, 

including 1 IVH 

grade I, 1 IVH grade 

III, and 3 PVL)

Prospective cohort (18-

42 months) 

Left the hospital soon 

after birth at the 

request of their 

families (28)

Families’ refusal for 

further imaging studies 

(26 normal infants and 

3 PVL infants)

Goetz

1995

96119489

Location: US

Years of Birth: 1/1/1989 to 

12/31/1992

Median GA (range), wk: ND

Mean BW (range), g: 550-1100

Male: ND

Race: ND

Enrolled: 115

Evaluated: 14

Number of sites: 1

LBW < 1500 g

Diagnosis of PVL

Death

Transferred prior to being 

studied

Not being followed-up

LBW infants with PVL 

(14)

Unclear (Retrospective 

or Prospective cohort, 

11 months to 3 2/1 

years)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

109

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Speechley

1995

96356544

Location: Canada

Years of Birth: 1978-1980

Mean GA:

 Sample 1: 37 (28-43)

 Sample 2: 40 (37-44)

Mean BW:

 Sample 1: 2790 (850-4550)

 Sample 2: 3503 (2660-5170)

Male:

 Sample 1: 56%

 Sample 2: 50%

Race: 

 Sample 1: whites : 90%

 Sample 2: whites: 90%

(Original study: was a randomized 

interventional study of having a 

family volunteer visit the home on a 

regular base for 6 months)

Eligible (for the original study): 828

Enrolled (for the original RCT): 

312 

Evaluated (at 12 yrs): 253 

Number of sites: 1

All infants born at a tertiary care 

hospital in Ontario

Born between 1978-1980

Transferred to NICU or Normal 

Neonatal Nursery (NNN)

Family residence

more than 120 Km from 

hospital

Newborn’s survival was in 

question

Language barrier

Refused to participate to 

the original RCT.

Sample 1:

Former NICU

graduates: [116]

Sample 2:

Former NNN 

graduates [137]

Prospective, longitudinal, 

comparative,

observational study 

(12 yrs)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

110

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Wildin

1995

95385294

Wildin

1997

97422739

*Data from 

same 

longitudinal 

study as 

Anderson, 1996

96314587 &

Smith, 1996

97081985; 

overlapped 

sample

Location: US

Years of Birth: 1991-1992

Median GA (range), wk: 

 Sample 1: 28.2±2.3

 Sample 2: 30.8±2.2

 Controls: 39.6±3.7

Median BW (range), g:

 Sample 1: 922±226

 Sample 2: 1245±209

 Controls: 3177±809

Male: 

 Sample 1: 46%

 Sample 2: 42%

 Controls: 51%

Race: African American

 Sample 1: 56%

 Sample 2: 56%

 Controls 3: 62%

Enrolled: 370

Evaluated: 184 (114)

Number of Setting: 2

(Sapme 1&2): 

BW< 1600g

GA< 36wk

Complete neurologic and 

developmental exams at 6 and 

12 month corrected age.

Controls:

GA 37-42wks

Apgar scores greater than 8 at 1 

and 5 min

Normal physical exam

“Significant” sensory 

impairment, meningitis, 

encephalitis, 

symptomatic congenital 

syphilis, congenital 

abnormality of brain, 

short bowel, HIV 

positive mother

Primary care giver< 16y/o, 

drug abuser or did not 

speak English

Cases: preterm LBW 

infants (184):

Sample 1: High risk 

(HR) (69)

Sample 2: Low risk 

(LR) (115)

Controls: Full Term 

(114)

Prospective cohort (at 6, 

and 12 months of age)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

111

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Anderson

1996

96314587

Smith

1996

97081985

(CNS+All)

*Data from 

same 

longitudinal 

study (U. of 

Texas Health 

Sciences 

Center in 

Houston and 

the U. of Texas 

Medical Branch 

in Galveston) 

as Wildin, 1995 

& 1997; 

overlapped 

sample

Location: US

Years of Birth: 1990-1992

Median GA (range), wk:

Sample 1: 28.2±2.3

Sample 2: 30.8±2.2

Controls: 39.6±3.7

Mean BW (range), g:

Sample 1: 922±226

Sample 2: 1245±209

Controls: 3177±809

Male: 50%

Race: 

African American: 

 Sample 1: 57%

 Sample 2: 62%

 Controls: 62%

Caucasian: 

 Sample 1: 25%

 Sample 2: 20%

 Controls: 25%

Hispanic: 

 Sample 1: 13%

 Sample 2: 15%

 Controls: 13%

Other: 

 Sample 1: 5%

 Sample 2: 3%

 Controls: 0%

Enrolled: 368

Evaluated: 212 (128 controls)

Number of sites: 2

(Sample 1&2):

VLBW (<1600g) and GA<36 wk

Female primary care giver 

completed both a 6 and 12 

month home visit

Controls:

FT infants examined at 6 and 12 

month corrected age

Infants with maternal 

substance abuse, major 

dysmorphisms, 

chromosomal 

anomalies, sensory 

impairment, meningitis, 

encephalitis, congenital 

syphilis, congenital 

abnormality of brain, 

cardiac abnormalities, 

NEC or HIV antibody 

positive

Primary caregiver age < 

16, drug abuser or not 

English-speaking (only 

in Smith, 1996)

Sample 1: High risk 

VLBW (89)

Sample 2: Low risk 

VLBW (123)

Controls: Full term 

(128)

Prospective cohort (6 

and 12 months)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

112

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Kato

1996

97182916

Location: Japan

Years of Birth: 1984-1993

Median GA (range), wk: 28+2.8

Mean BW (range), g: 

1031.3+271.7

Male: 48%

Race: ND

Enrolled: 305

Evaluated: 228

Number of sites: 2

VLBW singletons Major anomaly 

Multiple gestation

VLBW infants (228) Retrospective cohort 

(> 12 months)

Katz

1996

97145056

Location: UK

Years of Birth: 5/83- 4/85

Median GA (range), wk: 29.2+2.5

(26-34)

Mean BW (range), g: 1227.5+341.4 

(740-2240)

Male: 

Cases: 52%

Controls: 55%

Race: 

Cases: 75% White, 19% Black, 

6% Asian

Controls: 75% White, 12.5% 

Black, 12.5% Asian

Enrolled: 212

Evaluated: 64 (40 controls)

Number of sites: 2

<34 weeks, no major congenital 

anomaly, 3 cranial u/s in first 

week of life 

Lost to follow-up

Too impair due to multiple 

cognitive, sensory, or 

motor disabilities, to 

complete testing

Cases: Preterm infants 

(64)

Controls: Full-term 

comparison sample 

(40)

Prospective cohort 

(6-8 years)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

113

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Korkman

1996

96374730

Psy1996

Location:Finland

Years of Birth: ND

Mean GA:

 Sample 1: 30.8 ± 2.25

 Sample 2: 28.8 ± 1.41

 Sample 3: 39.7 ± 1.98

 Sample 4: 40.0 ± 0.77

Mean BW:

 Sample 1: 1068.5 ± 151.2

 Sample 2: 1212.2 ± 189.3

 Sample 3: 3596.7 ± 705.0

 Sample 4: 3469.9 ± 275.9

Males:

 Sample 1: 44%

 Sample 2: 49%

 Sample 3: 42%

 Sample 4: 55%

Race: ND

Enrolled: ND

Evaluated: 158

Number of sites: 2

Born at OB/GYN dept of Univ 

Helsinki

F/up at Children’s Hospital and 

Children’s Castle Hospital

Had neuropsychological 

assessment between 5yrs-9 yrs.

And specifically for each sample:

Sample 1: VLBW: less than 1500 g

 And SGA (at least 2 SD below 

mean for their GA)

Sample 2: VLBW and AGA

Sample 3: Asphyxiated Term 

infants,

GA> 34 weeks with: Umbilical 

arterial ph<7.05 Or Apgar scores 

at 5 min less than 6 (From a Birth 

Cohort of 982 deliveries that 

included all the term asphyxiated 

infants)

Sample 4: Healthy term with 

normal

delivery, AGA (within 1.5 SD),

Umbilical artery pH: 7.18 or more

Apgar score 1 min: 8 or more

Neonatal period: uneventful

Born in the same hospital from 

healthy mothers by a singleton 

uncomplicated pregnancy

Children with :

Cerebral Palsy

Mental retardation

Visual impairment

Sample 1:

VLBW and SGA [34]

Sample 2:

VLBW and AGA

[43]

Sample 3:

Birth asphyxia group of 

term infants [36]

Sample 4:

Control Group [45]

Prospective comparative

longitudinal study 

( 5-9 yrs )

(mean age: sample 1: 

7.1 yrs, sample 2: 7.3 

yrs, sample 3: 6.9 yrs, 

sample 4: 6.11 yrs)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

114

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Lucas

1996

96302121

Location: US

Years of Birth: 1988- 1991

Median GA (range), wk:

Sample 1: 29.8±0.2

Sample 2: 29.8±0.2

Mean BW (range), g:

Sample 1: 1306±28

Sample 2: 1263±26

Male: 

Sample 1: 47%

Sample 2: 47%

Race: ND

Enrolled: 275

Evaluated: 275

Number of sites: 2

Breast feeding BW<1850; GA< 37, 

Survived to randomization at 48-

72 hr; Received any breast milk

Not resident in UK and the 

present major congenital 

abnormalities (e.g. 

trisomy) known to 

influence 

neurodevelopment

Sample 1: Fortified 

breast milk (137)

Sample 2: Minimally 

supplemented 

breast milk (138)

RCT (9 and 18 months)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

115

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Rieck

1996

Psy 1996

06905005

Location: Israel

Years of Birth: ND

Mean GA: ND

Mean BW: ND

Males: ND

Race:

 Sample 1: whites 90%, asianafrican10%

 Sample 2: whites: 94%, AsianAfrican: 5%

Enrolled: 

 Sample 1,2,3 : ND

Evaluated:

 Sample 1: 103

 Sample 2,3: ND

Number of sites: ND

Sample 1:

Premature

VLBW < 1500 g

Sample 2::

Children from middle 

socioeconomic class (MC) families

Sample 3:

Children from low socioeconomic 

class (LC) families

ND Prospective 

longitudinal

component:

Sample 1:

Premature VLBW 

<1500)

[83]

(mean age at 

assessment: 4.5 yrs)

Cross-sectional 

comparative 

component:

Sample 1

Premature VLBW <

1500 [83]

Sample 2:

Term children of 

middle class families 

[71]

Matched with sample 1 

only for mean age at 

assessment : 5.1 yrs

Sample 3:

Term children from low

Class families [322]

Matched with sample 1

only for mean age at

assessment: 5.0 yrs

Longitudinal f/up study

of children participating 

in a previous prospective 

longitudinal study 

(3-7 yrs)

Cross sectional

comparative component 

(3 arms: 2 control arms) 

(3- 7 yrs)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

116

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Whitaker

1996

97040639

Location: US

Years of Birth: 9/1/84-6/30/87

Median GA (range), wk: 31.5

Median BW (range), g: 1480.7

Male: 51%

Race: White 74%, AfricanAmerican 22%, Other 5%

SES: middle class (19% of the 

families receiving public 

assistance)

Enrolled: 685

Evaluated: 597

Number of sites: ND

BW 501-2000 g

Survived to 6 years of age and 

participated in the study

Home visit interview subjects

Families refusal (45)

Unable to be located (143)

Had been adopted (25)

Central New Jersey 

Neonatal Brain 

Hemorrhage study 

cohort LBW infants 

(597):

Normal US finding 

(468)

GM/IVH (83)

PL/VE (46)

Prospective cohort 

(6 years)

Blitz

1997

97154301

Location: US

Years of Birth: 1/90- 8/90

Mean GA (range), wk: 26.5±2.4

Mean BW (range), g: 775.9±138.4

Male: 36%

Race: 40% White

Enrolled: 248

Evaluated: 100

Number of sites: 1

Preemies, BW < 1001 g

Maryland residents

Survived to hospital 

discharge

Declined participation

Serious congenital 

malformations, genetic 

disorder, diagnosed 

congenital syndromes 

with brain abnormality of 

known correlation with 

developmental disability, 

disorders secondary to 

prenatal toxic exposure 

with microcephaly, 

severe head injury after 

discharge

Developed meningitis after 

discharge

ELBW preemies (100):

Meningitis 6%

PVL 10%

Hydrocephalus 18%

Seizures 7%

IVH = grade III 26%

BPD 63%

ROP 49%

Retinopathy of 

prematurity 49%

Prospective cohort
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

117

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Cheung

1997

97310950

Location: Canada

Years of Birth: 1988-1993

Median GA (range), wk: 26 (24-30)

Mean BW (range), g: 891 (530-

1180)

Male: 67%

Race: ND

Enrolled: 52

Evaluated: 21

Number of sites: 1

Preterm neonates (GA < 30 

weeks, BW < 1200 g) with 

severe respiratory failure treated 

with high frequency ventilation 

(HFO)

ND Preterms with IVH (21) Retrospective cohort

Ekert

1997

97251211

Location: Canada

Years of Birth: 1988-1994

Median GA (range), wk: 27.6+2.1

Mean BW (range), g: 962+262g

Male: 50%

Race: ND

Enrolled: 123

Evaluated: 123

Number of sites: 2

GA<32 wks informed parental 

consent

Congenital anomalies, 

meningitis, congenital 

infections, GBS disease, 

lack of consent

Patients entering study 

(123)‡ 104 left in 

analysis for 

outcome studies

Prospective cohort 

(seen at corrected age 

4,8,12,18,24 months)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

118

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Gerner

1997

97329414

Location: Sweden

Years of birth: 1988-1993

Mean BW: 1047 ±258 g

Mean GA: 28.2 ±2.7 wks

Males: ND

Race: ND

Enrolled: 

 Sample 1 and 2: 211

 Sample 3: ND

Evaluated:

 Sample 1: 50

 Sample 2: 121

 Sample 3: 35

Number of sites: 2

Sample 1 and 2: 

Premature,VLBW infants<15000g

From NICU of Karolinska Hospital 

and St Goran’s Hospital in 

Stockholm

Born between 9/1988 and 2/1993.

Inborns and outborns included

Had neurodevelopmental 

assessment at 10 months 

corrected age

Sample 3:

Full term infants

Uneventful pregnancy and delivery

Apgar score at 5 min: 10

No neonatal complications

Born at Karolinska hospital

During the same period 

Matched with cases for:

sex, maternal age, maternal 

education and parity

Had neurodevelopmental 

assessment at 10 months 

corrected age

ND Sample 1:

Preterm VLBW infants

“healthy” without any 

risk factors [50 ]

Sample 2:

Preterm VLBW infants

With one or more risk 

factors [Brain 

hemorrhage, white 

matter lesion, surgical 

closure of PDA, 

ventilator treatment or 

septicemia (except 

Staph epi) [121]

(Risk factors and group 

definition were based 

on the risk factors that 

were statistically 

significantly correlated 

with outcome in the 

cohort of the 171 

preterm VLBW infants)

Sample 3:

Full term “ healthy” 

infants, born at 

Karolinska hospital, 

during the same 

period, and matched 

with the combined 

preterm VLBW cohort 

[35]

First component:

Prospective 

observational

cohort with 171 preterm

VLBW infants (sample 1

and 2)

Second component:

Prospective comparative

component :

sample 1 vs sample 3

Third component: 

Prospective 

Comparative

component:

Sample 2 vs sample 1

[10 months]
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

119

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Koller

1997

97193708

Location: US

Years of Birth: 1975-1989

Median GA (range), wk: 30.9 (25-

37)

Mean BW (range), g: 117+227

Male: 45%

Race: 51% Black

Enrolled: 203

Evaluated: 203

Number of sites: 3

GA <1500, data obtained at 4 

follow-up data points

ND VLBW infants (203) Retrospective cohort

Murphy

1997

97192793

Location: Korea

Years of Birth: 1984-1990

Median GA (range), wk:

Cases: 28.6±2.3 (24-32)

Control: 29.9±1.9 (23-32)

Median BW (range), g: ND

Male: 

Cases: 63%

Control: 57%

Race: ND

Enrolled: 638

Evaluated: 59 (234 controls)

Number of sites: 1

GA<32 weeks Singleton

Oxfordshire and West Berkshire 

resident

Neonatal notes were available

Multiple birth

Died before discharged

Cases: CP cases (59)

Controls (234)

Case-control study 
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

120

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Schendel

1997

98033417

Location: US

Years of Birth: 12/1/89 to 3/31/91

Mean GA (range), wk: 

Sample 1: 28.4 ±3.0

Sample 2: 35.6 ±2.8

Controls: 39.4 ±1.5

Mean BW (range), g:

Sample 1: 1088±268

Sample 2: 2184±267

Controls: 3417±432

Male: 

Sample 1: 49%

Sample 2: 46%

Controls: 52%

Race: Black

Sample 1: 37%

Sample 2: 37%

Controls: 41%

Enrolled: 920 (555 controls)

Evaluated: 920 (555)

Number of sites: 5

Singleton livebirths in MMIHS 

study population, survived to 1 

year of age

Cases: MLBW infants, BW 1500-

2499g; VLBW infants, 

BW<1500g

Controls: NBW infants randomly 

selected from the birth certificate 

files on the basis of frequency 

matching with cases by maternal 

race, age, and residence

ND Sample 1: VLBW 

infants (367)

Sample 2: MLBW 

infants (553)

Controls: NBW infants 

(555)

Case-control study

Thompson

1997

97268338

Location: US

Years of Birth: : 1986-1991

Median GA (range), wk: 

28.36±2.11(24-33)

Mean BW (range), g: 1100±2.11 

(700-1500)

Male: 46%

Race: ND

Enrolled: 111

Evaluated: 55

Number of sites: 1

Born at Duke

BW<1500g

Survived to discharge or to 6 mo. 

corrected age

ND VLBW infants (55) Prospective cohort 

(4 years)

Death (12), lost to followup (34), incomplete 

data (4), invalid score 

(5)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

121

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Victorian Infant 

Collaborative 

study Group 

1997

98026322

*There are a 

series of 

Victorian 

articles in LBWALL.

*This study will 

be combined in 

LBW-ALL table

Location: Australia

Years of Birth: 1979-80, 1985-87, 

1991-92

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 453 (242 controls)

Evaluated: 448 (242)

Number of sites: 3

(Sample 1-3):

ELBW infants, BW 500-999 g born 

in Victoria, Australia

Survived to age of 2 years

Controls:

Normal birth weight (>2499 g) 

infants born in 1991-1992

Excluded infants born in 

1979-1980 for current 

review

Cases: ELBW infants 

(448):

Sample 1: born in 

1985-1987 (212)

Sample 2: born in 

1991-1992 (241)

Controls: Normal BW 

(>2499 g) infants 

(242)

Retrospective cohort

Battin

1998

99002694

Location: British Columbia, Canada

Enrollment period: 1991-1993

Mean GA: ND (range: 23-25 wks)

Mean BW: ND 

(Mean BW for the 333 live births

during the study period : for GA of

23 wks: 581, for GA of 24 wks:

648, for GA of 25 wks: 764)

Male: ND

Race: ND

Enrolled: 333 

(total live births GA: 23-28 wks) 

Evaluated : 44 

(out of 49 of GA 23-25 surviving to 

NICU discharge)

Number of sites: 2

Prospective cohort:

Birth at British Children’s Hospital 

and British Womens’ Hospital

Born during 1991-1993

Extremely low gestational age 

(ELGA): 23-25 wks

Had follow up at 18 mo of age

Historical control group:

Born at the same institution

Born between 1983-1989

GA: 23-25 wks

Cases of therapeutic 

termination of pregnancies 

for lethal congenital 

anomalies

Outborns

Prospective cohort of

ELGA born during a

period when antenatal

steroids, surfactant

and dexamethasone

for BPD had become

an accepted treatment

[44]

Prospective 

observational cohort 

study and a comparative 

study with an historical 

control group

(18 months)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

122

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Bos

1998

98218970

Location: Netherlands

Years of Birth: 1992-1994

Mean GA (range), wk: 26-34

Mean BW (range), g: 835-1780

Male: ND

Race: ND

Enrolled: 27

Evaluated: 27

Number of sites: ND

AGA

GA <35 wks

Lived within 60km of hospital

Normal US findings

Major congenital 

anomalies

Developed cystic PVL, or 

grade 3 or 4 IVH 

Preterm infants with 

echodensities (27)

Prospective cohort

CherkesJulkowski

1998

98262696

Location: ND

Years of Birth: ND

Mean GA (range), wk: ND

Mean BW (range):

Cases: 4.14±1.87 lbs

Controls: 7.30±1.87 lbs

Male: 

Cases: 61%

Controls: 50%

Race: ND

SES: “middle class”

Enrolled: 48

Evaluated: 28 (20 controls)

Number of sites: 1

Preterm: 

<38 wks, BW<5 lbs, no 

congenital disorders, no 

retrolenteal fibroplasia, 

discharge from hospital prior to 

42 wks conceptional age, 

mother willing to participate

Controls: participants were 

enrolled in a longitudinal study 

before their second month of 

age

ND Preterms (28)

Controls: full term 

infants (20)

Retrospective cohort
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

123

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Emsley

1998

98238139

(CNS+ All)

Location: US

Years of Birth: 1984 to 1994

Median GA (range), wk:

Sample 1: 24.5

Sample 2: 24.2

Mean BW (range), g:

Sample 1: 751.7

Sample 2: 697.1

Male: 

Sample 1: 67%

Sample 2: 55%

Race: ND

Enrolled: 192

Evaluated: 64

Number of sites: 2

GA 23-25 weeks Survived until discharge Sample 1: Cohort 1 

Born 1984-1989 

(24)

Sample 2: Cohort 2 

born 1990-1994 

(40)

Prospective cohort 

(3.3 –10.6 years)

Pasman

1998

98196839

Location: Netherlands

Years of Birth: ND

Median GA (range), wk:

Sample 1: 28.9±1.5 (25-30)

Sample 2: 32.5±1.1 (31-34)

Sample 3:

Sample 4: 30.1±1.6 (25-34)

Controls: 39.4±1.5 (38-42)

Mean BW (range), g:

Sample 1: 1071±269

Sample 2: 1568±351

Sample 3: 

Sample 4: 1317±299

Controls: 3144±516

Male: ND

Race: ND

Enrolled: 81 (25 controls)

Evaluated: 45 (18 controls)

Number of sites: 2

GA=25-34 weeks, admitted to 

university hospital

Dysgenetic brain lesions

Major congenital 

anomalies

Clinical syndromes

Lost to follow-up

Sample 1: Early 

preterms, low risk 

(15)

Sample 2: Late 

preterms, low risk 

(21)

Sample 3: Early high 

risk preterms (8)

Sample 4: Late high 

risk preterms (9)

Controls: Full term (18)

Prospective cohort 

(followed to 5-7 years 

age)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

124

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Redline

1998

99086405

Location: US

Years of Birth: 1983-1991

Median GA (range), wk:

Sample 1: 27.3 ±2.3

Sample 2: 27.5 ± 2.2

Mean BW (range), g:

Sample 1: 978± 228

Sample 2: 1012±226

Male: ND

Race: African-American

Sample 1: 57%

Sample 2: 59%

Enrolled: 72

Evaluated: 60 (59 controls)

Number of sites: 2

Cases (Sample 1&2): Infants with 

major neurologic impairment at 

20 months (strictly defined CP, 

loosely defined CP, hypertonia, 

Hypotonia) and those with NL 

neurologic exam at 20 months.

Controls: infants born in the same 

year and matched for weight 

(±250 g), GA (±2 weeks), race, 

and sex who had a normal 

neurologic examination at 20 

months.

No placental reports and 

slides available

Cases: VLBW infants 

with major 

neurologic 

impairment at 20 

months (60)

Sample 1: Strict CP 

(42)

Sample 2: 

Neurologic 

abnormalities (18)

Controls (59)

Case-control 

(at 20 months corrected 

age)

Rogers

1998

98438124

Location: US

Years of Birth: 1988 to 1993

Median GA (range), wk:

Sample 1: 27.9 ±2.0

Sample 2: 27.6 ±1.8

Mean BW (range), g:

Sample 1: 1158±330

Sample 2: 1082± 290

Male: ND

Race: ND

Enrolled: 41

Evaluated: 41

Number of sites: 1

GA < 33 weeks live birth with 

unspecified IVH

ND Sample 1: No growth 

failure (23)

Sample 2: Growth 

failure (18)

Retrospective cohort 
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

125

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Spinillo

1998

98237382

Spinillo, 1997

98021316 & 

97277958

*have some 

overlapped 

sample with 

spinillo, 1994

Location: Italy

Years of Birth: 1987 to 1993

Median GA (range), wk:

Cases: 29.6

Controls: 30.5

Mean BW (range), g: 

Cases: 1317

Controls: 1451

Male: 52%

Race: ND

Enrolled: 461

Evaluated: 345

Number of sites: 2

GA 24–33 completed weeks

Had a US scan done before 20 

weeks’ gestation

Severe malformations or 

chromosome 

abnormalities

Sample 1:

Preterm infants with 

CP (40)

Sample 2:

Preterm infants without

CP (305)

Prospective cohort

( 3, 6, 12, and 24

months)

Tin

1998

99046171

Location: North of England

Years of Birth: 1983, 1990-1991

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 1983 (230); 1990-1 (566)

Evaluated: 1983 (230); 1990-1 

(566)

Number of sites: 5

GA 23-31 weeks ND 1983 cohort (230):

Child reviewed without 

difficulty (204)

Child traced with 

difficulty (14)

Child seen with 

difficulty after child 

was traced (12)

1990 to 1991 (566):

Child reviewed without 

difficulty (505)

Child traced with 

difficulty (26)

Child seen with 

difficulty after child 

was traced (35)

Prospective cohort

*2 Cohorts of different 

time periods
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

126

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Burguet

1999

99126269

Location: France

Years of Birth: : 10/1/90- 9/10/92

Mean GA (range), wk: 25-32

Mean BW (range), g: 8% 

BW>2000g

Male: 51%

Race: 86% Caucasian

SES: 5% Family precariousness

Enrolled: 203

Evaluated: 167

Number of sites: 20

All liveborn premature in 20 

maternity hospitals in FrancheComte region

Chromosomal or 

neurological congenital 

anomaly diagnosed in 

the neonatal period, 

discordance of 2 wks or 

more between pediatric 

and obstetrical or 

echographic 

determination of 

gestational age, triplets 

and more

Preemies (167):

RDS 40%

No RDS 60%

Prospective (93%) and 

retrospective (7%) 

cohort 

(followed until 2 years of 

age)

Cooke

1999

99257637

Location: UK

Years of Birth: 1982-1993

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 1722

Evaluated: 1187

Number of sites: 1

VLBW (not specifically defined)

Have data at 3 years old

ND VLBW infants (1187):

1982-19855 (411) 

1986-1989 (387)

1990-1993 (398)

Retrospective cohort 

(followed until 3 years 

corrected age)

Cooke

1999

99380719

Location: UK

Years of Birth: 1982-1993

Median GA (range), wk: 28.6±1.7 

(24-35)

Mean BW (range), g: 1103±203 

(630-1500)

Male: ND

Race: ND

Enrolled: 137

Evaluated: 87 (8 controls)

Number of sites: 1

VLBW infants prospectively 

followed birth to age 13 with 

MRIs between age 15-17 yrs

Controls: FT infants

ND VLBW infants (87), 

with white matter 

disorder, PVL, 

Ventriculomegaly, 

MRI abnormality

Controls: FT infants (8)

Prospectively cohort 

(15-17 years)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

127

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Finer

1999

99436635

Location: UK

Years of Birth: 1/1/94 to 12/31/96

Median GA (range), wk: 25 (24-28)

Mean BW (range), g: 663 (440-

968)

Male: 50%

Race: ND

Enrolled: 177

Evaluated: 10 (10 controls)

Number of sites: 1

Cases:

Inborn infants BW < 1000g

Received DR-CPR

Survived until discharge

Controls:

Matched controls with similar 

mean BW and length of followup

Lethal congenital 

malformations

Cases: ELBW 

survived infants 

received DR-CPR 

(10)

Controls (10)

Retrospective cohort 

(median 28 months)

Futagi

1999

99450356

Location: Japan

Years of Birth: 1981-1986 and 

1989

1993

Mean GA:

 Sample 1: 27.2±2.2

 Sample 2: 26.8±2.4

Mean BW:

 Sample 1: 834.1±133.4

 Sample 2: 786.0±133.2

Males:

 Sample 1: 38%

 Sample 2: 53%

Race: ND

Enrolled: 305

Evaluated: 276

Number of sites: 1

Presurfactant era cohort:

BW less than 1000 gms

Admitted to NICU 

Born during presurfactant era 

1981-1986

Follow up for at least 3 years.

Neurodevelopmental and Mental 

outcome documented in medical 

records

Surfactant era cohort:

same as above except 

Born during surfactant era, 1989-

1993

Hereditary disorders

Chromosomal 

abnormalities

Follow up less than 3 

years

Absence of documentation 

of neurodevelopmental or 

mental outcome in medical 

records

Sample 1

Presurfactant cohort:

Born during 

presurfactant era, 

between 1981-86 [107]

Sample 2:

Surfactant era cohort:

Born during surfactant

era, between 1989-

1993

[169]

Retrospective 

comparative longitudinal 

study.

Comparison done 

between 2 retrospective 

cohorts (pre-surfactant 

era cohort vs surfactant 

era cohort)

[ 3-8.8 years, mean f/up: 

6.0 ±1.3 yrs (not given 

per group)]
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

128

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Kim

1999

99416608

Location: UK

Years of Birth: July 1996 to 

November 1997

Median GA (range), wk:

Cases: 30.8±3.5

Control: 31.4± 2.2

Mean BW (range), g:

Cases: 1557±252

Control: 1418±376

Male: 

Cases: 47%

Control: 52%

Race: ND

Enrolled: 184

Evaluated: 17 (62 controls)

Number of sites: ND

Preterm (GA<37 wks) infants and 

term infants with an Apgar score 

of less than 6 at 5 minutes, 

neonatal hyperbilirubinemia 

(total bilirubin concentration of 

20 mg/dl or more) and bacterial 

meningitis

BW<2000 g

Chromosomal 

abnormalities and 

congenital malformation

Cases: VLBW infants 

with CP or 

Developmental D 

(17)

VLBW Controls (62)

Prospective cohort 

(at 2, 6, 12 months 

corrected age)

Krageloh-Mann 

1999

99431017

Location: Denmark

Years of Birth: 1986- 1989

Median GA (range), wk: 30.2 (27-

34)

Mean BW (range), g: 1461 (690-

2655)

Male: 66%

Race: ND

Enrolled: 40

Evaluated: 29 (57 controls)

Number of sites:1

Preterm infants Death (1), lost to follow-up 

(7), parental refusal (4), 

difficulties with sedation 

for MRI (1)

Cases: preterm infants 

(29)

Controls: term-born 

pre-school children 

(57)

Prospective cohort
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

129

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Salokorpi

1999

99353226

Location: Finland

Years of Birth: 1991 to 1994

Median GA (range), wk:

Sample 1: 26.7 ±2.0

Sample 2: 26.7 ±2.4

Mean BW (range), g:

Sample 1: 833±130

Sample 2: 817± 130

Male: 

Sample 1: 33%

Sample 2: 46%

Race: ND

Enrolled: 228

Evaluated: 143

Number of sites: 1

Premature infants, BW < 1000 g, 

admitted to NICU

ND Sample 1: CP present 

(27)

Sample 2: CP absence 

(116)

Prospective cohort 

Lost to follow-up (13) 

due to parent refusal 

or because had moved 

to remote areas

Died by the age of 2 

year (72)

Shepherd

1999

99165413

Location: Scotland

Years of Birth: 2/95 to 2/97

Median GA (range), wk: 25.7-35

Mean BW (range), g: 570-3200

Male: ND

Race: ND

Enrolled: 81 (68 controls)

Evaluated: 81 (68)

Number of sites: 1

Preterm infants admitted to the 

special-care unit

Genetic or prenatal 

anomalies

Cases: preterms (81)

Controls: term infants 

(68)

Prospective cohort
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

130

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Stathis

1999

99325758

Location: Australia

Years of Birth: :1977-1986

Median GA (range), wk: 27.7(27.3-

28.1)

Mean BW (range), g: 860 (837-

833)

Male: 36%

Race: ND

Enrolled: 124

Evaluated: 87

Number of sites: 1

BW 500-999g survived to 

discharge

Cared for in study NICU

Enrolled in follow-up programs

ND ELBW survived infants 

(87)

Prospective cohort 

(followed at 4, 8, 12, 

months)

Vohr

1999

99332101

Location: US

Years of Birth: 1989-1992

Median GA (range), wk:

Sample 1: 27.9±2

Sample 2: 28±2

Mean BW (range), g:

Sample 1: 960±178

Sample 2: 965±179

Male: 

Sample 1: 59%

Sample 2: 56%

Race: 

Sample 1: Black 21%, Hispanic 

3%, White 76%

Sample 2: Black 20%, White 

78%, Other 2%

Enrolled: 392

Evaluated: 278

Number of sites: 3

BW 600-1250g

Survived the first 3 years of life, 

and were seen for 

neurodevelopmental follow-up at 

36 months CA

Non-English speaking 

home

Sample 1: Early IVH 

positive (29)

Sample 2: Early IVH 

negative (249)

Unclear 

(Retrospective or 

prospective cohort, 

followed to 36 months 

corrected age)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

131

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Agustines

2000

20279724

Location: US

Years of Birth: 1990-1995

Median GA (range), wk: 25 (24-29)

Median BW (range), g: 674

Male: ND

Race: ND

Enrolled: 63

Evaluated: 36

Number of sites: 1

BW: 500-750 g

Born in Long Beach Hospital, 

between 1990 and 1995 (post 

corticosteroid, postsurfactant era)

Survived to discharge

Had follow up at 30 months

ND VLBW infants (36) Retrospective cohort 

(followed to 30 months 

CA) 

Lost to follow-up (27)

Breslau

2000

20298367

Location: US

Years of Birth: 1983-1985

Mean GA (range), wk: ND

Mean BW (range), g: ND Male: ND

Male: ND

Race: 

 Sample 1 (urban) Blacks: 80%

 Sample 1 (suburban) Blacks:11%

 Sample 2 (urban) Blacks:74%

 Sample 2 (suburban) Blacks: 3%

Enrolled: 1095

Evaluated: 823→717

Number of sites: ND

LBW cohort: <2500 g

NBW cohort:

Born between 1983-85, that were

6 yrs old during 1990-92; when the

fieldwork took place

From 2 major hospitals of South

Michigan: one urban and one

suburban

(In each hospital, random samples

of LBW and NBW children were

drawn).

From the target sample:

were excluded children

with severe neurologic

impairment: CP, MR, 

blindness 

From the analysis of

incidence of severe

attention problems were

excluded children that

already had severe 

attention problems at the

assessment at 6 yrs 

At 11 yrs (717):

Sample 1:

LBW (411) –

Urban LBW (217)

Suburban LBW (194 )

Sample 2:

NBW (306) -

Urban NBW )164)

Suburban NBW (142)

Prospective cohort

( 11 years)

Buhrer

2000

20280896

Location: Germany

Years of Birth: 1/192- 12/31/97

Mean GA (range), wk: 28.7 (23.2-

37.2)

Mean BW (range), g: 1149 (430-

1495)

Male: ND

Race: ND

Enrolled: 455

Evaluated: 352

Number of sites: 1

VLBW, BW < 1500 g ND VLBW infants (352) Prospective cohort 

(followed until 1 year 

CA)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

132

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Grether

2000

20448692

Location: US

Years of Birth: 1988-1994

Median GA (range), wk:

Cases: : 27.1±2.4

Controls: 37.6±2.6

Mean BW (range), g:

Cases: 1085±350

Controls: 1112±349

Male: 

Cases: 56%

Controls: 47%

Race: 

 Cases: 47% White

 Controls: 33% White

Enrolled: 170 (280 controls)

Evaluated: 170 (280)

Number of sites: 22

BW < 1500g or BW 1500-1999g 

and <33 GA

Postural cause of CP 

identified.

Congenital infection 

identified 

Cases: Cerebral palsy 

(170)

Controls (288)

Retrospective casecontrol study 

(2 years)

Katz-Salamon 

2000

20332284

Location: Sweden

Years of Birth: 1988-1993

Median GA (range), wk:

Cases: : 26.1±2.0

Controls: 26.7±1.3

Mean BW (range), g:

Cases: 874±183

Controls: 940±179

Male: ND

Race: ND

Enrolled: 70

Evaluated: 43 (43 controls)

Number of sites: 1

Cases:

VLBW

Survival with CLD

Controls:

No IVH>2

No CLD

No PVL

VLBW

Cases:

Unable to be examined 

because of other 

medical problems, 

including congenital 

cardiac malformation, 

hepatitis C, 

immobilization of the 

legs, severe visual 

defect, and severe 

cerebra infarction.

Cases: VLBW infants 

with CLD (43)

VLBW Controls (43)

Prospective cohort
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

133

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Marlow

2000

20150342

Location: UK

Years of Birth: 1990-1994

Mean GA: ND

(Median and Range)

 Sample 1: 28 (26-31)

 Sample 2: 28 (26-31)

Mean BW: ND

(Median and range)

 Sample 1: 960 (600-2914)

 Sample 2: 1026 (410-2814)

Male: ND

Race: ND

Enrolled : 27 

Evaluated: 15 

Number of sites: 1

For sensorineural hearing loss 

(SNHL) group

GA: <33 wks

Family resident of Greater Bristol 

area

Records at Hearing Assessment 

Center of Royal Hospital for Sick 

children.

Born during 1990-1994

Diagnosis of SNHL of 50 dB

For control group:

Matched controls 2:1 to cases

Admitted to the same NICUs as 

cases

Matched for sex and GA and next 

and preceding matching children in 

the admission books of St 

Michael’s and Sothmead hospitals

ND Sample 1:

SNHL group [15]

Sample 2:

Control group [30]

Matched with cases for

sex, GA, admission

dates in NICU

Retrospective case 

control study with a 

longitudinal component 

(unclear if retrospective 

or prospective)

(12 mo CA)

Palta

2000

20096107

(CNS+Eye)

Location: US

Years of Birth: August 1988-June 

1999

Median GA (range), wk: 

28.54±1.97

Mean BW (range), g: 1003±155

Male: 43%

Race: ND

Enrolled: 626

Evaluated: 425

Number of sites: 6

Birth weight =1500 g

Survived to 5 years of age

Parental agreement to potential 

follow-up and provided 

recontact information before 

discharge.

Refusing participation at 

follow-up

VLBW infants (425) Prospective cohort 

(followed to an average 

age of 5 years)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

134

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Torrioli

2000

20275419

(CNS+Eye)

Location: Italy

Years of Birth: 1991-1993

Median GA (range), wk: 32 (21-34)

Median BW (range), g: 1120(560-

1500)

Male: 42%

Race: ND

SES: “medium and there was the 

same ethnic background”

Enrolled: 86

Evaluated: 36 (ND on number of 

controls)

Number of sites: 1

BW < 1500 gm

Controls: born at term and without 

any perinatal or neonatal 

complication, matched for age, 

gender and socioeconomic 

condition including occupational 

status of the family and parents’ 

educational status was 

performed by the same 

observers that examined the 

study group

Frankly disabling 

conditions (CP, MR, 

blindness, CNS 

infections, genetic 

syndromes, etc.); 

abnormal head 

ultrasound findings

Refused to participate in 

the study

VLBW preterm infants 

(36)

Prospective cohort

Valkama

2000

20233239

Location: Finland

Years of Birth: 11/1/1993-

10/31/1995

Median GA (range), wk: 29.3±2.2 

(24.9-33.7)

Median BW (range), g: 1153+289

Male: 53%

Race: ND

Enrolled: 62

Evaluated: 51

Number of sites: 1

VLBW <1500g and <34 weeks Congenital anomalies

Died during neonatal 

period 

Parental refusal

VLBW preterm infants 

(51)

Prospective cohort 

(18 months)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

135

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Vohr

2000

20295211

Location: US

Years of Birth: 1/93-12/94

Median GA (range), wk:

Mean BW (range), g:

Male: 

Race: 

Enrolled: 

Evaluated: 

Number of sites: 12

Live born BW 401-1000 g ND 1151 extremely low 

birth weight 

survivors cared for 

in the 12 

participating centers 

of the National 

Institute of Child 

Health and Human 

Development 

Neonatal Research 

Network

Prospective cohort 

(18-22 months corrected 

age)

Dammann

2001

21334215

Location: Germany

Years of Birth: July 1983-June 

1986

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 591

Evaluated: 324

Number of sites: 1

BW<1500g ND LBW infants (324):

SGA (92)

AGA (232)

Prospective cohort 

(6 years)

7 non-BSCP cerebral 

palsy (no further 

explanation)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

136

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Gaillard

2001

21221175

Location: UK

Years of Birth:1994-1996

Mean GA: ND

 (only median and range given)

 Sample 1: 26 (23-34)

 Sample 2: 26 (23-33)

Mean BW: ND 

 (only median and range given)

 Sample 1: 852 (520-2710)

 Sample 2: 745 (580-1620)

Male:

 Sample 1: 57%

 Sample 2: 50%

Race: ND

Enrolled: 100

Evaluated: 84

Number of sites: 1

Retrospective cohort :

All infants born from 1/1/1994 to 

12/31/1996

Born at Liverpool Women’s 

Hospital

Ventilated beyond 27 postnatal 

days

If transferred from another

hospital after first postnatal

week (mostly surgical

referrals)

If ventilated after 27

postnatal days after a

surgical procedure requiring

anesthesia

Sample 1 :

Ventilated beyond 27 

(but not 50) postnatal 

ds (56)

 

Sample 2:

Ventilated beyond 

49ds ( 28)

First component:

Retrospective 

longitudinal cohort with 

case-control design and 

cases defined based on 

exposure (length of 

ventilation). Unmatched.

(3 years)

Second component:

Retrospective 

longitudinal cohort study

With two historical 

control groups (3 years)

Horwood

2001

20574647

Location: US

Years of Birth: 1/93 to 12/96

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 413

Evaluated: 298

Number of sites: 1

VLBW infants admitted to neonatal 

unit still living in New Zealand at 

time of assessment, 7-8 years of 

age

Death

17 children could not 

complete IQ testing 

because of substantial 

disability

VLBW infants (298) Prospective cohort
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part I

137

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Nadeau

2001

21163667

Location: Canada

Years of Birth: 1987-1990

Median GA (range), wk:

Cases: 27.4±1.1

Control: 39.8±1.6

Median BW (range), g:

Cases: 1024.3±204.2

Control: 3453.4±497.8

Male: 

Cases: 51%

Control: 50%

Race: ND

Enrolled: 129

Evaluated: 86 ? 61 (50 controls)

Number of sites: 1

Cases: GA<29 weeks, BW<1500 g

Controls: Normal BW children , 

born at the same hospital during 

the same time period

Cases:

Lost to follow-up at 5 years 

9 months: families had 

moved away (33), 

parents’ refusal (10)

Lost to follow-up at age 7: 

families had moved 

away (10), parents’ or 

school’s refusal (13)

Cases: EP/VLBW 

infants (86? 61)

Prospective cohort 

(at 18 months, 5 years 9 

months, and age 7)

Pierrat

2001

27221167

Location: France, Netherlands

Years of Birth: 1990-1998

Median GA (range), wk: 

28.54±1.97

Mean BW (range), g: 1003±155

Male: 43%

Race: ND

Enrolled: 72

Evaluated: 60 (59 controls)

Number of sites: 2

GA < 32 weeks, admitted to Lille 

and Utrecht

Diagnosis of grade II or III PVL

ND Preterm infants with 

PVL (78):

Grade II (39)

Grade III (39)

Prospective cohort 

(1 year)

Cysts on the first scan 

and therefore were 

considered to be of 

antenatal onset (7), 

admitted after the first 

month of life with 

evidence of cysts on the 

first scan (9); no definite 

classification could be 

achieved (2)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

138

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Leonard

1990

90204169

CNS Predictors:

Intracranial/ Intraventricular 

hemorrhage

Cardiovascular or Pulmonary 

Predictors:

Number of days on 

supplemental oxygen to help 

pO2 > 50

Other predictors:

Parenting risk factor

Low socioeconomic status

Intracranial/ Intraventricular 

hemorrhage - Grades 0-IV by 

Papille; head CT if born before 

1981, head U/S is born after 1981

Parenting risk factor - defined as 

referral by a physician, nurse, or 

health professional to child 

protective services for neglect or 

mild abuse (none were for severe 

abuse)

Low socioeconomic status - one or 

both parents unemployed, mother 

not complete high school or health 

insurance through public 

assistance

CNS:

Neurodevelopmental:

1) Cognitive delay

2) Neurologic abnormalities

Cognitive delay: measured by McCarthy 

Scales of Chilren's Abilities, Wechsler 

Intelligence Scale for Children 

(Revised), Wechsler Preschool and 

Primary Scale of Intelligence, and 

Stanford-Binet

"mild" - score between 1-2 SD 

below the mean (69-83)

"moderate to severe" - score >2 SD 

below the mean

Neurologic abnormalities: abnormalities 

in muscle strength, tone, reflexes or 

movement that cause functional 

impairment, i.e. hemiplegia, ataxia, 

quadriplegia. Clumsiness or mild 

tremors not included.

Lucas

1992

92122860

Primary predictor:

General:

1) Maternal choice to breast 

feed

Secondary predictors:

Others:

1) Received mother’s milk

2) Social class

3) Maternal education

4) Gender

5) Days of ventilation

Social class: 4 categories: 

• Social class I or II

• Non manual Social class III

• Manual social class III

• Social class IV or V

Mother’s education:

 5 point scale

From 1: no educational qualifications

To 5: degree or higher performance 

qualifications

IQ score in Weschler Intelligence 

Scale for Children-RevisedShortened version (WISC-R)-

Anglicised.

1) Verbal scale

2) Performance scale

3) Overall IQ

(Assessment at 9 mo, 18 mo, 7.5-8 

yrs)

Not further specified
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

139

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Robertson

1994

94181384

Birth weight ND CNS:

CP

Neurodevelopmental:

Motor delay

Seizure disorder

Multiple disabled 

Ophthalmology: Visual

Audiology: Hearing

CP definition was that of Bax, “A 

disorder of movement and posture

due to a defect or lesion of the 

immature brain”, along with more 

recent guidelines by Levine using at 

least four of six clinical motor 

abnormalities leading to a 

constellation of findings of the 

cerebra palsy syndrome

Mental retardation = scores Bayley 

mental scales.

Initially by newborm screening; with 

subsequently tested repeatedly in a 

sound booth and/or by bristem 

audiological evoked response.

Visual loss: acuity in the best seeing 

eye after correction, <20/60) 

including legal blindness (corrected 

acuity, <20/200)

Hearing loss (loss of >= 30 dB 

binaurally)

Spinillo

1994

94257064

*have some 

overlapped 

sample with 

spinillo, 1997

Cause of antepartum bleeding

CNS:

Intracranial hemorrhage

Periventricular leukolacia

Histological examination of deta ched 

placeta were used for confirmation 

of clinical classification

Diagnosis of IVH and PVL according 

to US finding

CNS:

CP

Neurodevelopmental:

Motor and cognitive delay

Mental retardation

Presence of grade 3-4 IVH or PVL

Amiel-Tison and Grenier Neonatal 

neurological Examination

Major neonatal handicaps included 

definite CP such as spastic diplegia, 

hemiplegia or tetraplegia causing 

definite physical disability with 

moderate to severe interference with 

functioning, or mental retardation 

(Bayley Scale)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

140

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Chen

1995

96009403

CNS:

1) Intracranial hemorrhage

2) Periventricular 

leukomalacia

ND CNS:

Motor delay

CP

Development Screening test, modified 

for Chinese children

Diagnosed by “complete neurological 

exams”, including transient spasticity 

and spastic di-/ quardriplegia

Goetz

1995

96119489

PVL ND CNS:

CP

Neurodevelopmental:

Motor and cognitive delay

Seizure disorder

Ophthalmology:

Visual impairment

ND
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

141

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Speechley

1995

96356544

General:

1) Former NICU graduate (of 

any BW)

2) Gender

Not further specified Physical health outcome at 12 yrs

1) Chronic physical health 

(mother’s report)

2) Lifetime hospitalizations 

(mother’s report)

3) Physical impairments (mother’s 

report)

4) Perception of child’s heath 

(child’s report)

5) Perception of child’s health 

(mother’s report)

Emotional and social well being at 12 

yrs:

1) Internalizing problems (child’s 

report)

2) Externalizing problems (child’s 

report)

3) Social competence (child’s 

report)

4) Social support (child’s report)

5) Self esteem (child’s report)

6) School performance (mother’s 

report)

Based on responses on an interviewer 

administered and self-report 

questionnaire.

Physical health outcome at 12 yrs

1) Chronic physical health (mother’s 

report): Precoded 25 chronic 

illnesses

2) Lifetime hospitalizations (mother’s 

report)

3) Physical impairments (mother’s 

report):response to a question 

asking whether their child had any 

physical impairments

4) Perception of child’s heath (child’s 

report): 4-item scale

5) Perception of child’s health 

(mother’s report): 4-item scale

Emotional and social well being at 12 

yrs:

1) Internalizing problems (child’s 

report) 3-item scale

2) Externalizing problems (child’s 

report) 3-item scale

3) Social competence (child’s report) 

36-item scale

4) Social support (child’s report) 24-

item scale

5) Self esteem (child’s report) 10-item 

scale

6) School performance (mother’s 

report) 5-item scale
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

142

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Wildin

1995

95385294

Wildin

1997

97422739

*Data from 

same 

longitudinal 

study as 

Anderson, 1996

96314587 &

Smith, 1996

97081985; 

overlapped 

sample

CNS: 

1) Neurological exam- 6 months 

- 12 months

2) Quantitative neurologic score

Other:

1) Socioeconomic status

2) Medical risk category: High 

Risk (HR); Low Risk (LR)

Based on Amiel-Tison examination 

done at 6 months corrected age

High medical risk = severe medical 

complications of prematurity 

CNS:

Neurodevelopmental:

Motor delay

Cognitive delay

Rate of development

Stanford-Binet developmental test

McCarthy Gross Motor subtests

Bayley scale
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

143

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Anderson

1996

96314587

Smith

1996

97081985

(CNS+All)

*Data from 

same 

longitudinal 

study (U. of

Texas Health 

Sciences 

Center in 

Houston and 

the U. of Texas 

Medical Branch 

in Galveston) 

as Wildin, 1995 

& 1997; 

overlapped 

sample

Other Predictors:

Illness Acuity – grouped into 

low-risk and high-risk.

Maternal Behaviors: 

1) warm sensitivity 

2) Maintaining of infant 

interests and directiveness. 

Based on the severity of neonatoal 

complications grouping into Highand Low- risk groups:

High risk: =1 severe neonatoal 

complications, including chronic 

lung disease (bronchopulmonary 

dysplasia), grade III or IV 

intraventricular hemorrhage, and 

periventicular leukomalacia

Low risk: : =1 less severe neonatal 

complications, including transient 

respiratory distress, respiratory 

distress syndrome, and grade I or II 

intraventricular hemorrhage, and 

periventicular leukomalacia

Maternal Behaviors - home 

observation with use of a rating 

scale.

CNS:

Neurodevelopmental:

Cognitive delay

Audiology: Language

Other: Living skills

Baley Mental and Psychomotor 

development indices (MDI, PDI)

Neurologic scores based on scales 

developed by Amiel-Tison, Baird and 

Gordon, and Swaiman

Sequenced mixture of communication 

development

Daily living skills subscale from 

Adaptive Behavior Scale

Kato

1996

97182916

VLBW

GA

Sex

Perinatal factors (mat age, 

parity, preeclampsia, previa, 

PROM, fetal presentation, 

VLBW= ND

Small for Dates = ND

PROM = ND

CNS

CP:

Neurodevelopmental:

Mental retardation

Seizure disorder 

Blindness

Lump all together as major 

handicap

ND
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

144

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Katz

1996

97145056

General: GA

CNS: 

1) Intracranial/ Intraventicular 

hemorrhage

2) Periventricular leukomalcia 

(cystic PVD)

3) PVD (if unilateral or bilateral 

periventicular echogenic 

lesions present on at least 3 

scans)

IA IVH: no lesion= consistently NC 

scans. 

Mild lesion = germinal hem or small 

IVH or PVD or mild vent dilation 

without hem.

Severe lesion: blood distends the 

vents or in parenchyma, or 

multicystic PVC.

CNS:

Neurodevelopmental:

Attention

IQ 

Measured by CPT test (continuous 

Performance Test) measuring errors 

of omission or commission. 

Is also measured by CBCC (Child 

Behavior Check List): parents check 

off behavior related to n attention and 

hyperactivity.

Measured by British Abilities Scale

1) 1)

Korkman

1996

96374730

Psy1996

Main predictors:

General:

1) VLBW and AGA

(surrogate for perinatal asphyxia 

in preterm)

2) VLBW and SGA 

(surrogate for ante-natal 

asphyxia in preterm)

Secondary predictors

General:

1) Apgar scores

2) Arterial PH at 2 hrs of life

3) Intrauterine growth 

retardation

4) BW

 Pulmonary:

1) RDS

2) Duration of ventilatory tx

 CNS:

1) IVH

2) VLBW: less than 1500 g

3) SGA: 2 SD below normal for GA

4) Birth asphyxia: Umbilical arterial 

ph<7.05

5) Or Apgar scores at 5 min less 

than 6

2) Psychometric Intelligence score.

3) Detailed Neuropsychological 

assessment score.

4) Neurological Disability status 

examination

(Assessment between 5-9 yrs)

Psychometric Intelligence score: by 

Finnish standardized Revised version of 

the Wechsler Intelligence Scale for 

Children (WISC-R 1984)

1) FSIQ: Full Scale IQ

2) VIQ: Verbal IQ

3) PIQ: performance IQ

Detailed Neuropsychological 

assessment score: 

1) NEPSY test 

( a new test consisting of testing of 

attention, language, motor, sensory, 

visuospatial and memory subsets)

2) The Token te st shortened version

3) The VMI test

Established Finnish norms.

Scores reported as SD scores (z 

scores)

Sum scores in all 3 tests also calculated

Neurological Disability status 

assessment: not specified
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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145

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Lucas

1996

96302121

General:

1) Full fortification for breast 

milk

Full breast milk Fortification vs Minim 

supplementation with minerals 

only, both groups received vitamins

CNS:

1) Neurodevelopmental:

2) Motor delay

3) Mental retardation

Audiology:

1) Language

Other:

2) Social development

At 9 month: Knobloch Developmental 

Inventory 

At 18 month: Knobloch; Bayley scales; 

Vineland test of social maturity
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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146

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Rieck

1996

Psy 1996

06905005

In prospective longitudinal 

component:

General:

1) Perinatal factors:

2) BW

3) GA

4) SGA 

5) Neurological complications 

in NICU

6) Sex

Growth:

1) HC percentile 

CNS:

1) Developmental scores at 1-

2 yrs of age

Others:

1) Age at assessment

2) Parental (mother’s and 

father’s) age

3) Parental education

4) Country of origin

Prospective comparative 

component.

• VLBW vs Middle class 

term child

And vs Low class term child

Neurologic complications in NICU:

1) Severe asphyxia

2) Loss of consciousness

3) Convulsions

4) IVH grade 3-4

5) CNS infections

HC percentile:

1) > 20%

2) 3-20%

3) < 3%

Country of origin:

Israel

Euro-American

Asian-African

CNS:

Neurodevelopmental outcome:

1) Scores in McCarthy ‘s 5 Scales 

of Children’s Abilities test 

(MSCA)

2) General Cognitive Index (GCI) 

score

(Assessment between 3-7 yrs of age)

MSCA: 

Translated in Hebrew

Adapted to Israeli children

5 scales: 

1) Verbal

2) Perceptual-Performance

3) Quantitative

4) Memory

5) Motor

 (GCI) scores:

From subtests of the :

1) Verbal

2) Perceptual-performance and

3) Quantitative scales
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

147

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Whitaker

1996

97040639

General predictors:

BW,GA, SGA/IUGR

Chronic illness, Apgar score

Sex

CNS Predictor:

IVH

PL/VE

Bronchopulmonary dysplasia

Maternal-social disadvantage

Mat-Social Disadvantage: not high 

school gradated; nonwhite race; 

income from public assist; <19 yrs; 

not married. 

According to US findings

CNS: 

Neurodevelopmental: 

Cognitive delay

Mental retardation

Memory

Ophthalmology : Visual perceptual

Audiology: Language

Test of language Development

Stanford-Binet Intelligence Scale

Blitz

1997

97154301

Neonatal complications of ELBW 

infants, including meningitis, 

PVL, hydrocephalus, seizures, 

IVH, BPD, ROP, and whether 

the infant was discharged on 

oxygen

Diagnosis based on hospital course. 

IVH = grade III

CNS:

CP 

Neurodevelopmental

Development outcome

Neurologic Outcome

Ophthalmology:

Visual problems

Audiology: 

Hearing loss

Hearing loss

Visual problem

BSID (Bayley Scale of Infant 

Development), MDI (Mental 

Developmental Index), PDI 

(Psychomotor developmental Index), 

CLAM (Clinical Linguisitc and 

Auditory Milestone Scale): Total 

(CLAM-T), Expressive (CLAM-E), 

and Receptive (CLAM-R) scores

Neurodevelopmental examination, 

modified after Amiel –Tison and the 

Primitive Reflex Profile

ND

Strabismus, hyperopia, myopia, or 

retinal detachment

Cheung

1997

97310950

IVH grade III or IV Diagnosed by US finding CNS:

Cognitive delay

Cognitive delay - Belay Mental and 

Psychomotor development indices 

(MDI, PDI)

Normal neurodeveloplement: free of 

neurodevelopmental disability, with 

Bayley scores higher than 2 SD 

below the mean

Neurodevelopmental disability: cerebral 

palsy or blindness or hearing loss
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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148

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Ekert

1997

97251211

General:

1) Birth weight

2) GA

3) Apgar score

CNS:

1) Intracranial / Intraventricular 

hemorrhage

2) Periventricular leukomalacia 

Cardiovascular/pulmonary: 

1) Bronchopulmonary dysplasia 

other: a) ventilator days, b) 02 

days

Other:

Hospital/health care resource 

(admission days) utilization. 

Diagnosis of IVE or PVE according to 

US findings

CNS:

Motor delay

Cerebral palsy

Cognitive delay

Motor and cognitive delays: Bayley 

score of < 84 (i.e., =1 SD below 

mean) or developmental quotient 

(developmental age divides by 

corrected age) of < 0.75

Evidence of hypertonicity and 

hyperreflexive in association with at 

least gross motor developmental 

delay
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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149

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Gerner

1997

97329414

General:

1) Prematurity (per se)

2) General maternal, 

obstetric, and perinatal 

predictors:

ÿ Maternal education

ÿ Maternal age

ÿ Parity

ÿ Maternal toxemia

ÿ Maternal septicemia

ÿ Placental bleeding

ÿ Sex, Gestational age, Birth 

weight, Intrauterine growth, 

Cardiotocography, Apgar 

score at 5 min

3) CNS:

 (Ultrasound findings)

ÿ Subependimal bleeding

ÿ Intraparenchymal lesions

4) Cardiovascular or 

Pulmonary:

ÿ PDA, RDS, Surfactant 

therapy, Days of Ventilatory 

tx, Chronic Lung Disease 

(CLD), Pneumothorax,

5) Other :

ÿ Age at time of test, Infantile 

septicemia.

Maternal education:3 levels

Parity: 0 or more

Maternal toxemia, Maternal 

septicemia, Placental bleeding: 

presence or absence

Intrauterine growth: SGA or AGA

Cardiotocography: normal or 

abnormal

All cranial U/S findings classified 

according to the most advanced 

stage observed

Subependymal bleeding: 3 grades:

B1: isolated germinal matrix/ 

subependymal haemorrhage 

B2:IVH without ventricular dilatation 

B3:IVH with ventricular dilatation 

Intraparenchymal lesions: 4 grades:

W1:Subtle or diffuse echodensity 

W2: Definite, distinct echodensity

W3: perventricular cystic formation 

(PVL) Intraparenchymal

W4: echodensity of haemorrhagic 

type or other gross pathology

W1 – W2: correspond to non-cystic 

PVL

B1-3 plus W1-4

PDA: none, spontaneous/ 

pharmacologic closure, Surgical 

ligation

RDS: presence or absence

CLD: according to Bacalari criteria

Infantile septicemia: verified by blood 

culture: staph epi, candida, naerobic 

bacteria, other. 

(The other predictors were not 

specifically defined)

1) Griffith’s Developmental Scale 

for Psychomotor development 

2) Total Score (sum of subclasses 

scores)

3) Individual subclasses Scores

(Assessment at 10 months of age)

Griffith’s developmental scale, 

standardized for Swedish infants: 5 

subclasses

Scale A: locomotor function, 

Scale B: Personal-social competence, 

Scale C: hearing and speech

Scale D: Hand and eye coordination: 

fine motor grasping

Scale E: Performance: Perception and 

intelligence scale

Scale Specificity of subclasses: limited 

when infants tested are immature/ 

Specificity increases with age.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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150

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Koller

1997

97193708

General:

1) Birth weight

2) GA

3) Illness severity -neonatal 

health index

4) maternal education

CNS:

Neurological status at 1 year

Neurological status at 1 year 

corrected age:

(1) abnormal, a severe abnormality, 

such as CP, global hypotonicity, 

chronic seizure, hydrocephaly, 

blindness, or severe 

sensorineural hearing loss, for 

which a diagnosis could be 

established

(2) suspicious, some atypical or 

questionable signs in tone, 

reflexes, gait, or movement, but 

for which there is no definitive 

diagnosis or syndrome

(3) Normal, based on a completely 

normal neurologic examination

CNS:

Neurodevelopmental:

Cognitive delay

 

Bayley MDI, Stanford-Binet IQ, 

Wechsler scale

Murphy

1997

97192793

General: GA, Apgar score

CNS:

Intracranial/Intraventricular 

hemorrhage

White Matter Disorder

Periventricular leukomalacia 

Ventriculomegaly/Ventricular 

diration.

Seizures

Cardiovascular:

Bronchopulmonary dysplasia

Preurmothora

GI: Total Patenteral Nutrition

Other: 

Infectious disease, Transfusion 

PDA, Prolonged ventilation.

Definitions not given for most 

predictors.

CNS:

Cerebral palsy Obtained diagnosis from regional 

registry of childhood impairments.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part II

151

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Schendel

1997

98033417

General Predictors

1) Birth Weight- 3 groups 

VLBM ( very low birth wt)

MLBW (moderately low birth wt.)

NBW (normal birth wt)

Other Predictors

1) Other: married at birth

2) Other: Medicaid recipient

ND CNS:

Other: Developmental Delay

Pulmonary Outcomes 

Birth weight

Developmental delay measured by 

Denver Developmental Screening 

Test II.

“DELAY” defined by 9 measures of 

performance on Denver 

Developmental Screening Test II at 

age 15 months corrected.

Thompson

1997

97268338

Other predictors:

1) Neurobiological Risk Score 

(NBRS)

2) Hasseles Scale Score 

(HSS) ‡ divided mothers 

into high and low risk; a 

“stress” score

3) Maternal variables

NBRS‡weighted scored of medical 

events: ventilation, acidosis, 

seizures, IVH, PVL, sepsis and 

hypoglycemia

CNS: 

Neurodevelopmental:

Cognitive delay

 

McCarthy scales at age 4 years

Definition: not clear on how well 

validated either of the predictors are.

Definitions of NBRS and Hasseles 

scores are probably OK, but I am not 

familiar with these.

Victorian Infant 

Collaborative 

study Group 

1997

98026322

*There are a 

series of 

Victorian 

articles in LBWALL.

*This study will 

be combined in 

LBW-ALL table

General: BW

Other: period of time when born

Each sample were subdivided into 

BW=500-749 g and BW=750-999 g

1985-1987 vs. 1991-1992

CNS:

Cerebral palsy

Neurodevelopmental:

Cognitive and motor delay

Disability

Ophthalmology: Blindness

Audiology: Deafness or hearing aid

CP was not defined

Bayley Scales of Infant Development

DQ, using the published mean and SD

Disability: “Sever” – bilateral blindness, 

cerebral palsy with the child unlikely 

ever to walk, or a DQ score <-3SD; 

“Moderate” – bilateral sensorineural 

deafness requiring hearing aids, 

cerebral palsy in children not walking 

at 2 but expected to walk, or a DQ 

score from –3SD to <-2 SD; “Mild” –

cerebral palsy but walking at 2 , or a 

DQ score form –2 SD to <-1 SD.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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152

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Battin

1998

99002694

General: 

1) GA (23-25 wks)

In comparative component with

Historical control group

General:

1) Birth during a period with 

routine use of: antenatal 

steroids, surfactant and 

dexamethasone for BPD ( 

vs birth in presurfactant, 

presteroid period)

ND CNS:

1) Neurodevelopmental outcome 

2) CP

3) Low MDI (below 2 SDs)

Ophthalmology- Audiology:

1) Blind, Deaf

Neurologic exam

Bayley scale: MDI, PDI

Formal hearing test

Ophthalmologic examination

Bos

1998

98218970

General predictors

Quality of general movements

CNS

Head ultrasound finding of 

transient periventricular 

Echodensities 

Diagnosed by US examination. The 

duration was determined for the 

frontal and the parieto-occipital 

region separately and classified 

according to four categories: (1) no 

echodensities, (2) echodensities 

between 1 and 6 d, (3) 

echodensities between 7 and 13 d, 

and (4) echodensities persisting for 

more than 14 d. 

CNS:

Neurodevelopmental

CP

Cognitive delay

Developmental trajectory of general 

movement quality, analyzed 

according to Prechtl’s method. 

Movements were judged globally 

based on visual Gestalt perception. 

Normal general movements are 

characterized by complexity, 

variability, and fluency.

CherkesJulkowski

1998

98262696

General: GA

Other: Mother perception of child 

competence

ND CNS:

Cognitive delay

Neurodevelopmental 

School problem

Neurological Impairment (NI)

Attention Deficit Disorder (ADD)

Audiology: 

Language 

Cognitive delay, measured by StanfordBinet

School programs (school concerns = 

SC)

Learning disabilities (LD)

Neurological Impairment (NI)

Attention deficit Disorder (ADD)

Language impairment = LI – dx made 

by speech and language clinician
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Emsley

1998

98238139

(CNS+ All)

General

1) Birth weight

2) GA

CNS

1) Other: significant cranial 

U/S findings (see page 1 for 

definition)

Other:

1) Illness acuity – CRIB score

2) Other: male sex

CRIB score is determined by BW, 

GA< congenital malformations, 

max base excess in first 12 hours, 

minimum FIO2 in first 12 hours and 

max FIO2 in first 12 hours 

CNS :

CP

Neurodevelopmental

Disability : normal, mild, moderate 

 severe

Behavioral disorders

Learning disabilities 

Seizure disorder

Developmental Delay

Ophthalmology :

Blindness

Other

Squint

Audiology:

Deafness

Speech delay 

ND

“Normal”- No clinically apparent 

developmental abnormality causing 

functional disability

“Mild Disability” - myopia, language 

delay, mild hearing loss, hyperactivity 

or clumsiness.

“Moderate Disability” – Spastic diplegia, 

hemiplegia, moderate learning 

disability (DQ 50-69)

“Severe Disability” – spastic 

quadriplegia, blindness, deafness (> 

70 dB), uncontrolled epilepsy or 

severe learning disability (DQ < 50) 

and multiple disabilities.

Not defined or how it is measured

ND

DQ < 70

> 70 dB, dot defined or how it is 

measured

ND

Pasman

1998

98196839

CNS

1) Other: Neurobiologic risk 

score (NBRS)

2) Neonatal Neurologic 

Inventory (NNI) table 1 

13 items of NBRS

4 items of NNI

CNS

Neurodevelopmental:

Cognitive delay

Mental retardation

Standardized testing:

VMI

Leiden diagnostic test

WISC-R

BWVR

ADIT

Rogers

1998

98438124

Birth weight 

GA

Periventricular

Bronchopulmonary dysplasia

Hospital/Health care resource 

utilization-length of stay

IVH according to discharge clinical 

record diagnosis

CNS:

CP

Neurodevelopmental:

Growth failure

According to discharge clinical record 

diagnosis (quadriplegia, diplegia, or 

hemiplegia)

Weight-for-age z score was more than 2 

SD below the mean and subsequently 

fell below –2 SDS
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Spinillo

1998

98237382

Spinillo, 1997

98021316 & 

97277958

*have some 

overlapped 

sample with 

spinillo, 1994

General predictors:

1) Birth weight’

2) GA

3) SGA/IUGR

4) Maternal disease (diabetes, 

respiratory, cardiovascular, 

renal etc)

5) Antenatal steroids

Other predictors:

1) Infectious disease

2) Dexamethasone

3) Perinatal factors 

(Socioeconomic factors, 

pregnancy variables, 

Delivery variables)

4) Meconum-stained amniotic 

fluid

Preeclampsia defined as:

1) Diastolic BP> 90

2) Systolic BP> 140

3) Proteinurea> 0.3 g

Severe preeclampsia defined as:

1) Diastolic BP> 110

2) Systolic BP> 160

3) Proteinurea> 3 g

Intrapartum Fetal HR abnormalities:

• Late decelerations

1) Variable decelerations

2) Bradycardia

Tachycardia

CNS

CP

Neurodevelopmental: Mental 

retardation

CP: Spastic diplegia, hemiplegia, 

tetraplegia , With moderate to severe 

interference with function, With or 

without mental retardation (MDI< 71)

Bayley scales

Tin

1998

99046171

General: GA (23-31 wks) ND CNS: 

Neurodevelopmental:

1) Mental retardation (IQ < 75)

2) Other; disability (severe, severe 

sensorimotor)

3) Other: development - assessed 

by Griffith’s mental and 

developmental scales

Definition of "severe disability” and 

"severe sensorimotor disability" 

were not given in this article . They 

referred to the wrong reference for 

these definitions, therefore, I am 

unable to find the definitions. 

Reference population for Griffith’s 

scales were "preterm babies in the 

study S serious sensorimotor 

disability"
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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155

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Burguet

1999

99126269

General Predictor:

1) Male gender

Cardiovascular

1) Bronchopulmonary 

dysplasia

Other predictor:

1) Infectious disease neonatal 

sepsis

2) Maternal hypertension

3) RDS

4) Outborn birth

5) Race

6) Urban residence

7) Family precariousness = 

father absent or both 

parents unemployed

8) PROM > 48 hours 

(preterm)

9) Monochorionic placentation

10) Singleton placentation

11) Dichorionic placentation

RDS diagnosed by chest radiography 

examination

PROM = premature rupture of 

membrane

CNS:

CP 

PVL

One or more of the following signs was 

observed – hemiplegia, diplegia, 

tetraplegia, dystonia, athetosis, 

blindness, or neurosensory deafness

Cooke

1999

99257637

General predictors:

Antenatal steroids

Period of birth

CNS:

IVH

Periventricular leukomalacia

Other:

Surfactant use

ND CNS:

CP

Data from Regional Cerebral Palsy 

Register
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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156

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Cooke

1999

99380719

Birth weight

CNS: white matter 

disorder, periventricular 

leukomalacia, ventriculomegaly, 

MRI abnormality, thinning of 

corpus callosum, povencephaly, 

Brain measurements (multiple)

ND CNS:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Behavioral disorders

School problems

Learning disabilities

IQ: WISC III

Motor delay (motor disability): 

Movement of ABC scores

Mental retardation

Behavioral disorders

School problems

Learning disability: Suffolk Reading 

Scale. Basic Math and Spelling Test 
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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157

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Finer

1999

99436635

CNS Predictors:

Delivery room resuscitation (DRCPR)Defined as chest compressions 

and/or epinephrine used.

CNS:

Neurodevelopmental

1) Motor delay

2) Post hemorrhagic 

hydrocephalus (PHH)

3) Apgar scores

4) IVH/echolucenies

5) Developmental

6) White matter injury

In the first year, neurodevelopmental 

assessment by Amiel-Tison 

Neurologic Screen. Thereafter, used 

Knoblick-Gesell Developmental 

Inventory. 

"Neuromotor Outcome - questionable": 

hypotonia, hypertonia, asymmetry

"Neuromotor Outcome - abnormal": 

cerebral palsy

"Developmental Outcome - normal": 

both mental and motor composite 

scores ?86

"Developmental Outcome -

questionable": either score 76-85 

"Developmental Outcome - abnormal": 

either score <75

"Neurodevelopmental Outcome -

normal" if both neuromotor and 

developmental evaluations are 

normal. "Neurodevelopmental 

Outcome - questionable" if either 

neuromotor or developmental 

evaluations are questionable.

"Neurodevelopmental Outcome -

abnormal" if either neuromotor or 

developmental evaluations are 

abnormal.

"White matter injury": presence of grade 

4 hemorrhage, echolucencies, or 

ventricular dilation unrelated to 

hemorrhage.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Futagi

1999

99450356

General:

1) Birth in surfactant era 1989-

1993 vs Birth in presurfactant era 1981-1986

Not specified further 1) Normal neurodevelopmental 

outcome

2) Cerebral palsy

3) Mental retardation

4) Borderline intelligence

(Assessment between 3-8 yrs,

mean age of assessment was 6 yrs)

1) Normal neurodevelopmental 

outcome: Absence of motor 

disturbances and developmental 

quotient and/or intelligence 

quotient more than 84.

2) Cerebral palsy: diagnosis based on 

Bax criteria (Outcome data also 

given for one child with spinal 

palsy: no definition given)

3) Mental retardation: 

DQ or IQ scores less than70

4) Borderline intelligence: 

DQ or IQ scores between 70-84, 

DQ and /or IQ scores: ( of latest 

exam)according to Kyoto child guidance 

clinic development scale for children for 

subjects up to 7 yrs of age,

Or according to the revised Wechsler 

Intelligence scale adapted for Japanese 

children for cases more than 7 yrs of 

age. (the results of gross motor skills in 

the former test were excluded for 

cerebral palsy children when computing 

DQs)

Kim

1999

99416608

Other PredictorPerinatal factorsND CNS:

CP

Neurodevelopmental:

Development delay

Non-progressive, often changing motor 

impairment syndromes secondary to 

lesions or anomalies of the brain 

arising in the early stages of 

development

Delay in parameters for motor 

development of more than two 

months according to the stages of 

motor development by Vojta
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Krageloh-Mann 

1999

99431017

CNS:

1) Intracranial/ Intraventricular 

hemorrhage 

2) PVL

3) Cerebral blood flow

4) Cerebral oxygen delivery

CBF measured with 133Xe clearance 

at 12.9 hours of life (range 1-48hr)

Cerebral oxygen flow calculated as 

CBF x ART 02 content

CNS:

Spastic CP

Neurodevelopmental:

Motor delay

Mental retardation

Anatomical abnormalities on MRI

Ophthalmology:

Visual blindness

Stott-Moyes-Henderson test - Spasticity 

of extremities with flexor hypertonicity, 

increased tendon reflexes and 

characteristic posturing

Motor disability was graded as severe if 

the child could not walk unaided at the 

age of 5 y, otherwise as mild

WISC

Salokorpi

1999

99353226

General: BW, GA, SGA/IUGR, 

Maternal disease

CNS:

IVH grade III or IV

PVL

Other: duration of ventilation, 

hypotension, hypocarbia, 

infectious disease

ND CNS:

CP

Mortality by 2 years

A diagnosis of CP was confirmed when 

abnormal muscular tone, persistent or 

exaggerated primitive reflexes and 

major delay in motor development 

were found.

The classification of CP syndromes was 

based on the definition by Hagberg et 

al.

Shepherd

1999

99165413

Ophthalmology :

VEP (visual evoked potential )

One flash per second 20 cm from 

eyes. Each trial included 30 

responses. 2 trials averaged. In 

preterms, VEP measured at 3 day 

of life in groups < 34 weeks, 34-36 

weeks and 40 weeks, when 3,6-12 

months.

CNS:

Cerebral palsy

No definition of CP given

Stathis

1999

99325758

CNS Predictors

1) Other: head circumference 

category 

2) Head growth velocity

Self-explanatory CNS:

Neurodevelopmental:

Cognitive delay

Behavioral disorders-ADHD 

School problems

Learning disabilities

Academic problems--Answer 

questionnaires given to teacher

ADHD--Dr. Paul rating scale

McCarthy’s scales
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Vohr

1999

99332101

Intracranial/Intraventricular 

hemorrhage

Cranial ultrasound finding CNS:

CP

Neurodevelopmental:

Cognitive and Motor delay

CP diagnosed by routine neurological 

exam. CP was based on the presence 

of hypertonicity, hyperreflexia, and 

dystonic or spastic movement quality 

in the affected limbs.

Stanford-Binet Intelligence Scale

PPVT-R

Agustines

2000

20279724

General predictors:

1) BW (500-750)

2) GA

ND Neurodevelopmental outcome:

Bayley scale

1) MDI

2) PDI

3) Overall neurodevelopmental 

outcome

4) Neurodevelopmental outcome 

stratified by GA

(assessment at 30 months corrected 

age)

1) Normal development: Performance 

within 1 SD

2) Mild delay: Performance below 1 

SD

3) Severe delay: Performance below 

2 SD
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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161

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Breslau

2000

20298367

General:

1) LBW (vs Normal BW= 

NBW)

2) Urban (vs suburban 

setting)

3) Maternal smoking during 

pregnancy

ND CNS/Behavior

1) Behavioral problems in 3

domains: Attention , Externalization

Internalization

2) Severe attention problems 

(above a cutoff point of 67)

Assessment at 11 yrs of age

(assessment at 6 yrs: reported in 

another publication)

Mother’s rating was done with:

Child Behavior Checklist (CBCL)

Teacher’s rating was done with Teacher 

Report Form (TRF)

(teachers were blind to the BW 

information of the child)

Assessments at 11 yrs were conducted 

blindly to the results of assessments 

at 6 yrs (reported in another 

publication)

Attention problem subscale; 20 items

Externalization problem subscale: 2 

subclasses

Internalization problem subscale: 3 

subclasses

Buhrer

2000

20280896

CRIB score Routinely measure on the first day of 

a baby’s life. CRIB score 

determined from: BW, GA, 

congenital life-threatening 

malformations, worse base excess, 

min+max FIO2 in first 12 hrs of life

CNS:

Neurodevelopmental

Griffith’s test

Grether

2000

20448692

Received Magnesium sulfate Chart review CNS:

CP

Mild, moderate, or severe CP assessed 

from record of 2 state agencies.

Katz-Salamon 

2000

20332284

Cardiovascular or pulmonary 

predictors: chronic lung disease

1

st week ? acute lung injury; clinical 

signs; supplemental O2 at 28 days; 

typical CXR

CNS:

Neurodevelopmental:

Cognitive delay

CP

Griffith’s development scale

Movement assessment index (MAI): the 

original number of items was reduced 

to include only those reported to be 

the most valid as predictors of CP
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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162

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Marlow

2000

20150342

General:

1) Birth weight 2) Apgar score

3) Illness severity (CRIB) scores

CNS:

1) Maximum bilirubin level

2) Abnormal cerebral US scan

Audiology:

1) Sensorineural hearing loss

Cardiovascular/Pulomonary:

1) Duration of intubation, 

respiratory support, oxygen, 

pH<7.2, base excess 

2) Dopamine 3) Furosemide

4) Indomethacin use

Other:

5) Netilmicin 6) Vancomycin

7) Positive blood cultures

8) Bilirubin >200 ?mol/l

9) Bilirubin>GA x 10

10) Creatinine >60 mmol/l

11) Netilmicin 12) Vancomycin

Combination of the above:

1) Bili.200 + acidosis

2) Bili> 200 + sepsis

3) Bili >200+ netilmicin

4) Bili> 200+ vancomycin

5) Bili>200+ furosemide

6) Peak bil+ acidosis

7) Peak bili+ sepsis

8) Peak bili+ netilmicin

9) Peak bili+ furosemide

10) Creatinine>60+ netilmicin 

or vancomycin or 

furosemide

11) Netilmicin+furosemide

• Vancomycin+ furosemide

Not further specified In case control component:

Audiology:

Sensorineural hearing loss (SNHL) of 

50 dB within 9 months from birth

In Longitudinal component:

CNS:

Cerebral palsy at 12 months of age in 

the 2 groups (SNHL and control 

group)

Cases of SNHL were identified if the 

hearing loss had been identified within 3 

months of discharge home, (within 9 mo 

from birth); after excluding cases with 

conductive hearing loss, possible 

congenital cause, or had neonatal 

bacterial meningitis
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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163

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Palta

2000

20096107

(CNS+Eye)

General: 1) Birth weight

 2)Antenatal steroids

 3)Multiple birth

CNS: Intracranial/ 

Intraventricular hemorrhage

Ophthalmology: Retinopathy of 

Prematurity (ROP)

Cardiovascular/ Pulmonary:

 1)Surfactant administration 

 2)Respiratory score

Other: 

 1)Multiple birth

 2)Socioeconomics

 3) Number days in NICU

BW <1500 gms VLBW

-Baseline respiratory scores = 

disease 1st 3 days of life 

0-100 based on increasing severity

BPD: O2 use at 36 wks post 

conceptional age postnatal used 

corticosteroid use mechanical 

ventilation or both = severe BPD at 

30 days

CNS:

CP

Neurodevelopmental:

Functional assessments

Ophthalmology: 

Visual impairment

Blindness

Standardized scores for self care, 

mobility and social function

CP: physician dx at parent interview and 

confirmed by clinic record 

abstraction as well as blindness and 

use of corrective lenses.

Pediatric Evaluation of Disability Index 

(PEDI): standardized scores for self 

care, mobility and social function

Torrioli

2000

20275419

(CNS+Eye)

General:

1) Birth weight

2) GA

3) SGA/IUGR

ND CNS: 

Neurodevelopmental:

Motor delay

Cognitive delay

Behavioral disorder

 

Ophthalmology: Visual impairment

For VMI &WISC measures, “abnormal” 

was defined as under the 5th%tile; 

“normal” was defined as over 15th

%tile of a control group

VMI Movement

WISC

Conner’s relent symptom questionnaire

Valkama

2000

20233239

General predictors:

Birth weight

GA

SGA/IUGR

CNS predictors:

IVH

White matter disorder

Periventricular leukomalacia

MRI findings

IVH grading according to Papile

PVL grading according to DeVries

CNS:

Cerebral palsy

Infants whose motor development was 

delayed and who had abnormal 

muscle tone and motor function as 

an impairment or disability at a 

corrected age of 18 mo were defined 

as having CP in the sense of 

Hasberg et al.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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164

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Vohr

2000

20295211

General:

1) Birth weight

2) Maternal disease (HTN)

3) Antenatal steroids

CNS:

1) Intracranial/Intraventricular 

hemorrhage ( GR 3 to $ 

IVH/PVL)

Cardiovascular or Pulmonary:

1) Chronic lung disease 

(oxygen requirement at 36 

weeks)

2) Other: postnatal steroids

3) Other: Surfactant

Gastrointestinal:

1) Necrotizing “enterocolitis”

Other:

1) Other: male sex

2) Other: Race (white)

3) Other: sepsis (early and 

late onset)

4) Other: maternal education

GR 3 to 4 IVH. PVL undefined sepsis 

undefined

CNS :

Cerebral palsy

Neurodevelopmental:

1) Motor delay (sitting, walking, 

pincer grasp, feeding)

2) Seizure disorder

3) Post hemorrhagic 

Hydrocephalus (PHH) and shunt

4) Other: Neurologic exam (normal; 

abnormal)

5) Development (MDI and PDI by 

Bayley II Scale) 

Ophthalmology :

1) Visual impairment (any)

2) Blindness (unilateral, bilateral)

Audiology:

1) Hearing disorders

“normal Neurologic exam”: no 

abnormalities on neurologic exams

Dammann

2001

21334215

General Predictors:

1) Birth weight

2) SGA/IUGR

CNS Predictors:

1) Intracranial/ Intraventricular 

hemorrhage

Other predictors:

1) Infectious disease

2) Perinatal factors - PTL, 

PROM, C-section

ND CNS:

CP

ND
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Gaillard

2001

21221175

In retrospective case-control 

component:

General:

1) shorter length of ventilation 

beyond 27 (but not 50) 

postnatal ds vs more 

prolonged ventilation 

beyond 49 ds

2) Number of days “off”” 

ventilator in the groups of 

27-49 postnatal ds 

ventilation and the group of 

>49ds ventilation

In retrospective cohort with 

historical control group 

component:

General:

1) Birth in a period where 

Antenatal steroids and 

Surfactant were more 

routinely used vs birth in 

pre-surfactant pre-antenatal 

steroid period

Not further specified CNS:

Neurodevelopmental outcome:

1) Normal

2) Mild disability

3) Moderate disability

4) Severe disability

Normal neurodevelopmentally: no 

clinically apparent 

neurodevelopmental abnormality 

causing functional disability

Mild disability: e.g. myopia, language 

delay, mild hearing loss, 

hyperactivity or motor clumsiness.

Moderate disability: for example: spastic 

diplegia, hemiplegia or moderate 

learning disability (Developmental 

Quotient: 50-69)

Severe disability: e.g. spastic 

quadriplegia, blindness, deafness (loss 

of 70 decibel or more), uncontrolled 

epilepsy, or severe learning disability 

(developmental quotient <50). Infants 

with multiple disabilities.

( 3 yrs CA)

Horwood

2001

20574647

Other: Breastfeeding duration Retrospective questioning CNS:

Neurodevelopmental:

Cognitive delay

Mental retardation

WISC-R verbal and performance IQ 

scores at age seven years.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Nadeau

2001

21163667

General: GA

Other: Family adversity Index

Evaluated at 5 years 9 months, was 

developed using SES data such as 

the family status (two-parent, singleparent, blended), age of each parent, 

their respective levels of education, 

and professional occupations. 0=low 

~ 7=high

CNS:

Neurodevelopmental:

Motor function

Cognitive delay

Behavioral disorders

Behavior

Neuromotor development index: 

Huttenlocher neurological task test

McCarthy Scales of Children’s Abilities

Behaviors were assessed by peers, 

teachers, and parents: RCP, TRF, 

parent’s CBCL

Pierrat

2001

27221167

CNS Predictors:

Periventricular leukomalacia 

(cystic) in <32 wk GA infants

Grade II - Transient periventricular 

densities, evolving into small cysts.

Grade III - Transient periventricular 

densities, evolving into large cysts.

CNS:

Neurodevelopmental:

Motor delay

Cerebral palsy

Motor delay - 12, 18, 24 month outcome 

as the protocol of Amiel-Tison and 

Stewart, and Touwen

Criteria of Hagberg et al.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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167

Author, Year Associations found Potential Biases Comments

Leonard

1990

90204169

Neurologic abnormalities:

Oxygen group (no IVH and no parenting risk): 0-29 days 9%, = 50 days 0%, p=NS 

among oxygen groups, total 6%

IVH (no parenting risk factor): none 6%, Gr 1-II 0%, Gr III-IV 21%

Parenting risk (no IVH): absent 6%, Present 17%, p=NS

Cognitive deficits:

Oxygen (no IVH and no parenting risk): 0-29 days 18%, = 50days 7%, total 17%

IVH (no parenting risk factor): none 17%, Gr I-II 29%, Gr III-IV 50%, p < .005 

between none and Gr III-IV groups

Parenting risk (no IVH): Absent 17%, Present 75%, p<.001

NO cognitive risk factors:

Low socioeconomic status with no parenting risk 74%

Low socioeconomic status with parenting risk: 20%

 p<.02

Abnormal cognitive outcome (logistic regression):

Oxygen: NS

IVH: Grades 0-IV p= .0042, Gr I-II p=.18, Grade III-IV p=.003

Parenting risk with no IVH p= .0002

Low socioeconomic status p= .0107

Almost 30% dropout rate.

Incomplete description of study groups

No description of how neurodevelopmental 

assessment was done (who evaluated 

and were they blinded to the group).

Conclusion that antenatal steroids and 

surfactant improves neurologic 

outcome is inappropriate since he had 

no control group that did not receive 

these treatments.

No data on funding source

Lucas

1992

92122860

Fortified breast-milk-fed vs. Minimally supplemented breast-milk-fed:

Gross motor development/Knobloch scale: 

 (Not significant) 102.7 +1.8 ; 102.9+2 

Language development/Knobloch scale:

 (Not significant) 92.6+0.9 ; 92.1+1.1

Social development:

 (Not significant) 104.6+1.1 ; 105.6+4

Motor development/Bayley:

 (Not significant) 92.3+1.6 ; 89.9+1.5

Mental development/Bayley:

 (Not significant) 106+2 ; 105.8+2

Social development/Vineland

 (Not significant) 118.9+1.7; 115.8+1.7

Not exclusively breast fed: in both groups 

total maternal intake was < 50 % breast 

milk with the 

Differential loss to follow up not reportedcannot determine BWT/GA of groups at 

follow-up

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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168

Author, Year Associations found Potential Biases Comments

Robertson

1994

94181384

CP

500 –749 g (20) 1/20

750 –999 g (54) 6/59

1000-1249 g (84) 4/84

500-1249 g (163) 11/163 (6.7%)

Vision loss 

500 –749 g (20) 2/20

750 –999 g (54) 0/59

1000-1249 g (84) 0/84

500-1249 g (163) 2/163 (1.2%)

Hearosensory 

500 –749 g (20) 1/20

750 –999 g (54) 0/59

1000-1249 g (84) 1/84

500-1249 g (163) 2/163 (1.2%)

Mental retardation

500 –749 g (20) 3/20

750 –999 g (54) 0/59

1000-1249 g (84) 0/84

500-1249 g (163) 3/163 (1.8%)

Convulsive disorder 

500 –749 g (20) 0/20

750 –999 g (54) 0/59

1000-1249 g (84) 0/84

500-1249 g (163) 0/163 (0%)

Does not give detailed characteristics of 

cohort

Study was private funded

Spinillo

1994

94257064

*have some 

overlapped 

sample with 

spinillo, 1997

Studied outcome of LBW infants after 3rd trimester bleeding.

Controls were LBW’s without 3rd trimester bleeding.

Abruption, n = 40; previa, n= 22; unclassified bleeding, n = 15; controls, n = 153.

Group Grade 3-4 IVH Cystic PVL Major handicap Poor Outcome

Abruption 12.5%* 5% 11.1%+ OR = 3.9 (1.2, 2.1)

Previa 13.6% 0 0 OR = 0.9 (0.2, 3.6)

Unclassified 6.7% 0 0 OR = 0.6 (0.1, 0.3)

Control 3.9% 0.6% 0.7% Reference group

*P = 0.02 vs. control

+P = 0.007 vs. control

Not all severe VLBW

No information regarding frequenting of 

VLBW

Bayley test score information no presented 

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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169

Author, Year Associations found Potential Biases Comments

Chen

1995

96009403

All of the LBW preterm infants with normal brain US finding (N=12) had “normal 

development”. Two (17%) of them developed spastic CP.

All of the LBW preterm infants with abnormal brain US finding (N=5) showed signs of 

spastic CP.

No reference of DDST

Cases report without statistical analyses

Vague or no definition of outcomes

No data on funding source

Goetz

1995

96119489

Tone abnormalities : (PVL) 12/12

Seizure disorder: (PVL) 1/12

Strabismus: (PVL) 3/12

Cognitive delay: (PVL) 6/12 mild 2/12 severe 4/12

They found cognitive delay in 6 of 12, seizures in 1 of 12 and strabismus in 3 of 12

Missing information

Small sample 

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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170

Author, Year Associations found Potential Biases Comments

Speechley

1995

96356544

General Health outcome:

Among boys around 12 yrs of age: NICU graduates as opposed to normal boys:

1) Are living with more chronic health problems

2) Are more likely to have a physical impairment

3) And have been hospitalized more often.

Among girls around 12 yrs of age: NICU graduates as compared to normal girls: No 

statistically significant differences in their physical health outcome. Among NICU 

graduates, boys were not different from girls in their long-term physical health 

outcomes.

Emotional and Social well being outcomes:

Among girls around 12 yrs of age: NICU graduates as opposed to normal girls:

1) Had significantly lower social competence

2) Lower social support

3) And Lower self-esteem.

Among boys around 12 yrs of age: NICU graduates as compared to normal boys:

1) They had no difference in their emotional or social well being. There was no 

interaction between family’s socioeconomic status and long term outcomes 

among NICU graduates.

Analytically:

The physical health outcomes at 12 yrs were 

(Boys NICU grads vs Boys NNN grads/ Girls NICU grads vs Girls NNN grads)

• Chronic physical health (mother’s report): 2.8 vs 1.8 (p<0.005)/ 2.4 vs 1.3

• Lifetime hospitalizations (mother’s report): 2.5 vs 1.6 (p<0.005)/ 1.7 vs 0.4

• Physical impairments (mother’s report): 0.29 vs 0.10 (p<0.005)/ 0.22 vs 0.06

• Perception of child’s heath (child’s report): 21.6 vs 22.2/ 21.1 vs 21.9

• Perception of child’s health (mother’s report): 16.9 vs 17.7/ 16.8vs 18.0

Emotional and social well being at 12 yrs:

(Boys NICU grads vs Boys NNN grads, Girls NICU grads vs Girls NNN grads)

• Internalizing problems (child’s report):15.3 vs 15.5/ 18.2 vs 14.8 

• Externalizing problems (child’s report): 15.9 vs 16.0 / 14.3 vs 13.5

• Social competence (child’s report): 109.1 vs 113.9 / 101.7 vs 115.7 (p<0.005

• Social support (child’s report): 81.6 vs 83.2/ 79.9 vs 86.1 (p<0.005)

• Self esteem (child’s report): 31.9 vs 32.4/ 29.8 vs 32.5 (p<0.005)

• School performance (mother’s report): 4.5 vs 4.6/ 4.8 vs 5.3

1) There is an Inconsistency in 

Mother’s appreciation of their child’s 

physical health: mothers of NICU graduate 

boys reported that their children had more 

physical impairments than NNN boy 

graduates; however, their overall 

perception of their child’s health status 

was not any different from NNN boys 

graduates.

2) Some of the outcomes

3) Collected are prone to recollection 

bias (e.g., frequency of lifetime 

hospitalizations).

1) In this NICU cohort, 

only 36% of infants had 

BW<2500 g and only 5% 

had BW < 1500 gs, reflecting 

more NICU populations in 

the 70s and early 80s, than 

the current ones. 

2) It is unclear whether 

statistically significant 

differences in psychometric 

scales reflect clinically 

significant differences in the 

emotional and social 

wellbeing of these children. 

3) Given the fact of many 

negative findings, post hoc 

power analyses demonstrated that the study had an 

80% power to detect a 40% 

difference between the 2 

groups. 

4) The fact that girls ex 

NICU graduates had a more 

substantial psychological 

effect than boys may reflect 

that girls are further into 

adolescence than the boys, 

experiencing the sequelae 

earlier. Thus in order to 

determine whether the 

differences observed are a 

temporary effect/related to 

adolescence, this cohort had 

to be followed further into 

their teenage years
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Wildin

1995

95385294

Wildin

1997

97422739

*Data from 

same 

longitudinal 

study as 

Anderson, 1996

96314587 &

Smith, 1996

97081985; 

overlapped 

sample

High risk (HR) preterms, low risk (LR) preterms and full term controls. Most infants 

who were classified as high risk were classified as such due to BPD. Bayley MDI 

and PDI at 12 months corrected age:

Group n Bayley MDI Bayley PDI

HR 49 92.8 (24.9) 89.8 (20.7)

LR 92 103.8 (16.3) 99.1 (19.5)

Control 114 108.2 (11.3) 108.5 (12.3)

In Hierarchical linear models analyses:

Cognitive/Bayley, Stanford-Binet

Medical risk category LR (N=115) Hierarchical linear 

 HR (N=69) model P=0.02

Rate of mental development/Bayley, Stanford-Binet

Medical risk category LR (N=115)

 HR (N=69) P=0.0004

Socioeconomic status and cognitive/ Bayley Stanford-Binet association not 

significant.

Medical risk category SES and rate of mental development/Bayley, Stanford-Binet 

association not significant.

SES and rate of mental development/Bayley, Stanford-Binet association not 

significant.

Motor development not significant 

Preterm HR (high risk) 

Group: 

 84% were HR because of BPD only, so 

this groups is really a BPD group

Many exclusion criteria

Full developmental evaluation only done 

on a subgroup; others only partly 

examined

Only analyzed infants retained through all 

40 months 

Do not account for infants lost to follow-up

Do not describe how group at 40 months 

differed in composition from group at 

enrollment.

Use one-tailed test to achieve significance.

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Anderson

1996

96314587

Smith

1996

97081985

(CNS+All)

*Data from 

same 

longitudinal 

study (U. of 

Texas Health 

Sciences 

Center in 

Houston and 

the U. of Texas 

Medical Branch 

in Galveston) 

as Wildin, 1995 

& 1997; 

overlapped 

sample

Cognitive Development (Bayley MDI) at 6 and 12 months, respectively: 

VLBW high risk (N=58): 100.7 (24.9), 92.8 (19.2)

VLBW low risk (N=96): 106.8 (19.5), 103.8 (16.3)

FT (N=119): 113.6 (15.8), 108.2 (11.3)

Motor Development (Bayley PDI) at 6 and 12 months, respectively: 

VLBW high risk (N=58): 100.7 (24.9), 92.8 (19.2)

VLBW low risk (N=96): 106.8 (19.5), 103.8 (16.3)

FT (N=119): 113.6 (15.8), 108.2 (11.3)

All groups differed significantly on MDI and PDI at 6 months (p<.001). At 12 months, 

only the high-risk infants differed from the term infants (p<.001). The means for all 

three groups at 6 and 12 months were within the normal range. However, 

significantly more high-risk infants fell within the moderately and severely delayed 

ranged than low-risk and term infants did (data not given)

Total neurologic score at 6 and 12 months, respectively:

VLBW high risk (N=58): 0.30 (0.23), 0.16 (0.22)

VLBW low risk (N=96): 0.16 (0.17), 0.08 (0.12)

FT (N=119): 0.05 (0.07), 0.04 (0.05)

All groups differed significantly on total neurologic score at both 6 and 12 months 

(p<.001). Total score significantly improved from 6 to 12 months of age in all groups 

(p<.001). Total score in high-risk group still remained abnormal after improvement, 

while the score in low-risk and term infants were normal at 12 months of age.

Assessed risk status in relation to outcome in areas of development of cognitive 

skills, communication development and daily living skills. Mental Age and daily living 

skills data are in months and language data are in raw scores: 

Language

Infant status n Mental Age Daily living skills Expressive Receptive

High risk 88 11.6 (2.4)* 11.9 (2.65) 18.0 (5.4)# 14.2 (2.6)

Low risk 123 12.8 (1.7)* 12.97 (2.45) 20.5 (5.9) 15.3 (3.3)

Full term 128 12.9 (1.1)* 13.29 (2.0) 20.6 (4.7)# 15.3 (2.4)

*p < 0.01 for High risk v. low risk and full term

# p < 0.01 for high risk v. full term

Other differences are not significant.

Some comparison scores not shown

The overwhelming majority of HR VLBW’s 

were HR because of BPD with or 

without IVH

Low socioeconomic status, inner city 

population

Study was government 

funded

Significantly more abnormal 

neurologic scores at 12 

month of age in VLBW 

high-risk infants 

compared to FT controls. 

Higher abnormal scores 

suggest degree of 

abnormality at 12 months 

depending on level of risk 

as neonate.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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173

Author, Year Associations found Potential Biases Comments

Kato

1996

97182916

Independent predictors of CP/MR

Fetal malpresentation vs. cephalic presentation (p<0.01)

Use of tocolytics vs. no tocolytics (p<0.005)

Umb cord artery pH<7.2 (p<0.05)

Major handicap (CP/MR/Blindess) increased in VLBW infants delivered by 

breech/vag (25%) v. ceph/vag (0%) vs. Breech/c-section (5%) vs. cephalic/csection (8.5%) (p<0.05)

Retrospective –completeness data 

(predictors/outcomes) not known. 

Predictors and outcomes poorly 

defined.

No FT comparison.

No data on funding source

Katz

1996

97145056

Attention deficit is measured by the CPT test (error of omission). Hyperactivity

and impulsivity is measured by the CPT test (error of commission).

There were no differences among the preterm infants with mild, moderate and 

severe intracranial lesions. However, there was a significant increase in both 

errors of commission and omission in preterm with mild lesions compared to full 

term infants as well as in preterm with severe lesions compared to full term infants. 

With increasing severity of lesions in preterm infants, increasing percentage in 

each group commit errors of commission. Even in the absence of detectable 

intracranial lesions, preterm infants are still at higher risk for developing attention 

deficits than full term infants.

Exactly how FT controls were selected in 

an unbiased way is not described.

No data on funding source

This study does not explore 

relationship of attention 

deficits identified with the 

CPT test with actual 

school performance and 

achievement in this group 

of preterm infants.

This study includes older 

preterm 26-34 weeks and 

does not include the 

extremely preterm 24-25 

wk infants.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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174

Author, Year Associations found Potential Biases Comments

Korkman

1996

96374730

Psy1996

Overall: the VLBW/SGA group had the poorest test results. The VLBW/AGA group 

was somewhat less impaired, whereas the birth asphyxia group performed at the 

control group level

Impairment when present tended to be diffuse in all groups, affecting: psychometric 

intelligence, naming, visuo-motor performance, tactile finger discrimination, 

attention and phonological analysis.

Predictors evaluation for CNS outcome (Intelligence evaluation):

1) VLBW/AGA was associated with poorer WISC-R score, when compared to 

healthy full term (FT) (p<0.05)

2) VLBW/SGA was associated with poorer WISC-R score, when compared to 

healthy FT (p<0.05)

3) VLBW/SGA was associated with poorer WISC-R score when compared to 

asphyxiated term infants (There was no difference in the scores between 

asphyxiated terms and healthy terms)

Predictors evaluation for CNS outcome (Neuropsychological evaluation):

1) VLBW/SGA was associated with poorer NEPSY score (p<0.05) when 

compared to healthy FT

2) In the VLBW cohort, impairment when present tended to be diffuse (in all items 

examined).

3) VLBW/SGA was associated with poorer NEPSY score when compared to 

asphyxiated terms.

Overall In the VLBW group (AGA and SGA) (n=77): 

1) Apgar scores were not correlated with outcome measures

2) Arteria PH was correlated with FSIQ score

3) Intrauterine growth retardation correlated with NEPSY score

4) BW correlated with NEPSY score

5) There was no correlation between RDS, IVH , duration of ventilatory tx and 

cognitive dysfunction

Combined CNS / Ophthalmology outcome:

1) VLBW/AGA: 21% (both mild and severe)

2) VLBW/SGA : 6/34 (18%) (mostly lids)

3) Birth asphyxia/ Term: 7/32 (22%) (mostly severe)

1) Cannot exclude potential selection 

bias (no description of patient flow in 

each group)

2) Cannot exclude diagnosis bias/no 

information on blinding of personnel 

evaluating developmental outcome 

component on PMHx.

3) The authors investigated 

associations between 7 predictors 

and many outcomes (the different 

subcomponents of WISC-R test and 

the NEPSY test)/ thus cannot exclude 

“multiple comparison” effect

Supported by nongovernmental foundations
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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175

Author, Year Associations found Potential Biases Comments

Lucas

1996

96302121

Predictor evaluation for CNS outcomes:

(Unadjusted analysis)

Mother’s choice to breast feed was associated with higher IQ scores at 7 years:

(No mother’s milk group vs Mother’s milk group)

• WISC-R verbal scale (mean): 92.0 vs 102.1 (p<0.001)

• WISC-R Performance scale : 93.2 vs 103.3 (p<0.001)

• Overall IQ: 92.8 vs 103.0 (p<0.001)

(Adjusted regression analysis for confounders)

Mothers choice to Breast feed infant: N=210 babies

• Higher Verbal scale scores: (p<0.001)

• Higher Performance scale scores (p< 0.0001)

• Higher Overall IQ: (p<0.0001)

Successfully breast fed infants only:

(Received breast milk) N=193 babies

• Higher Verbal scale scores: (p<0.0001)

• Higher Performance scale scores (<0.0001)

• Higher Overall IQ: (p<0.0001)

Overall (Regression analysis)

• Whether Received breast milk: offered advantage of 8.3 points (p<0.001)

• Social class: -3.5/class (p<0.004)

• Mother’s education: 2.0/ group (p=0.01)

• Female sex (p=0.01)

• Days of ventilation: -2.6/ week (p=0.02)

Cannot exclude false association due to 

unrecognized confounders between the 2 

groups as this study was non-randomized 

(despite matching for BW, GA, need for 

ventilation, NICU stay and other diets ; 

there are still exist important unconsidered 

confounders)
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Rieck

1996

Psy 1996

06905005

In Prospective longitudinal component of the study:

Predictor evaluation for CNS outcome:

1) Female Sex, HC percentile and Maternal education were independently 

associated with CGI score (r2= 0.41, p< 0.001)

2) Age at assessment, GA and HC percentile were independently associated with 

Verbal scale score. (r2= 0.36, p< 0.001)

3) HC percentile was independently associated with Perception-performance 

score (r2= 0.12, p< 0.05)

4) Neurologic complication and HC percentile were independently associated with 

Quantitative scale score (r2= 0.30, p< 0.01)

5) Neurologic complications and HC percentile were independently associated 

with Memory scale score (r2= 0.36, p< 0.05)

6) HC’s percentile were associated with higher scores in the 4 scales of 

McCarthy’s test and in the GCI . (p<0.05)

In Cross sectional component of the study:

Predictor evaluation for CNS outcome:

1) VLBW children with normal IQ, score significantly lower than the Middle class 

group on many cognitive tasks, and may demonstrate more learning disabilities 

than Middle class children

2) VLBW and Low Class children had significantly lower score in all scales of 

McCarthy’s test , as compared to Middle Class children. (p<0.01)

3) VLBW had no different scores from Low class children.

4) Evaluation of the change of scores with age revealed that from age 3-7 yrs, 

VLBW advanced significantly less than Middle class children in Word 

Knowledge, Conceptual grouping and Numerical Memory backwards.

5) The gap between the scores of the 2 groups increased with age.

1) There was no matching, except for 

the age between VLBW and MC, LC 

children. Thus, there was no control 

for possible confounders, 

2) Selection bias might exists: As only 

those that had completed the test 

were analyzed. (Only 58% of VLBW 

children had completed the test) 

3) Selection bias also might exist as no 

information is given in the selection 

process of the 103 VLBW infants that 

had participated in the original study

1) No data on the absolute 

size of the association 

between predictors and 

outcomes were given.

2) Statistically significant 

correlation does not 

always mean a clinically 

significant association.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Whitaker

1996

97040639

MR higher in LBW<2kg (5%) than in general pop distribution (2.5%)

OR for MR vs Normal Intelligence: 

PVL/VE OR 65.83 (19.1-227.4)

Isolated GMH/IVH OR 4.64(1.2-18.6)

Verbal reasoning (Stanford-Binet area score) p<0.05

 PVL/VE: 98.9 (10.8)

 GMH/IVH 102.9 (10.5)

No abnormality 104.3 (10.9)

Visual perception organization

All abstract visual reasoning, visual-motor integration, and visual-perceptual stills 

were significantly (p<0.01 or p<0.005) were significantly lower for children who 

had PVL/VE compared to those with isolated GMH/IVH or No abnormality. 

50% of MR attributable to PVL/VE independent of other factors.

(None) Study was government and 

privately funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Blitz

1997

97154301

Developmental outcome:

The mean MDI, PID, CLAMS Total, Expressive, and Receptive scores were 99.7 

(19.8), 88.9 (19.8), 94.9 (23.0), 90.8 (26.2), and 99.7 (21.3), respectively.

MDI < 70 9%

PDI < 70 18%

Language delay (>1 SD below the mean) 34%

Significant language delay (>2 SD below the mean)12%

Multiple regression analysis showed BW and surfactant did not relate to 

developmental outcome. BPD, PVL and IVH significantly increased the risk of 

impairment. PVL, BPD, seizures and hydrocephalus account for 29.7% of the 

variance on the MDI scores (F=10.05, p<. 001). PVL, IVH, and BPD accounted 

for 23 % of the variance on the PDI scores (F=9.6, p < .001). For the total 

CLAMS score, 11% of the variance was accounted for by PVL and BPD (F= 7.1, 

p < .002)

Neurologic outcome: 

Multiple regression analysis showed low BW was not associated with neurological 

impairment. On the contrary, BPD and PVL significantly increased the risk 

(14.8% if variance; F=8.4, p<. 001). No other individual variables reach the 

significance level.

CP: present 24 %, suspect 27%, No CP 49%

Audiology:

Hearing loss 16%. None of the children were profoundly hearing-impaired.

Visual problem 18%. None were clinically blind

36% declined or did not appear (possible 

selection bias).

Language assessment at 2 years is too 

early to determine more subtle 

language delays.

No control group.

No data on funding source

Cheung

1997

97310950

Of the 21 preterms with IVH treated with rescue HFO, 8 (38%) has 

neurodevelopmental disabilities.

Of the 8 preterms with grade III or IV IVH treated with rescue HFO, 6 (75%) has 

neurodevelopmental disabilities.

The title is “High Frequency Oscillatory 

Ventilation” but the authors state that a 

high frequency flow interrupt ventilator 

is used in their nursery. These distinct 

modes of ventilation should not be 

confused

60% mortality among cohort meeting 

inclusion criteria 

Time of follow-up not well standardized

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Ekert

1997

97251211

Association between outcome (CP and/or developmental delay) and 

perinatal/neonatal variables:

Multiple logistic regression analysis showed that only PVL was associated with 

abnormal outcome (PLV: p=0.0001)

(None) Study was government 

funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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180

Author, Year Associations found Potential Biases Comments

Gerner

1997

97329414

Predictors evaluation for CNS outcome:

1) Healthy preterms did not differ significantly in psychodevelopmental outcome 

2) Prematurity was not associated with the sum score in the Griffith’s test

3) Prematurity was associated only with lower score Hand-Eye coordination scale

4) The predictors associated with poor psychodevelopmental outcome in preterms 

were (univariate analysis):

General predictors: Low GA: Pearson correlation coefficient r= 0.19 (171 pts) (p< 

0.05); Low BW: Pearson correlation coefficient r= 0.25 (171 pts) (p< 0.001); 

Intraventricular hemorrhage (IVH) + ventricular dilatation: Pearson correlation 

coefficient r= -0.27 (p< 0.001)

CNS predictors: Periventricular Cystic leukomalacia, (PVL) r= -0.24 (p< 0.01); B1-3 + 

W1-4 U/S findings, r= -0.27 (p< 0.001)

Cardiovascular predictors: PDA (n=72 pts), r= -0.32 (p< 0.001)

Pulmonary predictors: Prolonged ventilatory therapy (n-94 pts), r= -0.39 (p< 0.001); 

CLD: (n=56 pts), r= -0.26 (p< 0.001)

5) Although the screening indicated that several risk factors were associated with 

adverse neurodevelopmental outcome- in the multiple regression model the 

contribution of individual variables was very low (less than 20%). 80% of the 

outcome variance still remained unexplained. 

6) Only predictors independently associated with total sum score in Griffith’s test 

were (multivariate analysis): combination contributed to outcome variance by 21%: 

Pulmonary predictors: Duration of ventilatory tx (r 2=16%) and CNS: PVL (r2=5%)

7) Predictors independently associated with scores of individual subscales:

Locomotor subscale : combination contributed to outcome variance by 14%

• Duration of ventilatory tx (r2=9%), PVL (r2=5%)

Personal-Social subscale: combination contributed to outcome variance by 17%

• BW (r2=10%), PVL (r2=7%)

Hearing and speech subscale:

• Duration of ventilatory tx (r2=13%)

Hand and eye coordination subscale: combination contributed to outcome variance 

by 15%

• PDA requiring surgical ligation (r2=11%),

• Hemorrhage plus White matter lesions (r2=4%) 

Performance subscale: combination contributed to outcome variance by 18%

• Duration of Ventilatory tx (r2=12%) and White matter lesions (r2=6%)

1) In the comparative components 

(Group A vs C and Group B vs A), 

there was no control for possible 

confounders, as not appropriate 

matching was done between these 

compared groups 

2) Cannot exclude diagnosis bias as no 

information is given about blinding of 

personnel performing the 

neurodevelopmental assessment on 

the infants’ risk factors

3) Two many predictors investigated 

(28) for the total number of patients in 

the VLBW group (cannot exclude 

false associations found in the 

regression analysis)

4) Cannot exclude false associations 

due to chance, as multiple subgroup 

analyses were done (subclasses of 

Griffith’s test)

5) The subclasses of Griffith’s test have 

limited specificity, thus limited 

differentiating capacity at 10 months 

of age and especially for infants with 

neonatal complications as 

performance in one scale requires 

skills assessed in another scale.

Supported by nongovernmental Foundations.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Koller

1997

97193708

Cognitive Development:

Birth weight:

Gestational age:

Neonatal health index:

Neurological status @ 1 yr:

Male gender:

Maternal education:

 

P <0.001

P<0.001

P<0.01

P <0.001

P <0.005

P<0.005

Selection bias-does not include all VLBW 

infants- only those for whom all followup data are available--how are these 

different from the ones who did not 

show for follow-up?

Study was government 

funded

Murphy

1997

97192793

Apgar score <3 at 5minutes - 5.3% cerebral palsy

Patent ductus arteriousus - 2.0% cerebral palsy

Hypotension - 2.2% cerebral palsy

Transfusion - 3.2% cerebral palsy

Prolonged ventilation - 2.7% cerebral palsy

Pneumothorax - 3.4% cerebral palsy

Sepsis - 2.8 % cerebral palsy

Total parenteral nutrition – 3.0% cerebral palsy

Hyponatremia - 6.8% cerebral palsy

Chorioamnionitis and neonatal sepsis - 7.1% cerebral palsy

Any maternal infection and neonatal sepsis - 4.2% cerebral palsy

Seizure - 10.0% cerebral palsy

Parenchymal damage - 32.0% cerebral palsy

Ascertainment of CP was from registry--

not examined as part of study

Absence of CP was not obtained by exam 

as part of study

Multiply definitions of predictor variables 

not reported

Retrospective acquirement of risk factorsno standard definitions 

Study was privately funded

Schendel

1997

98033417

Even apparently well VLBW with no overt physical impairment are consistently at 

higher risk for all measures of DELAY than MLBW or NBW infants. VLBW have 

DELAY in all areas of function with greatest risk for delay in gross motor domain. 

“Abnormal” – VLBW 10.9%, NBW 2.9%, p = 0.001

Personal-Social =1 delays: VLBW 7.1%, NBW 2.2%, p = 0.001

Language = 1delays: VLBW 8.8%, NBW 4%, p = 0.01

Fine motor-adaptive = 1 delays: VLBW 7.9%, NBW 2.2%, p = 0.001

Gross motor =1 delays: VLBW 10.7%, NBW 1.8%, p = 0.001

The people administering the Denver test 

were not blinded and were aware of 

degree of prematurity and this is a major 

source of bias. 

The adjusted age at f/u had very wide range 

9-34 months

Study was government 

funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Thompson

1997

97268338

Neurobiologic risk score (NBRS) investigated to determine predictive value for 

performance on McCarthy Scales at 4 years age. N = 55.

McCarthy Scale Mean (SD) Range

General cognitive index 89 (20) 49-126

Verbal 44 (10) 21-65

Perceptual-Performance 44 (12) 21-69

Quantitative 46 (12) 22-67

Memory 46(10) 21-67

Motor 42 (12) 20-70

Also: The NBRS was not found to be predictive of the McCarthy General Cognitive 

Index; in multiple regression analysis only birth weight, gestational age and gender 

were significantly related to the McCarthy scores.

One institution

No control group

Combined high NBRS and intermediate 

NRS patients into one group

Study was government 

funded

Victorian Infant 

Collaborative 

study Group 

1997

98026322

*There are a 

series of 

Victorian 

articles in LBWALL.

*This study will 

be combined in 

LBW-ALL table

Birth weight < 1000g; assessed at 2 years corrected age.

Cohort n DQ < -3 SD DQ –3 to –2 SD DQ –2 to –1 SD DQ> -1 SD

‘91-’92 237 5.9% 6.3% 13.9% 73.4%

‘85-’87 211 6.2% 4.3% 14.2% 75.4%

Cohort n Mild CP Mod. CP Severe CP Any CP Blindness Deaf

‘91-’92 237 3.8% 1.7% 3.8% 9.3% 2.1% 0.8%

‘85-’87 211 NS NS NS 6.6% 4.3% 0.5%

Cohort No disability Mild Disability Moderate disability Severe disability

‘91-92 71.3% 14.8% 7.2% 6.8%

n = 237

‘85-’87 71.6% 15.6% 6.2% 6.6%

n = 211

Incomplete reporting of demographic data, 

methods and results.

Study was government 

funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Battin

1998

99002694

CNS outcomes:

Major impairment was present in 36% of infants born at 23-25 wks GA, during 1991-

1993 (N=44)

1) Cerebral palsy 9/44 (20%)

2) Low MDI 8/44 (18%)

Ophthalmology outcome:

1) Blind 4/44 (9%)

Audiology outcome:

1) Deaf 4/44 (9%)

Combined outcome:

1) Overall impaired 16/44 (36%)

2) Multiple handicaps 6/16 (38%)

Analysis of only 24-25 wks GA infants (N=43):

Major handicaps: 15/44 (34%)

The percentage of infants with major impairments and/ or multiple handicaps, for the 

23-25 wks GA group, was the same in 1991-1993 and 1983-1989 periods 

(However, no data on the number of infants from this cohort that were actually 

followed up at 18 mo of age)

1) During 1991-93 period there is no 

concurrent control group for the 

comparative assessment of 

neurodevelopmental outcome 

2) Group of infants of 23-25 wks GA, 

born during 1991-1993, was not 

matched to the historical control 

group born during 1983-1989. 

Possibility of confounders cannot be 

excluded.

3) No data were given on the number of 

infants in the historical control group 

that had f/up at 18 mo of age.

No report on source of 

funding

Bos

1998

98218970

The developmental course of the quality of general movements significantly 

correlated only with the duration of parieto-occipital echodensities (r=0.482, 

p<.02), while the duration of PVE frontal was not associated with the 

developmental outcome (r=0.241, NS)

No power estimates for defecting modest 

effects

No data on funding source

CherkesJulkowski

1998

98262696

No disorder identified: PT 25%, FT 75 %

Attention deficit disorder: PT 17.8%, FT 7.1%

Learning disability: PT 17.8%, FT 14.2%

Language impairment: PT 3.5%, FT 0%

Neurological impairment: PT 7.1%, FT 0%

School concerns: PT 28.5%, FT 21.4%

This group of only mildly preterm, seemingly healthy PT infants have significantly 

more disability than expected χ2(5)=62.577, p= .0001

Evaluators were people in the community 

and social system so that there may be 

significant variations in evaluations.

Sample size too small for statistical 

analysis.

No data on funding source

This study is more a study of 

predictability of the 

attention deployment test 

in identifying minimal 

brain dysfunction at 13 

and 15 mos, rather than 

a study of predictors of 

long-term outcome.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Emsley

1998

98238139

(CNS+ All)

Disability in 1st cohort 1984-1989 of 23-25 wks: 

Any disability: 38%

CP: 21%

Data on 2nd cohort 1990-1994 of 23-25 wks:

CP: 18%

Blindness due to ROP: 18%, Myopia: 15%, Squint: 13%

Developmental delay (DQ < 70): 15%

Deafness: 3 %

Epileptic seizures: 0

Speech delay: 15%

Clumsy, learning difficulties, behavioral disorder: 3%

Disability: Mild 38%, Moderate 13%, Severe 18%

Infants with disability have lower GA, worse CRIB scores and significant cranial 

ultrasound findings.

In comparing the 2 cohorts, increased survival is associated with increased disability 

but mostly mild disability. No significant change in %CP. High CRIB score assoc. 

with disability.

Sample numbers small.

Does not state when the assessments 

were carried out and whether the 

evaluators were blinded to the GA and 

history of the infants.

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Pasman

1998

98196839

Assessment at 5 to 7 years of age. Full-term (FT) controls, neurologically normal low 

risk preterm (normal LR) infants, neurologically abnormal low risk preterm infants 

(abnormal LR), and high-risk preterm infants (HR). Risk classification was based 

on the neonatal neurologic inventory.

Group n Total IQ Verbal IQ Performance IQ

FT: 18 114 (17) 113 (18) 111 (14)

Normal LR

w/ GA 25-30

weeks: 15 108 (15) 107 (16) 106 (11)

Normal LR

w/ GA 31-34

weeks : 21 113 (15) 114 (18) 107 (10)

Abnormal LR

w/GA 25-34

weeks: 8 99 (12) 104 (12) 93 (14)

HR w/ GA

25-34 

weeks: 9 78 (20) 79 (19) 81 (19)

HR infants excluded from statistical analysis. Term infants vs. all low risk infants: 

Total IQ, no significant difference. Verbal IQ, no significant difference. 

Performance IQ P = 0.02.

Year of birth not given

Small numbers in subgroups (e.g., 8,9)

Incomplete reporting of results

Study was privately funded

Rogers

1998

98438124

There are no association between GA, BW, BPD Length of stay with growth 

failure P>0.05

Growth failure with CPVL 16/41

CP with CPVL 39/41

(None) Study was privately funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Spinillo

1998

98237382

Spinillo, 1997

98021316 & 

97277958

*have some 

overlapped 

sample with 

spinillo, 1994

CP prevalence 12.3% in 24-33 wk preemies

Minor neurologic problems (abnormal tone or reflex but functionally normal) or 

borderline (71-84) Bayley MDI : 16.1%

Factors assoc with increased CP:

PROM > 48 hrs OR 2.98 (1.12-7.96 CI 95th)

Meconium- stained amniotic fluid OR 4.36 (1.69-11.2)

Male sex OR 3.01 (1.32-6.71)

Decreasing gestation: CP 22.2% in 24-25 wks, 23.1% in 26-27 wks, 14.5% in 28-29 

%, 8.3% in 30-31 wks, 9.3% in 32-33 wk infants.

 CP

Meconium- stained fluid (N=17) 41% (7/17%)

Clear fluid (N=246) 13.4% (33/246) P=0.06

CNS outcome:

1) The incidence of cerebral palsy in this cohort of preterm infants was : 40/345: 

(12%), but this refer only to those survived: 391/450 (87%) and to those that 

completed the 2 yr f/up: 345/450 (77%)

Predictors evaluation for Survival at 2 yrs:

1) Survival at 2 yrs was associated with higher GA (p<0.0001), higher BW, 

(p<0.0001) And History of fewer previous abortions.

Predictors evaluation of CNS outcomes:

(In a univariate analysis) From the maternal and neonatal characteristics and the 

pregnancy complication/predictors, those found to be associated with CP were

 Odds Ratio (95% CI)

1) Higher Maternal age 1.07 (1.0-1.15)

2) Lower GA 0.87 (0.76-0.99)

3) Lower BW 0.94 (0.87-1.00)

4) male gender 2.65 (1.28-5.50)

5) More Previous voluntary abortion (25% vs 7%) 4.51 (1.94-10.5)

6) Preeclampsia (5% vs 19%) 0.22 (0.05-0.94)

In a multivariate regression model (including maternal age, BW Standard deviation 

score, GA and preeclampsia) only preeclampsia was independently associated with 

the risk of cerebral palsy: OR: 0.16 (0.04-0.74) The authors conclude a protective 

effect of preeclampsia against CP, in the absence of Mg sulfate utilization

1) Major confounding postnatal factors 

such as BPD, IVH, and PVL, which 

may be associated with CP, were not 

controlled for.

2) We cannot exclude selection bias. 

The associations found were relevant 

to the group of surviving infants with 

cerebral palsy who also had f/up at 2 

yrs. A large number of infants were 

excluded from the analysis: 46 infants 

that were lost to f/up and 59 that had 

died.

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Tin

1998

99046171

Result of 1983 cohort at 6 years:

Severe disability:

Sample 1: 4.4%, Sample 2 : 2.1%, Sample 3: 50%

IQ < 75 without sensorimotor disability:

Sample 1 : 4.9%, Sample 2 : 0, Sample 3 : 25%

Severe sensorimotor disability:

Sample 1 : 5.9%, Sample 2 : 21.4%, Sample 3 : 41.7%

Severe sensorimotor or cognitive disability:

Sample 1 : 8.4% (5 - 13.1%, 95% CI)

Sample 2 : 21.4% ( 4.7-50.8%)

Sample 3: 41.7% (15.2-72.3%)

Result of 1990 cohort at 2 years:

Severe disability:

Sample 1: 7.9%, Sample 2: 15.4%, Sample 3: 57.1%

High f/u rate is critical because it may underestimate incidence of the outcome.

No definitions of outcome, incomplete 

methods description, wrong reference

Study was privately funded

Burguet

1999

99126269

In univariate analysis:

The prevalence of CP in LBW preemies with RDS (N=66) was 20%, compared to 9% 

in preemies without RDS (N=101). The difference was significant (p=0.04)

Incidence of CP 7% in no PROM, 20% in PROM < 48 hrs, 30% in PROM 48h to 7 

days, 11% in PROM >7 days, χ2 trend: p= .004

In multivariate analysis:

Controlling for environmental and maternal factors, the risk of CP was about 3 times 

in preemies with RDS, than preemies without RDS (adjusted OR 2.8, 95% CI 1.1-

7.1). “The introduction of surfactant in the second stage of our study was not 

shown to have any impact on the incidence of CP among the children of this 

cohort.”

PROM = 48 hours (OR 4.3, 95% CI 1.6-11.8), p= .005

Monochorionic twin placentation (OR 6.0, 1.7-21.3), p = .007

RDS (OR 2.8, 1.1-7.1)

PROM +, PTL + (OR 7.5, 2.2-26.2), p= .001

8% BW>2000g

Nonstandard definition of CP

Suspected infant (mild hypotonia or delay 

to normal acquisition) were included in 

the normal group

Evaluations done by community physician 

of parents’ choice so, no 

standardization, and unblinded

Used uncorrected age

No data on funding source

Severe disability is common 

among extremely preterm 

infants of GA 22-25 wk
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Cooke

1999

99257637

CP prevalences:

1982-5 (411) 45 10.9%

1986-9 (387) 42 10.9%

1990-3 (398) 29 7.3% P=0.046

ND No data on funding source

Cooke

1999

99380719

MRI abnormality: VLBW group : 37/87 (42.5%)

 FT Control group: 0/8 (0%)

Abnormal MRI not associated with ADHA, IQ, or motor coordination scores.

No statistical/ data analysis section

Few controls (n=8)

Disagree and interpretation (i.e. 

conclusion)

Study was privately funded

Overall sample of LBW<2 kg 

had increased rate of MR 

compared to gen pop. 

PVL/VE was 

independently related to 

MR (OR 66) and to 

borderline IQ .

Among children with nl IQ, 

those with PVL/VE vs. no 

PVL/VE performed more 

poorly on visualperceptual organization. 

White matter injury is 

associated with adverse 

cognitive and visual 

perceptual disability.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Finer

1999

99436635

IVH: Sample 1: 70%, Sample 2 : 10%, p = .015.

Normal neuromotor outcome: 

Sample 1: 70 %, Sample 2: 70%.

Abnormal neuromotor outcome:

Sample 1 : 20%, Sample 2: 0

Normal developmental outcome:

Sample 1: 80%, Sample 2: 60%

Abnormal developmental outcome:

Sample 1: 20%, Sample 2: 20%

Normal neurodevelopmetal outcome: 

Sample 1: 70%, Sample 2 60%

No difference in developmental scores of following domains: composite mental, 

composite motor, adaptive, language, personal/social, fine motor, gross motor.

They conclude that intact survival is possible for infants weighting <750 g who 

received CPR in the DR.

Very small sample size with 28% lost to 

f/u.

Results are from a single center, difficult to 

generalize the results.

Exact criteria for chest compressions and 

epinephrine not specified

 No information about the evaluators or 

whether they were blinded.

Infants evaluated at wide range of ages 

where infants seen later may have 

done better or worse

No data on funding source

Missing information

Retrospective collection of 

breast feeding data
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

Part III

190

Author, Year Associations found Potential Biases Comments

Futagi

1999

99450356

Predictor evaluation for CNS outcome:

1) Birth in surfactant era was not associated with neurodevelopmental outcome 

(good or poor prognosis) for infants of less than 1000 gms

(Pre-surfactant era[107] vs surfactant era [169]

• Neurodevelopmental outcome: 71/107 (66%) vs 100/169 (59%)

• Cerebral palsy: 13/107 (12%) vs 18/169 (11%)

• Mental retardation: 11/107 (10%) vs 16/169 (9.5%)

• Borderline intelligence: 11/107 (10%) vs 35/169 (21%)

2) Birth in surfactant era was associated with higher incidence of borderline 

intelligence (20.6% in surfactant era vs 10.3% in pre-surfactant era)

3) Birth in surfactant era :was not associated with DQ or IQ scores in the 

individual neurodevelopmental categories (normal neurodevelopmentally, 

cerebral palsy, mental retardation, borderline intelligence)

• Normal: 99.7 vs 100.1

• Cerebral palsy: 57.5 vs 62.5

• Mental retardation: 62.4 vs 55.1

• Borderline intelligence: 77.1 vs 77.6

4) Birth in surfactant era: was not associated with the distribution of subtypes of 

cerebral palsy.(spastic diplegia, spastic hemiplegia, spastic quadriplegia)

5) Birth in surfactant era was not associated with severity of cerebral 

palsy.(minimal, mild, moderate, severe)

1) Assessed the association between 

birth in the surfactant era and 

neurodevelopmental outcome and not 

of surfactant administration itself 

problems of ecological fallacy in that 

type of studies)

2) It is unknown if the results of this 

study could be generalized in other 

NICU populations where more than 

50% of infants receive surfactant

3) The possibility of a masked 

association cannot be excluded due 

to existence of possible cofounders in 

the 2 groups.

4) Many subgroup exploratory analyses 

were performed that were not 

described in the Method section

Source of funding not 

reported

Kim

1999

99416608

Infants with BW < 2000g. Assessed at 12 months age.

Risk Factor CP Devel. Delay Both CP+DD Neither

Neonatal sepsis 4/9* 1/8 5/17* 4/62

BPD 4/9* 3/8* 7/17* 9/62

IVH > grade 2 4/9* 1/8 5/17* 6/62

Days on ventilator 18.1 (25.1)* 11.3 (8.7)* 12.2 (19.6)* 3.3 (3.3)

Ventriculomegaly 5/9* 0 5/17 8/62

P < 0.05 vs. neither CP/ DD

Multivariate logistic regression, the following were not significant risk factors:

Apgar score at 5 minutes, BPD, IVH, PDA, duration of mechanical ventilation, Sepsis

Study group as a whole is not describedonly those infants developing CP

CP infants are compared to “controls”, but 

no description of how the control group 

was recruited or in what ways they were 

similar to or different from the study 

group. Concurrent? Historical? 

Matched for gestational age or birth 

weight? We are not told. Leaves open 

the possibility of massive 

bias/confounding.

In this cohort of preterm 

infants (BW 600-1250 

grams) <1%blind or deaf; 

1%- 3% had seizure 

disorder; and 

7% had CP.

Full scale IQ <80 occurred in 

28% of total sample (BW 

600-1250 grams) at 54 

months follow-up
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Krageloh-Mann 

1999

99431017

 MRI normal (n=10)(%) MRI abnormal (n=19)(%) P

Preeclampsia 50 11 0.03

Placental abruption 0 32 0.07

Mechanical 

Ventilation>7d 0 42 0.03

ICH grades III + III 0 16 0.53

DO2 <ml O2/100g/min 12.5% 63% 0.03

1) Selection of preterm subject bias

2) No MRI of controls

3) Controls, “From Copewnagen suburb”-

well matched with regard to SES, 

health-care measures, etc.?

4) Design is bizarre, complicated, and 

difficult to interpret.

5) Statistical analysis is not well described. 

It appears that they did not correct for 

multiple comparisons, which renders 

their positive findings suspect. They did 

not do a power analysis, which renders 

their negative findings suspect.

6) Much of the paper analyzes association 

between outcomes evident at 5-7 yrs 

f/u, for ex., association between 

abnormal MRI at 5 yr. And IQ at 5 yr.; 

this does not examine association 

between neonatal MRI+ IQ at 5 yr.

No data on funding source

Salokorpi

1999

99353226

Assessed selected risk factor in relation to cerebral palsy (CP) diagnosed at two 

years age.

CP present, n = 27; CP absent, n = 116.

Risk Factor Odds ratio (CI)

Grade 3 or four IVH on head sonogram 7.94 (2.75, 22.95)

Hypotension 1.26 (0.47, 3.35)

Hypocarbia 2.20 (0.77, 6.31)

Also found no association between average duration of ventilation and CP.

Study was privately funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Shepherd

1999

99165413

CP 9% in this group of preemies who were followed-up at least once after term age 

(N=53)

Of the 5 infants with CP, 3 had abnormal VEP.

Of those without CP, 4 had abnormal VEP.

Sensitivity of VEP before term for CP = 60%.

Specificity is 92%.

Positive predictive value of abnormal VEP for CP is 43%.

Negative predictive value is 96%.

CP not defined.

CP evaluated by generalists with no 

uniform definition.

Incomplete Methods and large number of 

missing information.

No data on funding source

Stathis

1999

99325758

Head circumference category at 8 months corrected age related to learning delay 

greater than one year when assessed at 6 years:

HC Category n % with delay

< 3rd percentile 23 61% (39, 80)

3

rd to 10th 13 77% (46, 95) P = 0.004

> 10th 40 30% (17, 47)

Head circumference category at 12 months CA did predict McCarthy General 

Cognitive index at six years, but head circumference category at 24 months CA did 

not significantly predict McCarthy CGI at 6 years.

Head circumference and head growth velocity was not shown to have a relationship 

with attention deficit hyperactivity disorder.

Head circumference category < 10th vs. greater than 10th percentile at four and 8 

months corrected age were significantly associated with McCarthy CGI at 6 years 

age

One nursery

High rate of patients lost to follow-up 

(30%)

Small numbers: limited ability to detect 

small differences; high chances of type 

2 error

Study was privately funded
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Vohr

1999

99332101

Normal Neurologic Examination: 75%

CP overall: 17% but 29% in 401-500 g babies

CP (quadriplegia): 6.4%

CP (left hemiplegia): 0.45%

CP (right hemiplegia): 0.91%

CP (diplegia): 8.2%

Seizure disorder: 5%

Hydrocephalus with shunt: 4%

Visual impairment (any): 9%

Unilateral blindness: 1% overall but 7 % in 401-500g and 801-900g babies

Bilateral blindness: 2 % overall but 14 % in 401-500 g babies

Legally blind in one or both eyes: 3%

Hearing impairment: overall 11 %

Wearing hearing aids: overall 3 %

Sits unsupported: 93%

Sits well alone: 86%

Walks: 83%, Walks fluently: 70%

Independently feeds self: 80%

Bayley MDI < 85 : 66%, Bayley MDI <70: 37%

Bayley PDI <85: 57%, Bayley PDI <70: 29%

Chronic lung disease, grades 3-4 IVH/PVL, steroids for CLD, NEC, and male gender 

associated with increased risk for morbidity

Poor f/u rate of 78% and this may 

significantly underestimate outcome.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Agustines

2000

20279724

Predictors for CNS outcome:

Rates of developmental delay at 30 months of corrected age, were significant 

among extremely VLBW infants 500-750 g

Overall CNS outcomes in the 36 infants:

1) Normal MDI: 32%

2) Mild delay in MDI: 40%

3) Severe Delay in MDI: 28%

4) Combined mild and severe delay in MDI: 58%

5) Normal PDI: 42%

6) Mild delay in PDI: 16%

7) Severe delay in PDI: 42%

8) Combined mild and severe delay in PDI: 58%

 24 wks 25 wks 26-29

Stratified by GA: ( N=14) (N=14) (N=8)

1) Normal MDI: 11% 50% 33%

2) Mild delay in MDI: 55% 25% 50%

3) Severe Delay in MDI: 33% 25% 17%

4) Combined mild and severe delay in MDI: 88% 50% 67%

5) Normal PDI: 34% 50% 0%

6) Mild delay in PDI: 22% 0% 20%

7) Severe delay in PDI: 44% 50% 80%

8) Combined mild and severe delay in PDI: 68% 50% 100%

1) Long term f/up for only 57% (36/63

infants that had survived)

Those who had f/up had less morbidity 

than those lost to f/up (incidence of RDS 

was 47% vs 92% in lost to f/up group)

2) There was no control group to 

compare outcomes of extremely 

VLBW with VLBW infants.

3) Stratified analysis for outcome in 

different GA subgroups had very few 

patients in each subgroup, thus the 

confidence intervals are very wide.

4) This study was not designed to 

compare outcomes of SGA vs AGA 

infants in the group of 500-750g: post 

hoc comparisons (most of the infants 

in the 26-29 GA group were SGA)

Funding source not report
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Breslau

2000

20298367

1) Information from mothers and teachers on children’s behavior problems at age 

11 revealed that the effect of LBW on attention problems differed between urban and 

suburban settings.

2) LBW children had an excess of attention problems in the urban disadvantaged 

communities and not in the suburban middle class communities.

3) LBW infants in the urban setting had twice as high incidence of attention 

problems as more than twice as high in LBW than in NBW.

4) In Urban Setting LBW children had more than 2-fold severe attention problems 

than NBW children

5) In suburban setting there was no difference in severe attention problems 

between LBW and NBW children.

6) LBW children had externalizing problems both in the urban and suburban 

settings (this effect was mainly accounted for by maternal smoking in pregnancy)

7) No LBW effect was observed with respect to internalizing problems

8) Regardless of LBW status, maternal smoking during pregnancy was associated 

with an increase in externalizing problems

9) No association was found between maternal smoking during pregnancy and 

internalizing or attention problems

OVERALL SCORES Attention scores Internalizing Externalizing

MOTHER’S SCORES 

Urban LBW (n=217) 58.8 52.7 52.2

NBW (n=164) 55.8 51.5 50.4

Suburban LBW (n=194) 55.1 50.4 48.4

NBW (n=142) 53.8 48.6 46.3

TEACHER’S SCORES

Urban LBW (n=186) 56.9 50.3 53.9

NBW (n=151) 54.7 48.8 48.5

Suburban LBW (n=180) 53.7 49.0 48.5

NBW (n=135) 54.0 48.7 48.3

1) According to mother’s ratings: For attention, externalizing and internalizing 

problems: LBW scored higher (had more problems) than NBW children.

2) According to teacher’s rating: Only for externalizing and internalizing problems: 

LBW scored slightly higher than NBW.

3) Urban children received higher scores than suburban children on all 3 domains, 

according to both mother'’ and teacher’s ratings

1) Recollection bias: The Hx of maternal 

smoking during pregnancy was 

elicited when the child was 6 yrs old. 

This bias would have resulted in 

underestimation of the confounding 

effect of smoking during pregnancy.

2) Diagnosis bias: Although there was a 

correspondence of the findings of 

teachers’ reports (who were blind to 

the LBW status of children) and the 

mothers’ reports, mothers’ reports 

could have been biased (worse 

scores from mothers of LBW infants)

Supported by grant from

National Institute of Mental

Health and National Institute

of Drug Abuse
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Buhrer

2000

20280896

Major Neurodevelopmental impairment 22%

Independent predictors of neurodevelopmental impairment (logistic regression):

CRIB score: R =0.216, ß =0.2233, SE =0.051

Maximum FIO2: R = 0.1201, ß = 1.23, SE 0.4553

Griffith’s general quotient = 85 in this population: 21.6%...

A CRIB score of 6 or more has a sensitivity and specificity 27.6% and 91.3% for 

predicting neurologic impairment.

No information as to whether evaluators 

were blinded 

No data on funding source

Grether

2000

20448692

Receipt of MgSO4 treatment: CP Control

 (N=170) (N=288)

 98 (58%) 178 (62%) 

 OR: 0.84 95% CI: 0.56-1.26 

Total duration (HR): 51 ± 78 53 ± 72 NS

(mean SD)

Retrospective case control

CP defined from chart review

No data on funding source

Katz-Salamon 

2000

20332284

Infants were assessed at 10 months corrected age. Authors used Griffith’s 

Development Scale and the Movement Assessment Index (MAI, a surrogate for 

evolving CP) to assess children without high-grade IVH or PVL to determine 

whether chronic lung disease (CLD) itself was a risk factor for adverse outcomes. 

CLD was associated with significantly lower performance scores on each Griffith’s 

subscale and with significantly higher MAI scores predicting a higher risk of CP. 

Even in the absence of high-grade IVH or PVL, CLD has a deleterious effect on 

early development.

One institution; small number of 

infants/group

Oldest evaluation <10 months of age

Used a surrogate measure, the MAI for CP

Study was privately funded

Incomplete result data.
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Marlow

2000

20150342

Pulmonary and Other predictors evaluation for Audiology outcome.

Children with sensorineural hearing loss [15] as compared to control group[30] had 

longer periods of:

1) Intubation, (14 ds vs 2 ds)

2) Ventilation (34 ds vs 6 ds)

3) Oxygen therapy (57 ds vs 10 ds) 

4) Acidosis (12 ds vs 0.5 ds), and 

5) More treatments with dopamine (33% vs 7%)or

6) Furosemide (87% vs 53%)

7) Neither P/T of aminoglycosides 

8) nor duration of jaundice 

9) or level of bilirubin varied between the 2 groups. 

SNHL was more likely when :

1) netilmicin use coexisted with the peak of bilirubin (87% vs 14%)_

2) when acidosis occurred when bilirubin was over 200 ?mol/l, (31% vs 4%)

3) when furosemide was used in the face of high creatinine levels (64% vs 27%)

4) when furosemide was used with netilmicin (67% vs 37%)

CNS outcome at 12 mo:

At 12 months of age evidence of cerebral palsy was present in 7/15 (47%) of children 

with SNHL vs 2/30 (7%) of children without SNHL.(p=0.022)

1) Very small sample size (cases with 

SNHL only 15)

2) Analyzed too many predictors and 

combination thereof, for very few 

outcomes. Very wide confidence 

intervals; and even those predictors 

found to be associated with the 

SNHL this may have been due to 

chance.

3) The association found between 

SNHL and cerebral palsy was not

based on an adjusted analyses for 

possible confounders; 

4) The 2 groups were different in many 

factors that were associated with both 

SNHL and CP

Did not report source of 

funding

Palta

2000

20096107

(CNS+Eye)

CP 12.6%.

Independent predictors of CP and functional outcome:

IVH OR 2.3 per grade (95 % CI 1.8-2.8)

BPD OR 2.3 (95% CI 1.2-4.6)

Percent of the children scoring at least 2 SDs below the normative means for the 

following functional outcomes:

Self-care 11.7%

Mobility 29.5%

Social function 10.7%

(None) Study was government 

funded

No ophthalmology results 

were reported
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Torrioli

2000

20275419

(CNS+Eye)

Movement ABC:

Study: 15.58+7.96

Control: 7.08+4.61 P<0.001

Bell test rapidity:

Study: 19.08+7.92

Control: 22.02 + 7.36 P<0.05

Bell test rapidity:

Study: 57.34+19.67

Control: 69.08 + 18.10 P<0.05

Visual function (stereopsis %):

Study: 41.7

Control: 66.7 P<0.05

Did not give the size of the control group.

Baseline demographic data not presented.

Study was privately funded

Valkama

2000

20233239

51 BW < 1500g GA <34 wks: 

Severe CP: 5; Mod CP: 3; mild CP: 1

14 SGA: 2/14 CP (14%)

16 EVLBW<1000g: 6/16 CP (0.34)

<29 wks : 12 CP

Abnormal MRI 11/19

Delayed myelination 3/8

(None) Study was privately funded

Vohr

2000

20295211

Studied effect of early IVH at 5 to 11 hours of age on IQ distribution and presence of 

cerebral palsy (CP). Assessed at 36 months CA.

 Early IVH present Early IVH absent P value

 N 29 249

Binet IQ 78.7 (25) 87.5 (20) 0.09

Binet IQ < 70 38% 19% 0.03

PPVT-R 76.6 (28) 86.0 (21) 0.15

CP at 36 months 25% 8% 0.01

Later IVH had effect on Binet IQ similar to early IVH.

IVH rates seems high No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Dammann

2001

21334215

CP prevalence:

 BW < 1500g & AGA: 16%

 BW < 1500g & SGA: 4% P=0.005

In this skewed population, 16 % of AGA infants and 4 % of SGA infants had CP at 6 

years. 

(None) Study was privately funded

Gaillard

2001

21221175

Predictors for Neurodevelopmental outcome:

1) Shorter length of ventilation (beyond 27(but not 50) postnatal days) was 

associated with better neurodevelopmental outcome :

 59% (33/56) neurodevelopmentally normal or only mildly disabled survivors vs 

25% (7/28) with more prolonged ventilation( > 49 ds )

Ventilated beyond 27 (but not 50)ds vs Ventilated beyond 49 ds

Total: 56 vs 28

Survived: 48/56 (86%) vs 14/28 (50%

Normal neurodevelopmentally: 26/48 (54%) vs 5/14 (36%)

Mild disability: 7/48 (15%) vs 2/14 (14%)

Moderate disability: 11/48 (23%) vs 4/14 (29%)

Severe disability: 4/48 (8%) 3/14 (21%)

2) Number of days “off”” ventilator was not associated with the 

neurodevelopmental outcome at 3 yrs neither in the groups of 27-49 postnatal 

ds ventilation nor in the group of >49ds ventilation

Ventilated beyond 27 (but not 50)ds and O ds “off” ventilator vs 1-7 ds “off” ventilator 

vs > 7 ds off ventilator

Total: 18 vs 17 vs 21

Survived: 13 (72%) vs 15 (88%) vs 20 (95%)

Neurodevelopmentally normal: 8 (44%) vs 7 (41%) vs 11 (52%)

Mild disability: 2 (11%) vs 2 (12%) vs 3 (14%)

Moderate disability: 3 (17%) vs 4 (24%) vs 4 (19%)

Severe disability: 0 vs 2 (12%) vs 2 (10%)

(In the second component: comparison of the retrospective cohort with

the historical control)

3) Birth in a period where antenatal steroids and exogenous surfactant was more 

routinely used was associated with better neurodevelopmental outcome (69% 

vs 40% and 45% respectively in the 2 historical control cohorts) 

In First component:

retrospective cases control design:

1) the 2 groups were unmatched for 

possible confounders, thus cannot 

exclude false associations

2) Cannot exclude selection

bias as only 62 survivors were analyzed 

from the 84 initially included in the 2 

groups

In the Second component:

3) Problems of confounders due to 

historical control group could be 

even greater

Failed to report % of antenatal use in each 

group.

Demographic data included babies that 

died prior to neurologic evaluation, 

possible source of bias.

No information on comorbidities that may 

have led to prolonged intubation with no 

attempt to adjust for these

No data on funding source
Evidence Table 3. Studies Evaluating Association of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year Associations found Potential Biases Comments

Horwood

2001

20574647

Assessed influence of breastfeeding (BF) duration on outcome at 7-8 years age.

IQ scores before adjusting for covariates.

Group n Verbal IQ Performance IQ

Not BF 76 94.4 (18.4) 98.7 (19.6)

BF < 4 mo 99 97.2 (18.4) 101.4 (15.6)

BF 4-7 mo 46 101.7 (17.3) 101.1 (14.0)

BF > 8 mo 59 104.6 (14.7) 104.9 (15.3)

Adjustment for covariates of maternal education, two parent families, higher income 

families, non- smoking during pregnancy and non-Polynesian ethnicity did not 

change the hierarchy of results. Verbal IQ beta value = 0.12, P < 0.05 and 

performance IQ beta value 0.08 with P > 0.15

Retrospective collection of breast feeding 

data

17 children could not be tested because of 

sensorineural problems

No information about perinatal medical 

condition

Not clear if examiners were aware of

feeding history 

Study was government 

funded

Goal of study was to assess 

predictive value of NBRS 

(neurobiologic risk score) 

and neonatal neurologic 

inventory, NNI, with 

respect to long-term 

neurodevelopment 

outcome of preterms 

between 25-34 weeks.

Nadeau

2001

21163667

EP/ VLBW, n = 61 and controls, n = 44. 

 EP/ VLBW Control Significance

Normal neuromotor function 67% 97% NS

Abnormal neuromotor function 33% 3% 

McCarthy IQ [mean (SD)] 100.3 (19.1) 112.8 (16.2) P < 0.01

Behavioral ratings at 7 years age:

Peers rated EP/ VLBW’s as significantly more sensitive/ isolated than controls

Teachers rated EP/ VLBW’s as significantly more inattentive than controls

Parents rated EP/ VLBW’s as more hyperactive than controls

Significantly = P < 0.01

(None) No data on funding source

Data on neuromotor and 

intellectual functioning 

only collected once

Data on behavior collected 

once

Pierrat

2001

27221167

Overall, majority of premature infants with cystic PVL are not normal. Cystic-PVL 

(both Gr II and Gr III) is highly associated with CP. 29 of 30 infants with c-PVL + 

Ventriculomegaly at 40 wk PMA had CP. 

The following show differences in outcome based on whether the infant had cystic 

PVL (Grade II) or cystic PVL (Grade III):

 c-PVL (Gr II) c-PVL (Gr III) 

No motor sequelae 24% 3%

CP 76% 97%

Independent walking 22/29 3/26

(None) No data on funding source
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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201

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Als

1994

94358983

(CNS+ 

Pulmonary)

Location: US

Years of Birth: ND

Median GA (range), wk:

Experiment: 27.1±1.6

Control: 26.5±1.4

Median BW (range), g:

Experiment: 827±173

Control: : 862±145

Male: 

Experiment: 45%

Control: 61%

Race: Black

Experiment: 40%

Control: 17%

SES I, II/III/IV, and V:

Experiment: 45%, 20%, 35%

Control: 56%, 17%, 27%

Enrolled: 43

Evaluated: 38

Number of sites: 1

BW < 1250 g

GA < 30 weeks and more than 24 

weeks of estimated GA at birth

Mechanical ventilation starting 

within the first 3 hrs after birth 

and lasting longer than 24 hrs in 

the first 48 hrs

Alive at 48 hrs

Absence of chromosomal or other 

major genetic anomalies, 

congenital infections, and known 

fetal exposure to drugs of 

addiction

Singleton

At least one family member with 

some English-language facility

Telephone access

Living within the greater Boston 

area

ND Experiment: VLBW 

infants participated 

in individualized 

developmental care 

(20)

Controls: VLBW infants 

received standard 

care (18)

Randomized controlled 

trial 

(2 weeks and 9 months)
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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202

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Corbet

1995

95264244

Location; USA

Years of Birth: 1986-1989

Mean GA:

 Sample 1: 27 ± 2

 Sample 2: 27 ± 2

Mean BW:

 Sample 1: 934 ± 179

 Sample 2: 931 ± 191

Males:

 Sample 1: 50%

 Sample 2: 50%

Race:

 Sample 1: whites: 41%, blacks: 

37%, others: 22%

 Sample 2: whites: 46%, blacks: 

36%, others: 18%

Enrolled: 1046

Evaluated: 597

Number of sites: Multicenter

Born alive

Qualifying BW (not specified in this 

publication)

That were intubated and assigned 

randomly to receive either 

synthetic surfactant or air placebo 

as part of their participation in 3 

multicenter RCTS.

Had follow up at 1 yr of age

ND Sample 1:

Synthetic surfactant:

[314]

Sample 2:

Air placebo [283]

Combination of 3

multicenter, randomized, 

double blind studies of 

synthetic surfactant vs 

air placebo

[1 yr]
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Allan

1997

97336492

Ment

1996

97040638

Ment

2000

20164956

(CNS+All)

Location: US

Years of Birth: 1989-1992

Median GA (range), wk:

Experiment: 27.7±1.9

Control: 28.4±2.0

Median BW (range), g:

Experiment: 945±191

Control: : 988±164

Male: 

Experiment: 56%

Control: 57%

Race: ND

Enrolled: 505

Evaluated: 431 ? 343 at 36 

months ? 337 at 54 months

Number of sites: 3

BW 600-1250g 

Age< 6 hours

No IVH presence at 6-12 hours

Died by age of 1 year

Lost to follow-up

Presence of IVH in 

sonogram between 6-12 

hr of age

Bilingual or non–English 

speaking at home

Experiment: 

Indomethacin group 

(173)

Controls: Placebo 

(170)

At 36 months:

Experiment: 

Indomethacin group 

(173)

Controls: Placebo 

(170)

At 54 months:

Experiment: 

Indomethacin group 

(170)

Controls: Placebo 

(167)

Randomized Controlled 

Trial 

(36, and 54 months)
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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204

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Van Wassenaer

1997

98103082

Location: Amsterdam

Years of Birth: 1991-1993

Mean GA: ND

Mean BW:

 Sample 1/subgr 1: 856 ±153

 Sample 1/subgr 2: 1048 ± 195

 Sample 1/subgr 3: 1140 ± 156

 Sample 1/subgr 4: 1160 ± 246

 Sample 2/subgr 1: 914 ± 111

 Sample 2/subgr 2: 914 ± 137

 Sample 2/subgr 3: 1173 ± 156

 Sample 2/subgr 4: 1285 ± 236

Males:

 Sample 1/subgr 1: 54%

 Sample 1/subgr 2: 41%

 Sample 1/subgr 3: 44%

 Sample 1/subgr 4: 59%

 Sample 2/subgr 1: 56%

 Sample 2/subgr 2: 23%

 Sample 2/subgr 3: 38%

 Sample 2/subgr 4: 50%

Race: ND

Enrolled: 200 (100 in thyroxine 

group and 100 in placebo group)

Evaluated: 158

Number of sites: 1

Premature : 25-30 wks

Admitted to their NICU within first 

24 hrs of life

Admitted between 1991-1993

Congenital malformations

Maternal endocrine 

disorders

Maternal illicit drug use

Sample 1

Thyroxine (8 ?g/kg BW 

once daily) for the first 

6 wks of life starting 

during the first 12-24

[ 82]

Subgroup 1:

25-26 GA [13]

Subgroup 2:

27 GA [17]

Subgroup 3:

28 GA [23]

Subgroup 4:

29 GA [29]

Sample 2:

Placebo [ 76]

Subgroup 1:

25-26 GA [18]

Subgroup 2:

27 GA [13]

Subgroup 3:

28 GA [ 21]

Subgroup 4:

29 GA [24]

Prospective comparative 

study

(The initial study was a

randomized, double 

blind, placebo-controlled 

trial but in the current 

comparative component 

the patients in the 

subgroups of different 

GA that were compared 

were no longer randomly 

assigned)
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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205

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

O’Shea

1999

99318938

Location: Korea

Years of Birth: 1992-1995

Median GA (range), wk:

Experiment: 25 (23-29)

Control: 26 (23-31)

Median BW (range), g: 

Experiment: 747 (420-1362)

Control: 775 (495-1324)

Male: 

Experiment: 48%

Control: 51%

Race: African-American

Experiment: 34%

Control: 49%

Enrolled: 118

Evaluated: 95

Number of sites: 2

BW < 1501 g

Age 15-25 days old

Not wearing ventilator, no sepsis; 

no PDA , an echocardiogram 

indicating the absence of a 

patent ductus arteriosus

Parental refusal

Survived to 1-year 

adjusted age

Experiment: 

Dexamethasone x 

42 days (50)

Controls: Placebo (45)

Randomized controlled 

trial (1 year)
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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206

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Als

1994

94358983

Other:

Participation in individualized 

developmental care staffing by 

specially educated nurses

The psychologist and clinical nurse 

specialist provided ongoing support 

for the care teams and parents of 

the infants in the experimental 

group in jointly planning and 

implementing individually 

supportive care and environments.

CNS:

Neurodevelopmental:

Cognitive delay

Pulmonary:

BPD severity

Baley Scale of Infant Development at 9 

months of age

Assessed by double-blind review of 

cranial US scans by a consultant 

senior radiologist
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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207

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Corbet

1995

95264244

General:

1) Synthetic surfactant (single 

dose via ET tube of 5 

mg/kg vs air placebo)

Not further specified Growth:

Growth status at 1 yr:

1) Weight

2) Height, 

3) HC and percentiles distribution

Other: Health status at 1 yr:

1) Surgeries

2) Readmissions to hospital

3) CLD, medications for CLD

4) Respiratory support on exam 

day

5) Medications for chronic 

neurologic disease

6) Asthma, Eczema

CNS: Neurodevelopmental outcome

1) MDI

2) PDI

3) Impairments: Present absent

4) Severity of impairment

5) Type of impairment (MDI<69, 

MDI 69-84)

6) CP

Audiology

1) B/L sensorineural deafness

2) Deafness not requiring 

amplification

Ophthalmology: (worst exam and 

last)

1) B/L blindness

2) Visual defect

3) No ROP, mild/moderate ROP, 

severe ROP)

4) Treatment for ROP (surgery, 

cryotherapy)

Assessment at 1 yr of corrected age

Not further specified
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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208

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Allan

1997

97336492

Ment

1996

97040638

Ment

2000

20164956

(CNS+All)

General: SGA/IUGR, Antenatal 

steroids; Apgar score, Gender

CNS : 

Intracranial/Intraventricular 

hemorrhage

Indomethacin

Seizures

Indomethacin

Pulmonary: bronchopulmonary 

dysplasia

Other: multiple birth, MgSO4, 

Surfactant

Diagnoses according to radiologic 

assessments.

The grading system for hemorrhages 

was: grade 1, blood in the 

periventricular germinal matrix 

regions; grade 2, blood within the 

lateral ventricular system without 

ventricular dilation; grade 3, blood 

within and distending the lateral 

ventricles; and, grade 4, blood 

within the ventricular system and 

parencyhmal involvement.

CNS: 

Cerebral palsy

Neurodevelopmental:

Cognitive delay 

Mental retardation

Behavioral Disorders

Seizure disorder

Ophthalmology: Blindness

Audiology: Deafness 

Neurologic examination

At 36 months:

Stanford-Binet IQ

PPVT-R

At 54 months:

Cognitive delay: WPPSI-R or PPVT-R 

(Full scale IQ<70)

Vineland adaptive checklist and child 

behavior checklist
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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209

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Van Wassenaer 

1997

9810382

Other/General:

1) Thyroxine administration 

during first 6 weeks of life 

(vs placebo)

2) GA

Thyroxine administration started at 

12-24 hrs of life in a fixed dose of 8 

?g/kg BW, once daily

CNS

1) Neurologic outcome

2) Developmental outcome

(Assessment at 24 mo corrected 

age)

Neurodevelopmental outcome:

Described in another publication

Abnormal if:

1) Severe abnormality of tone

2) Severe abnormality of posture

3) Severe abnormality of movement

Leading to functional impairment or

Delay in motor development

Suspect if:

1) Moderate abnormality of tone

2) Moderate abnormality of posture

3) Moderate abnormality of 

movement

Leading to mild or moderate functional 

impairment or developmental delay

MDI (Mental Development Index by 

Bayley)

PDI (Psychomotor development index 

by Bayley)

According to Dutch standards

1) Abnormal if: < 2 SDs below mean

Or if score< 68

2) Suspect if < 1 SD or score: 68-84

3) Normal if score> 83
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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210

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

O’Shea, 1999

99318938

Other: Dexamethasone ND CNS: 

CP

Neurodevelopmnetal:

Cognitive delay

Neurological exam

CP was diagnosed only if both a 

pediatrician and a physical therapist

agreed with impaired motor function

Bayley scale

Based on subjective assessment of the 

physician and therapist, the 

neurologic exam was classified into 

no, mild, moderate, and severe 

abnormality.

“Mild abnormality” – hypotonia (which 

typically was most prominent in the 

truncal musculature) but not CP

No definition for moderate and severe 

abnormality.
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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211

Author, Year Associations found Potential Biases Comments

Als

1994

94358983

Studied effect of an individualized developmental care plan on Bayley score at 

9 months age and occurrence and severity of BPD.

Experimental group Controls P value

N 20 18

Bayley MDI 118.30 (17.35) 94.38 (23.31) < 0.001

Bayley PDI 100.6 (20.19) 83.56 (17.97) < 0.01

No BPD 2/20 3/18

Mild BPD 13/20 7/18

Moderate BPD 5/20 2/18

Severe BPD 0 6/18 0.03

Small number of babies studied

Only one NICU

Only one neurodevelopmental assessment at 

9 months of age

Reported timing of IVH different from many 

other studies

High potential for contamination

Study was government 

funded
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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212

Author, Year Associations found Potential Biases Comments

Corbet

1995

95264244

GROWTH AT 1 YR: Mean measurements of Height (74 cm), weight (9.1 kg) 

and HC (46 cm) and growth percentiles were equivalent in the 2 groups.

HEALTH STATUS AT 1 YR: No difference in parameters between 2 groups

1) Surgeries (33% vs 34%) 2) Readmission to hospital (45% vs 39%)

2) CLD (11% vs 10%) 4) Medications for CLD (14% vs 14%)

3) Respiratory support (4% vs 2%)

4) Med. for chronic neurologic problems (1% vs 2%)

5) Asthma (this only was s/s : 9% vs 3%) 8) Eczema (2% vs 1%)

NEURODEVELOPMENTAL OUTCOME: No difference in the outcomes 

between the 2 groups in these parameters.

1) Mean MDI (values <50= 49): 2) Mean MDI (only children with MDI>69)

2) Number of children with MDI<69: 4) Number of children with PDI<69

3) Mean PDI (values<50=49) 6) Mean PDI (only children with PDI>69)

CNS IMPAIRMENT: No difference in any impairments between 2 groups

1) Present: 43% vs 37% 2) Absent: 57% vs 63%

2) Mild/moderate: 20% vs 14% 4) Severe:23% vs 23%

3) MDI<69: 17% vs 16% 6) MDI: 69-84: 18% vs 14%

4) CP mild: 8% vs 7% 8) CP moderate/severe: 7% vs 7%

Audiology:

1) B/L sensorineural hearing deafness: 0% vs 1% 

2) Deafness not needing amplification: 0% vs 1%

Ophthalmology:

1) B/L blindness: 3% vs 2% 2) Visual defect: 8% vs 8%

Worst examination

2) No ROP: 30% vs 33% 2) Mild/moderate ROP: 53% vs 52%

3) Severe ROP: 17% vs 15% 4) Surgical treatment for ROP:10% vs 12%

4) Cryotherapy for ROP: 5% vs 6%

Last examination

5) No ROP: 69% vs 72% 2) Mild/moderate ROP: 26% vs 22%

6) Severe ROP: 5% vs 6% 4) Surgical treatment for ROP: 4% vs 4%

7) Cryotherapy for ROP: 2% vs 3%

Infants who survived after treatment at birth with single-dose synthetic 

surfactant fare as well in terms of growth, development and late morbidities as 

infants who survive without treatment. No difference in medical history during 

first year of life, growth, incidence of visual or auditory defects, CP, 

neurodevelopmental delay at 1 yr adjusted age.

1) The incidence of severe impairment in 

the 19% of infants who did not return for 

evaluation at the age of 1 yr may be 

higher than in those who were evaluated.

Source of funding not 

reported.

1) The

neurodevelopmental 

evaluation of infants at 1 

yr may not be absolutely 

reliable for the estimation 

of later outcome.

2) The estimated mental

retardation is likely to be 

low, and the estimated CP 

is likely to be high, 

compared to estimates at 

2 and 3 yrs.
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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213

Author, Year Associations found Potential Biases Comments

Allan

1997

97336492

Ment

1996

97040638

Ment

2000

20164956

(CNS+All)

Antecedents of Cerebral Palsy (CP).

Risk Factor n Percent with CP P value

BPD Yes 177 15%

No 203 4% < 0.001

Surfactant Yes 245 13%

No 136 4% 0.003

Grade 3 or 4 IVH Yes 15 53%

No 366 8% < 0.001

PVL Yes 25 53%

No 352 6% < 0.001

Ventriculomegaly Yes 17 59%

No 328 7% < 0.001

Assessed at 36 months corrected age:

No significant differences between placebo and indo. for: Presence of CP/ 

abnormal neurologic exam (8% vs. 8%, Placebo vs. Indo); Blindness (1% in 

each); Deafness (1% in each); Stanford-Binet IQ (85.0±20.8 vs. 89.6±18.9, 

Placebo vs. Indo)

Presence of IVH was associated with a significant decrease in Stanford-Binet 

IQ: IVH absent, 84.4 + 19.6 vs. IVH present 80.2 + 20.9 (P = 0.03)

Assessed at 54 months corrected age:

 Indomethacin Placebo P-value

N 170 167 

Blind 1 (<1%) 1 (<1%) ns 

Deaf 1 (<1%) 1 (<1%) ns

Seizures 1 (1%) 5 (3%) ns

CP 7% 7% ns

WPPSI Full IQ<70 9% 17% 0.035

WPPSI Full IQ 70-80 12% 18%

PPVT-R IQ<70 12% 26% 0.02

PPVT-R IQ70-80 19% 6% 

N 119 114

Vineland Total Score *There was no significant difference between groups: 

Communication; Daily living skills; Socialization; Motor skills

For CBCL results, children in Indo. group has significant lower score in 

Withdrawn subscale than children in Placebo group (52.7 vs. 54.6, p=0.02). 

There is no significant difference found in the other subscales of CBCL.

Stanford-Binet testing limited to monolingual, 

English-speaking families

Study was government 

funded

Study in a follow-up of 

originally randomized 

cohort; followed at 36 

and 54 months age, 

corrected
Evidence Table 4. Studies Evaluating Treatment Effects of LBW and Cerebral Palsy and Neurological Outcomes

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214

Author, Year Associations found Potential Biases Comments

Van Wassenaer 

1997

9810382

1) In infants of 25-26 wks GA, thyroxine administration during the first 6 

weeks after birth is associated with an improvement in mental 

developmental outcome/MDIs.(p<0.01)

2) Thyroxine administration does not improve and might even harm mental 

(but not psychomotor/PDIs or neurological ) outcomes in infants 27-20 

wks.

3) There was also a trend towards a better psychomotor and neurologic 

outcome (normal, suspect, abnormal).

1) In this study, many pot hoc exploratory 

subgroup analyses were done: Small 

number of patients in each subgroup and 

although the patients were randomly 

assigned in the original 2 groups, this 

does not continue to be the same for the 

subgroups of different GA analyzed.

2) Thus association proposed for beneficial 

effect of T4 particularly for the subgroup 

of infants less than 27, weeks and only 

for the MDI scores; and not for the PDI 

scores or the neurological outcomes; 

must be viewed cautiously.

3) Except for Thyroxine and GA the effect of 

the other covariates/predictors included 

in the linear regression model was not 

discussed.

It should be taken into 

consideration that the 

initial RCT with 200 

infants less than 30 wks 

had shown no clear 

association between 

thyroxine administration 

and neurodevelopmental 

outcome. 

O’Shea, 1999

99318938

 Dexamethasone (N=50) Placebo (N=45) P

Definite Cerebral Palsy: 12 3 

Possible CP: 5 2 

Overall CP: 17 5 0.006

Neuro exam severe

Abnormal: 4 2

Mild abnormal: 16 6

Overall abnormal

Neuro exam: 20 8 0.03

(None) Study was government 

funded
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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215

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria Disease/Condition Type (N)

Study Design

(Duration)

Wood

2000

20373840

Location: UK and Ireland

Years of Birth: 1995-1996

Mean GA (range), wk: 22-25

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 314

Evaluated: 283

Number of sites: 276

GA 20-25 weeks survivors ND Preterm infants (283) Prospective cohort 

(30 [28-40] months)

Lefebvre

1998

98387703

Location: Canada

Years of Birth: 1987-1992

Mean GA (range), wk: 27.0±1.2

Mean BW (range), g: 961±179

 (585-1450)

Male: 52%

Race: ND

Enrolled: 139

Evaluated: 121

Number of sites: 1

GA<28 weeks

3 or more cranial ultrasounds

Survival to discharge

ND Preterm infants (121):

Low risk (50)

Moderate risk (37)

High risk (34)

Prospective cohort 

(CA 18.6±1.2 [17-19] 

months)
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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216

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria Disease/Condition Type (N)

Study Design

(Duration)

Wolke

1999

10075095

Location: Germany

Years of Birth:1985-1986

Description of group:

 Sample 1: VLBW

 Sample 2: Full term/ controls

 Sample 3: Normative sample

Mean GA (range), wk:

 VLBW: 29.5± .2 (29.3-29.7) 

 Control: 39.6± .1 (39.5-39.7)

Mean BW (range), g:

 VLBW: 1288±42 (1247-1330)

 Control: 3407±58 (3351-3463)

Male (%):

 VLBW: 56.4%

 Control: 56.4%

 Normative: 51%

Race: ND

Enrolled: 

 VLBW: 560

 Control: 916 

 Normative: 311

Evaluated:

 VLBW: 264

 Control: 264

 Normative: 311

Number of sites: 17 (hospitals)

Cases: 1) Requiring admission to 1 

of 17 hospitals in S. Bavaria 

within first 10 days. 2) 

Assessments at 5 and 20 

months, 4 years 8 months, and 6 

years 3 months. 3) VLBW (very 

preterm) GA≤ 32 weeks at birth.

Controls: 1) Control group (full 

term) GA>36 weeks at birth.

For all groups: German- speaking

ND Cases:

Sample 1: VLBW (or 

very preterm): 264

Controls:

Sample 2: Full term/ 

controls: 264

Sample 3: Normative: 

311

Non-randomized 

comparison trial 
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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217

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria Disease/Condition Type (N)

Study Design

(Duration)

Smith 

1996

97081985

Location: US

Years of Birth: 1990-1992

Description of group:

 Sample 1: High risk VLBW

 Sample 2: Low risk VLBW

 Sample 3: Full term (controls)

Mean GA (range), wk:

 HR VLBW: 28± 2 

 LR VLBW: 30.9±2

 FT: 39.1±5.9

Mean BW (range), g:

 HR VLBW: 930±233

 LR VLBW: 1263±202

 FT: 3187±767

Male (%):

 HR VLBW: 50%

 LR VLBW: 41%

 FT: 50%

Race (% African-American):

 HR VLBW: 57%

 LR VLBW: 62%

 FT: 62%

Enrolled: 

 HR VLBW: 89 

 LR VLBW: 123 

 FT: 128

Evaluated:

 HR VLBW: 88

 LR VLBW: 123

 FT: 128

Number of sites: 2

Cases: 1)VLBW≤1600 g 2)Female 

primary caregiver 3)Completed 

both a 6 and 12 mos. home visit. 

4)GA≤ 36 weeks at birth.

Sample 1: HR VLBW: one or more 

severe medical complications:

bronchopulmonary dysplasia 

(BPD) defined as need for O2 for 

more than 28 days, severe IVH 

with progressive dilitation 

defined as a Grades III or IV 

subependymal hemorrhage, 

and/or periventricular 

leukomalacia characterized by 

ischemic lesions.

Sample 2: LR VLBW: one or more 

less severe medical 

complications, including 

transient respiratory distress 

where O2 is required for less 

than 28 days and/or mild IVH 

without dilitation- Grades I and II.

Controls:

Sample 3: FT: GA: 37-42 weeks 

with normal pregnancy history 

and physical examination at 

birth.

1) Primary caregiver 

age<16, drug abuser, or 

not English-speaking. 

2) Sensory impairment, 

meningitis, encephalitis, 

congenital syphilis, 

congenital abnormality of 

the brain, cardiac 

abnormalities, NEC or HIV 

antibody positive. 

Cases:

 Total VLBW: 211

 Sample 1: HR VLBW: 

88

 Sample 2: LR VLBR: 

123

Controls:

 Sample 3: Full-term 

infants: 128

Non-randomized 

comparison trial
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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218

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria Disease/Condition Type (N)

Study Design

(Duration)

Sajaniemi

2001

11227991

Location: Finland

Years of birth:1989-1991

Description of group: VLBW

Mean GA (range), wk: 29.4± 3 

Mean BW (range), g: 1246±472 

Male: ND

Race: ND

Days of mechanical ventilation: 

12.3±26

Enrolled: 138

Evaluated: 63

Number of sites: 1

Cases: 1) Mothers referred to 

University Central Hospital in 

Helsinki for threatened pre-term 

delivery 2) Assessments at 2 

and 4 months, 3) VLBW (very 

preterm) GA≤ 29.4± 3 weeks at 

birth.

Major disabilities (CP or 

mental retardation)

Cases:

VLBW (or very 

preterm): 63

No control group

Prospective (single 

arm) cohort 

Briscoe

1998

98300800

Location: UK

Years of Birth: 7/91- 7/92

Mean GA (range), wk: 28±1.9 (26-

32)

Mean BW (range), g: 1206±345 

(815-1985)

Male: ND

Race: ND

Enrolled: 26 (26 controls)

Evaluated: 26 (26)

Number of sites: 1

Cases: Preterm infants, GA<32 

weeks, from an Avon Premature 

Infant Project, Marlow, 1997. 

Free of major and minor physical 

impairment at 2 years of age

Controls: Children age between 

3years 7 months and 4 years 5 

months born full-term, GA>37 

weeks.

ND Cases: Preterm infants 

(26)

Controls: Full term 

infants (26)

Case-control study
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

Part I

219

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria Disease/Condition Type (N)

Study Design

(Duration)

Saigal

2001

21376729

Location: Canada

Years of Birth: 1977-1982

Mean GA (range), wk:

Cases: 27±2

Controls: “Term”

Mean BW (range), g:

Cases: 835±124

Controls: 3401±481

Male: 

Cases: 31%

Controls: 36%

Race: ND

SES: middle class

Cases: 30%

Controls: 30%

Enrolled: 179 (145 controls)

Evaluated: 154 (125)

Number of sites: 1

ELBW survivors, BW= 501-1000g

Controls: term infants recruited at 

8 years of age from a random list 

obtained through the directors of 2 

school boards and matched for 

gender, age, and SES to each 

case

ND

(Died after discharge (10)

Lost to follow-up (8)

Refusal (5)

Unable to be reached (2)

Controls:

Lost to follow-up (10)

Refusal (8)

Unable to be reached (2))

Cases: ELBW infants 

(154)

Controls: Term infants 

(125)

Prospective cohort 

(followed to 12-16 years 

age)
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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220

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria Disease/Condition Type (N)

Study Design

(Duration)

Schendel

1997

98033417

Location: US

Years of Birth: 12/1/89 to 3/31/91

Mean GA (range), wk: 

Sample 1: 28.4 ±3.0

Sample 2: 35.6 ±2.8

Controls: 39.4 ±1.5

Mean BW (range), g:

Sample 1: 1088±268

Sample 2: 2184±267

Controls: 3417±432

Male: 

Sample 1: 49%

Sample 2: 46%

Controls: 52%

Race: Black

Sample 1: 37%

Sample 2: 37%

Controls: 41%

Enrolled: 920 (555 controls)

Evaluated: 920 (555)

Number of sites: 5

Singleton livebirths in MMIHS 

study population, survived to 1 

year of age

Cases: MLBW infants, BW 1500-

2499g; VLBW infants, 

BW<1500g

Controls: NBW infants randomly 

selected from the birth certificate 

files on the basis of frequency 

matching with cases by maternal 

race, age, and residence

ND Sample 1: VLBW 

infants (367)

Sample 2: MLBW 

infants (553)

Controls: NBW infants 

(555)

Case-control study
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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221

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Singer

2001

21163669

Cardiovascular or pulmonary 

predictors: 

1) Bronchopulmonary 

dysplasia

General : BW, Neurologic risk

Other: Race, Socioeconomic 

status

BPD: preterm,<1500g BW, oxygen 

for >28 days with radiographic 

evidence of CLD

CNS outcomes:

Cerebral palsy

Cognitive delay

Mental retardation

Ophthalmology outcomes:

Visual impairment

Audiology outcomes:

Hearing disorders

Speech

Language

Communication disorder

Bayley scale of infant development

Language (speech/communication) 

measured by Battelle Developmental 

Communication Subscale Domain‡

receptive, expressive and total 

communication scores converted to 

DQ mean 100 and SD 15.

Wood

2000

20373840

General:

1) GA

2) Gender

Other: Perinatal Factors‡

Multiple gestation

ND CNS: 

Motor delay

Cognitive delay

Seizure disorder

Overall development

Ophthalmology:

Visual impairment

Blindness

Audiology:

Hearing disorders

Deafness

Speech

Communication disorder

Other:

Severely disabled

Other disability

No disability

Disability of hearing, vision, or 

communication

Bayley scales 

Severe disability = need of physical 

assistance to perform daily activities. 

If disability didn’t fit into this category = 

“other disability”
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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222

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Lefebvre

1998

98387703

Other: Neurobiologic risk score 

(NBRS)

Items in NBRS: ventilation, PH, 

surgeries, IVH< PVL, infection, 

hypoglycemia-items scored zero or 

greater in progression

CNS:

Cerebral palsy 

Cognitive delayOther: neurodevelopmental 

impairment

Ophthalmology: Blindness

Audiology: hearing disorders-free 

fetal audiogram

Neurologic exam

Griffith’s mental development scale 

Mental retardation-Griffith’s mental 

development scale

1) Global developmental quotient 

(DA)

2) Mild/moderate: DA 80-89 or CP

3) Severe: DA<80, severe CP 

unilateral blindness or severe 

hearing defect 

4) Normal: more of the above

Areas of Griffith’s Developmental 

Scales:

- Locomotor

- Personal-social

- Hearing and speech

- Eye and hand coordination

- Performance

Control mean DA=110+or- in literature 
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

Part II

223

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Wolke

1999

10075095

General predictors: GA Gestational age GA≤32 for VLBW, 

GA>36 weeks for full term control 

group.

Audiology outcomes:

1) Language development

2) Prereading skills

3) Cognitive status

I. Language development:

a) Heidelberger

Sprachentwicklungstest 

(HSET) (German test)

II. Prereading skills:

 a) Rhyming and sound-to-word-

 matching tasks

III. Cognitive status:

 a) Kaufman Assessment Battery 

 for Children (K-ABC) for 

 cognitive assessment. 

 Intelligence was measured 

 with the Mental Processing 

 Composite (MPC):

 simultaneous and sequential

 information processing 

 subtests (SGD and SED), and 

 The Achievement Score (AS)

Smith 

1996

97081985

General predictors: Illness 

acuity, grouped into LR VLBW 

and HR VLBW, and maternal 

behavior, warm sensitivity and 

maintaining of infants interests 

and directiveness.

Gestational age GA≤ 36 weeks at 

birth.

Audiology outcomes:

1) Cognitive skills 

2) Language development

3) Living skills

I. Cognitive skills:

a) Bayley Scales of infant 

 Development expressed as

 mental age

II. Language development:

a) Sequenced Inventory of 

Communication Development

III. Living Skills:

a) Daily Living Skills subscale 

from the Vineland Adaptive 

Behavior Scale
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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224

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Sajaniemi

2001

11227991

General predictors: Gestational age GA≤ 29.4± 3 Audiology outcomes:

1) Temperamental characteristics 

(at 2 years of age)

2) Behavioral characteristics (at 2 

years of age)

3) Cognitive precursors (at 2 and 4 

years of age)

4) Neuropsychological assessment 

(at 4 years of age) 

I. Temperamental 

characteristics:

 a) Toddler Temperament 

Questionnaire (TTQ), 

measuring activity, rhyhmicity, 

approach, adaptability, 

intensity, mood, persistence, 

distractability, and sensory 

threshold.

II. Behavioral characteristics:

 a) Infant Behavior Record 

(IBR) of the Bayley Scales, 

measuring fearfulness, 

emotional tone, activity, 

attention span, and goal 

directness.

 

III. Cognitive precursors:

 a) Mental Development Index 

(MDI) from the Bayley Scales 

of Infant Development was 

used to measure cognitive 

level at 2 years.

a) Wechsler Preschool-Primary 

Scale of Intelligence 

(WPPSI) (Finnish version) 

was used at 4 years of age.

IV. Neuropsychological 

assessment:

 a) pre-standard version of the 

Finnish Neuropsychological 

Investigation for Children 

(NEPSY-r, extended version) 

 
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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225

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Briscoe

1998

98300800

General predictors: GA Gestational age < 32 weeks based on 

expected date of delivery

Audiology outcomes:

1) Language

2) Short-term memory

3) General non-verbal ability

II. Vocabulary knowledge:

a) British picture vocabulary 

scales

b) Oral vocabulary component of 

McCarthy scales of Children's 

Abilities

c) Bus Story test of Continuous 

speech tested expressive 

language ability (retelling 

story using pictures as on aid)

III. Phonological short-term 

memory: 

a) Digit span: set of pseudorandom numbers to repeat

b) Non-word repetition

IV. Non-verbal ability :

a) Raven's Progressive Coloured 

Matrices adapted for use here 

under 5 years of age

V. Early Development 

Assessment:

a) Griffith's mental development 

scales
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

Part II

226

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Saigal

2001

21376729

Birth weight

GA

ELBW=500-1000 g CNS:

Motor delay 

Cognitive delay

Other: neurosensory impairment

Ophthalmology:

Visual impairment 

Growth:

Height 

Weight 

Head circumferences

BMI (wt/ht2)

Other:

Health status and problems; current 

 and past

Extra health care expenses

Utilization and health care resources

Reported previously in the authors’ 

other paper

Growth reference population was using 

the age- and gender-specific 

reference data provided by the NCHS 

growth chart

Schendel

1997

98033417

General Predictors

1) Birth Weight- 3 groups 

VLBM ( very low birth wt)

MLBW (moderately low birth wt.)

NBW (normal birth wt)

Other Predictors

1) Other: married at birth

2) Other: Medicaid recipient

ND CNS:

Other: Developmental Delay

Pulmonary:

Birth weight

Developmental delay measured by 

Denver Developmental Screening 

Test II.

“DELAY” defined by 9 measures of 

performance on Denver 

Developmental Screening Test II at 

age 15 months corrected.
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

Part III

227

Author, Year Associations found Potential Biases Comments

Singer

2001

21163669

Evaluation at 36 months corrected age. VLBW, VLBW with BPD, full term (FT).

 Bayley MDI % with MDI below 70

VLBW 90 + 16 (38-126) 11%

VLBW w/ BPD 84 + 24 (10-116) 21%

FT 96 + 12 (57-127) 4%

P = 0.001 for VLBW vs. VLBW w/ BPD

 Bayley PDI % with PDI below 70

VLBW 98 + 20 (33-122) 9%

VLBW w/ BPD 84 + 29 (8-127) 9%

FT 103 + 15 (58-128) 1%

 P = 0.001 for VLBW vs. VLBW w/ BPD

At 3 years BPD predicted poorer motor outcome but not poorer mental 

outcome.

Receptive DQ: BPD < VLBW < Term, p < 05

Receptive DQ < 85: BPD 49%, VLBW 34%, Term 30%,

BPD < VLBW + Term p < .05

Expressive DQ: BPD < VLBW + Term, p < .05

Expressive DQ<85: BPD 44%, VLBW 25%, Term 25%

BPD < VLBW + Term p < .05

Communication DQ: BPD < VLBW + Term, p < .05

Communication DQ < 85: BPD 43%, VLBW 31%, Term 28%, NS

Rank order listing of risk factors in order of magnitude of effect and the number 

of communication DQ lowered by the risk factor: PDA lowered DQ by 13 

points, Minority race by 6 points, lower socioeconomic status by 5 points, and 

higher neurologic risk by 5 points. p .001

Bayley Scales MDI:

BPD 83.7 ± 24, VLBW 90 ±16, Term 96.4 ± 12, BPD < VLBW < Term, p< 

0.05

Bayley Scales PDI:

BPD 84.1 28, VLBW 97.4 19, Term 102.8 14

BPD < VLBW + Term, p< .05

ROP: BPD 43%, VLBW 4%, p= .001

Seizures: BPD 7%, 

Neurologic score: BPD 1.3 ± 2, VLBW 58 ± 1, p < .001

Single region, but at least it is a region

Unclear if examiners were blinded to groups’ 

status

Study was government 

funded

Wood Infants 22-25 weeks GA developmentally assessed at median 30 months (None) Severe disability common
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

Part III

228

Author, Year Associations found Potential Biases Comments

2000

20373840

• 138/283 had disability (49%:64 met criteria for severe disability)

• 49% no disability

• 53/283 severely delayed 19%(Bayley below 3 SD)

• 32/283 2-3 below SD 11%

• 28 severe neuromotor disability 10%; 7 blind or perceived light only 2%

• 8 hearing loss that was uncorrectable or required hearing aids 3%

 Survived without overall disability

 22 wks--------------0.7 %

 23 wks--------------5%

 24 wks--------------12%

 25 wks--------------23%

Severe disability at 30 months

 22 -------------------0.7%

 23 --------------------3%

 24---------------------6%

 25---------------------9%

• no relation between morbidity pattern and either gestational age &multiple 

birth; boys were likely to be disabled than girls

Children born extremely 

premature

Lefebvre

1998

98387703

Assessed at 18 months corrected age. Divided into low, moderate and high 

risk group based on Neurobiologic risk score (NBRS). Tested with Griffith’s 

Developmental Scales.

 Griffiths Developmental Score Category

Risk Group n Severe impairment, <80 All < 80

Low 50 0% 12%

Moderate 37 22% 24%

High 34 50% 71%

Significance: for severe or any delay the NBRS was predictive, P < 0.0001

Risk Group n Severe CP (+) Any CP

Low 50 0% 4%

Moderate 37 13% 19%

High 34 26% 41%

Significance: NBRS predictive of CP, severe CP, P < 0.0009, any CP P < 

0.0001

(None) Study was privately 

funded

Wolke • Preterm birth is significantly associated with deficits in wide range of Drop-out rate <25%. Internal validity: A
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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229

Author, Year Associations found Potential Biases Comments

1999

10075095

abilities including all measures of cognition, language comprehension and 

expression, articulation, and prereading skills compare to full-term 

controls. 

• Specific intellectual deficit is in simultaneous central information 

processing 

• Specific language deficits include problems with grammatical rules, 

detecting semantically incorrect sentences, motor aspects of speech, 

articulation, and pronunciation

• Specific prereading skills deficits include problems with rhyming tasks, 

sound-to-word matching and naming or number/letters.

• Deafness 0% in the preterm group

Smith 

1996

97081985

• HR infants have a significantly lower mental age (cognitive skills) at 6 and 

at 12 mos. then either FT controls or LR infants.

• HR infants scored lower in living skills at 6 mos. than FT’s but not LR 

infants. There was no difference between groups at 12 mos.

• HR infants scored lower for language development at 6 and 12 mos. than 

FT controls 

The overwhelming majority of HR VLBW’s 

were HR because of BPD with or without 

IVH.

Low socioeconomic status, inner city 

population

Study was privately 

funded

Sajaniemi

2001

11227991

• Cognition, behavior and temperament as early as 2 year of age predicted 

impaired language functioning at age 4 years in infants without major 

disabilities.

• Preterm children were temperamentally less active, less persistent, and 

less goal-directed with passive attitude toward environmental stimulus.

• Preterm infants were less cooperative and highly distractable.

No full-term controls Internal validity B

Briscoe

1998

98300800

When comparing short-term memory and language outcomes, across all 

measures, preterm infants performed at a lower level, typically one half SD 

lower. 

• 2/3 of preterm infants had normal cognitive profiles.

• “at risk” subgroup of preterms for language impairment can be identified 

using an expressive screening tool at an early age (less than 5 yrs) when 

intervention can be effective(Bus Story Test).

• Meta-analysis 80 studies, preterm IQ lower than full terms but still in the 

normal range.

No difference in regard to social class, 

maternal education or single parent status.

No GA less than 26 weeks

Small sample made effect of IVH/PVL difficult 

to interpret

“Most” children were recruited through friends 

and relatives (excluding siblings) of the 

preterm children in order to minimize social 

and economic disparity

Study was privately 

funded

Saigal

2001

Neurosensory Impairment:: ELBW 28%, FT Controls 2%, p= 0.001

Growth: Weight: diff. between ELBW and FT (mean z scores ) –5.78 

Didn’t specify exclusion criteria but these are

implied based on clear industry criteria units; 

Study was privately 

funded
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

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230

Author, Year Associations found Potential Biases Comments

21376729 (p<0.0001)

Visual Problems: ELBW 57%, FT Controls 21%, p=<0.001 (OR 5.1, CI 2.89-

9.05)

Current Health Problems (multiple/patient): ≥3 Health Problems: ELBW 35%, 

FT Controls 7%, p<0.0001

Past Health Problems:

 Seizures: ELBW 11%, FT Controls 2%, p<0.005

 Asthma: ELBW 25%, FT Controls 14%, p=0.05

 Recurrent bronchiolitis/pneumonia: ELBW 14%, FT Controls 3%, p=0.005

Current (at 12-16 yr age) Functional Limitation (Table 4 page 411) 

(multiple/patient)

 Visual difficulty: ELBW 57%, FT Controls 21%, p<0.001

 Hearing Difficulty: ELBW 7%, FT Controls 5%, ns.

 Emotional problems: ELBW 4%, FT Controls 1%, ns

 Mental problems: ELBW 4%, FT Controls 1%, ns.

 Clumsiness: ELBW 25%, FT Controls 1%, p<0.001

 Developmental Delay: ELBW 26%, FT Controls 1%, p<0.001

 Learning Disability: ELBW 34%, FT Controls 10%, p<0.001

 Hyperactivity: ELBW 9%, FT Controls 2%, p=0.04

 Reduced self-abilities: ELBW 5%, FT Controls 0%, p=0.02

Limitation in school or in normal activity: ELBW 31%, FT Controls 9%, 

p<0.002

Any functional limitation: ELBW 81%, FT Controls 42%, p<0.001

Functional limitation/child [Mean (SD)]: ELBW 2.0 (1.8), FT Controls 0.6 

(0.8), p<0.001

Utilization of Health Care Resources:

Pediatrician: ELBW 34%, FT Controls 14%, p<0.0002

Ophthalmologist: ELBW 62%, FT Controls 34%, p<0.0001

Ear/nose/throat: ELBW 14%, FT Controls 6%, p<0.05

Occupational therapist: ELBW 7%, FT Controls 1%, p=0.002

Speech therapist: ELBW 8%, FT Controls 0%, p<0.002

Special Education: ELBW 48%, FT Controls 10%, p<0.0001

Prescription Glasses: ELBW 36%, FT Controls 10%, p<0.001

to generalizability: different era of natural care 

2 white race 3 access to universal health care 

in Canada 
Evidence Table 5A. Studies Evaluating Association of LBW to Speech and Language Disorders

Part III

231

Author, Year Associations found Potential Biases Comments

Schendel

1997

98033417

Even apparently well VLBW infants with no overt physical impairment are 

consistently at higher risk for all measures of DELAY than MLBW or NBW 

infants. VLBW have DELAY in all areas of function with greatest risk for 

delay in gross motor domain. 

“Abnormal” – VLBW 10.9%, NBW 2.9%, p = 0.001

Personal-Social =1 delays: VLBW 7.1%, NBW 2.2%, p = 0.001

Language = 1delays: VLBW 8.8%, NBW 4%, p = 0.01

Fine motor-adaptive = 1 delays: VLBW 7.9%, NBW 2.2%, p = 0.001

Gross motor =1 delays: VLBW 10.7%, NBW 1.8%, p = 0.001

The people administering the Denver test were 

not blinded and were aware of degree of 

prematurity. 

The adjusted age at f/u had very wide range 9-

34 months

Study was government 

funded
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

232

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Northern 

Neonatal 

Nursing Initative 

Trial Group

1996

96304894

Location: UK

Years of Birth: 1990-1992

Mean GA (range), wk: 29 (27-31)

Mean BW (range), g: 1253 (965-

1543)

Male: 39%

Race: ND

Enrolled: 776

Evaluated: 776

Number of sites: 16

GA <32 weeks; resident in 

northern UK

ND Experiment 1: fresh 

frozen plasma 

treatment (257)

Experiment 2: gelatin 

plasma substitute 

(261)

Glucose controls (258)

Randomized controlled 

trial (2 years)

Hack

1996

97066007

Location: US

Years of Birth: 7/1982-6/1988, 

1/1990-12/1992

Mean GA (range), wk:

Sample 1: 25.9±2 (22-31)

Sample 1: 25.7±2 (22-31)

Mean BW (range), g:

Sample 1: 688.6±73 (560-740)

Sample 2: 670.6±56 (502-742)

Male: 

Sample 1: 28%

Sample 2: 29%

Race: White

Sample 1: 31%

Sample 2: 37%

Enrolled: 280

Evaluated: 280

Number of sites: 1

BW 500-759 g

Survived to 20 months corrected 

Age

ND Sample 1: VLBW 

survived infants born 

in 1990-1992 

(surfactant/dex era) 

(114)

Sample 2: VLBW 

survived infants born 

in 1982-1988 

(surfactant and less 

dex. era) (166) 

Prospective cohort 

(followed to 20 months 

corrected age)

Hack

2000

20358826

Location: US

Years of Birth: : 1/1/1992-

2/31/1995

Mean GA (range), wk: 26.4±1.8

Mean BW (range), g: 813±125

Male: 43%

Race: ND

Enrolled: 333

Evaluated: 221

Number of sites: 1

BW<1000g Major congenital 

malformations

VLBW infants (221) Prospective cohort
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

233

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Wood

2000

20373840

Location: UK and Ireland

Years of Birth: 1995-1996

Mean GA (range), wk: 22-25

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 314

Evaluated: 283

Number of sites: 276

GA 20-25 weeks survivors ND Preterm infants (283) Prospective cohort 

(30 [28-40] months)

Singer

1997

98049057

Singer

2001

21163669

Location: US

Years of Birth: 1989-1991

Mean GA (range), wk: 

Sample 1: 27±2

Sample 2: 30±2

Controls: 40±2

Mean BW (range), g: 

Sample 1: 956±248

Sample 2: 1252±178

Controls: 3451±526

Male: 

Sample 1: 52%

Sample 2: 43%

Controls: 50%

Race: White

Sample 1: 55%

Sample 2: 48%

Controls: 51%

SES: Hollingshed classification: 

Sample 1: 3.5±1

Sample 2: 3.6±1

Controls: 3.6±1

Enrolled: 464

Evaluated: 206 (123 controls)

Number of sites: 3

Cases (sample 1&2): premature 

infants, BW < 1500g

Controls: term infants with no 

diagnosed medical illness or 

abnormalities at birth, >36 

weeks, GW>2500g

Major congenital 

abnormality

Drug exposure

Maternal illness

HIV

Maternal mental 

retardation

>2 hours driving time from 

hospital

Sample 1: VLBW infants 

with BPD infants 

(122)

Sample 2: VLBW 

without BPD (84)

Sample 3: Full term 

infants (123)

Prospective cohort 

(followed to 3 years 

corrected age)
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

234

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Schmidt

2001

21298249

Location: Canada, USA, Australia, 

New Zealand, Hong Kong

Years of Birth: 1996-1998

Mean GA:

 Sample 1: 25.9 ±1.8

 Sample 2: 26 ±1.9

Mean BW:

 Sample 1: 782 ±131

 Sample 2: 783 ± 130

Male: 51%

Race:

Sample 1:White: 69%, black: 13%, 

Asian: 5%, other: 12%

Sample 2: White: 67%, black: 14%, 

Asian: 7%, other: 12%

Enrolled: 2756

Evaluated: 1202

Number of sites: 32

BW: 500-999g

2 hrs old

Born in 1 of the 32 participating 

centers in Canada, USA or 

Australia.

Born during 1/1996-3/1998

Excluded total 981 (not 

eligible)

Unable to administer study

drug within 6 hrs of birth , 

n=469

Structural heart disease

Renal disease or both, or 

strongly suspected (n=24)

dysmorphic feature or 

congenital abnormalities 

likely to affect life 

expectancy or neurologic 

development or to be 

associated with structural 

heart disease or renal 

disease (n=49)

Maternal tocolytic therapy 

with indomethacin or 

another prostaglandin 

inhibitor within 72hr before 

delivery (n=245)

Overt clinical bleeding at

more than one site (n=8)

Platelet count <50.000 

(n=25)

Hydrops (n=9)

Not considered viable 

(n=171)

Unlikely to be available for 

f/up (n=31)

Sample 1:

Indomethacin group 

[574]

Sample 2:

Placebo group [569]

Randomized, 

multicenter, 

placebo/controlled,

double-blind trial

[18 mo CA]
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

235

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Battin

1998

99002694

Location: British Columbia, Canada

Enrollment period: 1991-1993

Mean GA: ND (range: 23-25 wks)

Mean BW: ND

(Mean BW for the 333 live births

during the study period : for GA of

23 wks: 581, for GA of 24 wks:

648, for GA of 25 wks: 764)

Male: ND

Race: ND

Enrolled: 333 

(total live births GA: 23-28 wks) 

Evaluated : 44 

(out of 49 of GA 23-25 surviving to 

NICU discharge)

Number of sites: 2

Prospective cohort:

Birth at British Children’s Hospital 

and British Womens’ Hospital

Born during 1991-1993

Extremely low gestational age 

(ELGA): 23-25 wks

Had follow up at 18 mo of age

Historical control group:

Born at the same institution

Born between 1983-1989

GA: 23-25 wks

Cases of therapeutic 

termination of pregnancies 

for lethal congenital 

anomalies

Outborns

Prospective cohort of

ELGA born during a

period when antenatal

steroids, surfactant

and dexamethasone

for BPD had become

an accepted treatment

[44]

Prospective 

observational cohort 

study and a 

comparative study with 

an historical control 

group

(18 months)

Vohr

2000

20295211

Location: US

Years of Birth: 1/93-12/94

Median GA (range), wk:

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: ND

Evaluated: ND

Number of sites: 12

Live born BW 401-1000 g ND 1151 extremely low birth 

weight survivors 

cared for in the 12 

participating centers 

of the National 

Institute of Child 

Health and Human 

Development 

Neonatal Research 

Network

Prospective cohort 

(18-22 months 

corrected age)
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

236

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Piecuch

1997 

98012134

Location: US

Years of Birth: 1990-1994

Mean GA (range), wk:

Sample 1: 24

Sample 2: 25

Sample 3: 26

Mean BW (range), g:

Sample 1: 668±91 (450-850)

Sample 2: 790±115 (550-1000)

Sample 3: 842±158 (505-1260)

Male: 

Sample 1: 50%

Sample 2: 73%

Sample 3: 50%

Race: ND

SES: high social risk

Sample 1: 89%

Sample 2: 43%

Sample 3: 68%

Enrolled: 94

Evaluated: 86

Number of sites: 1

24, 25 or 26 week GA

Non-anomalous

Born at University of California, 

San Francisco

ND

(Died after discharge (2)

Accidental severe 

central 

nervous system insult 

after 

discharge (1)

Lost to follow-up (5)}

Sample 1: GA 24 

weeks (18)

Sample 2: GA 25 

weeks (30)

Sample 3: GA 26 

weeks (38)

Prospective cohort 

(at 12 months, 18 

months, 2 1⁄2 years, 4 1⁄2 

years. 7-8 years)

Victorian Infant 

Collaborative 

study Group, 

1997 

97466059

Location: Australia

Years of Birth: 1979-80, 1985-87, 

1991-92

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 36

Evaluated: 35

Number of sites: 3

ELBW infants, BW 500-999 g born 

outside the level III perinatal 

centers in Victoria, Australia 

survived to age of 2 years

Excluded infants born in 

1979-1980 for current 

review

ELBW infants (36):

Sample 1: born in 

1985-1987 (19)

Sample 2: born in 1991-

1992 (16)

Retrospective cohort 

(2 years)

Ambalavanan

2000

21031370

Location: US

Years of Birth: 1/1990 to 12/1994

Mean GA (range), wk: 26±2

Mean BW (range), g: 829±123

Male: 45%

Race: African-American 66%

Enrolled: 218

Evaluated: 218

Number of sites: 1

ELBW infants, BW <1000 g ND ELBW infants (218) Retrospective cohort 

(followed to 18 months 

of age)
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

237

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Cheung

1999

99146391

Location: Canada

Years of Birth: 1990-1993

Mean GA (range), wk:

Sample 1: 25 (22-29)

Sample 2: 26 (24-30)

Sample 3: 28 (23-32)

Mean BW (range), g:

Sample 1: 660±56

Sample 2: 873±73

Sample 3: 1127±71

Male: total 57%

Race: ND

Enrolled: 187

Evaluated: 164

Number of sites: 2

BW<1250 gm

GA < 32 weeks

Mild or no significant respiratory 

disease (O2 < 30%, RR < 70)

Major congenital 

abnormalities, 

syndromes

Infants with neurologic 

insult after discharge 

from NICU.

Sample 1: 

BW 500-749 g (26)

Sample 2:

BW 750-999 g (63)

Sample 3:

BW 1000-1249 g (75)

Prospective cohort 

(followed to 24 months 

adjusted age)

Doyle

2001

21326609

Victorian Infant 

Collaborative 

study Group, 

1997

97290716

*some 

subjects were 

overlapped 

with 20307288 

(stated in text)

*possibly 

overlapped 

with 98026322

Location: Australia

Years of Birth: 1991-92

Mean GA (range), wk: 23-27

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 225

Evaluated: 225 (265 controls)

Number of sites: 1

Cases: GA 23-27 weeks, survived 

to 2 and 5 years of age

Controls: randomly selected 

Contemporaneous normal birth 

weight controls (BW > 2499 g)

ND Sample 1:

Pretem survivors

(N= 401)

Controls: Randomly 

selected 

contemporaneous 

normal birth weight 

controls (BW>2499 

grams) (N=265)

Prospective cohort 

(Doyle - 5 years; 

Victorian – 2 years)
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

238

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Corbet

1995

95264244

Location; USA

Years of Birth: 1986-1989

Mean GA:

 Sample 1: 27 ± 2

 Sample 2: 27 ± 2

Mean BW:

 Sample 1: 934 ± 179

 Sample 2: 931 ± 191

Males:

 Sample 1: 50%

 Sample 2: 50%

Race:

 Sample 1: whites: 41%, blacks: 

37%, others: 22%

 Sample 2: whites: 46%, blacks: 

36%, others: 18%

Enrolled: 1046

Evaluated: 597

Number of sites: Multicenter

Born alive

Qualifying BW (Not specified in 

this publications)

That were intubated and assigned 

randomly to receive either 

synthetic surfactant or air placebo 

as part of their participation in 3 

multicenter RCTS.

Had follow up at 1 yr of age

ND Sample 1:

Synthetic surfactant:

[314]

Sample 2:

Air placebo [283]

Combination of 3

multicenter, 

randomized, double 

blind studies of 

synthetic surfactant vs 

air placebo

[1 yr]

Gerdes

1995

95264241

Location: US

Years of Birth: 3/1989-4/1990

Mean GA (range), wk:

Experiment 1: 27.2±1.7

Experiment 2: 27.2±1.8

Mean BW (range), g:

Experiment 1: 907±121

Experiment 2: : 911±125

Male: 

Experiment 1: 55%

Experiment 2: 56%

Race: 

Experiment 1: White 55%, Black 

37%, Hispanic 4%, Other 5%

Experiment 2: White 60%, Black 

30%, Hispanic 5%, Other 5%

Enrolled: 826

Evaluated: 508

Number of sites: 33

Mothers who were expected to 

deliver premature infants with BW 

700-1100 g

All exclusion prenatal.

1) Proven fetal lung maturity 

2) Known malformation or 

chromosome anomaly

3) Fetal growth retardation

4) Hydrops

5) Purulent amnionitis

6) Maternal heroin addiction

7) Obstetric decision not to 

support fetus

Postnatal exclusions:

1) Major malformation

2) >3 minor anomalies

3) Hydrops

Experiment 1: One 

doses surfactant (244)

Experiment 2: Three 

doses surfactant (264)

Randomized 

comparison trial 

(1 year)
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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239

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Marlow

2000

20150342

Location: UK

Years of Birth: 1990-1994

Mean GA: ND

(Median and Range)

 Sample 1: 28 (26-31)

 Sample 2: 28 (26-31)

Mean BW: ND

(Median and range)

 Sample 1: 960 (600-2914)

 Sample 2: 1026 (410-2814)

Male: ND

Race: ND

Enrolled : 27 

Evaluated: 15 

Number of sites: 1

For sensorineural hearing loss 

(SNHL) group

GA: <33 wks

Family resident of Greater Bristol 

area

Records at Hearing Assessment 

Center of Royal Hospital for Sick 

children.

Born during 1990-1994

Diagnosis of SNHL of 50 dB

For control group:

Matched controls 2:1 to cases

Admitted to the same NICUs as 

cases

Matched for sex and GA and next 

and preceding matching children 

in the admission books of St 

Michael’s and Sothmead hospitals

ND Sample 1:

SNHL group [15]

Sample 2:

Control group [30]

Matched with cases for

sex, GA, admission

dates in NICU

Retrospective case 

control study with a 

longitudinal component 

(unclear if retrospective 

or prospective)

(12 mo CA)

Lee

1998

98442293

Location: Canada

Years of Birth: 1990-1995

Mean GA: ND

Mean BW:

 Sample 1: 763 ±157

 Sample 2: 807±176

Male: ND

Race: ND

Enrolled: ND (total N not given, 

data only for enrolled cases with 

candidemia: N= 29)

Evaluated: 50

Assessed for outcome: 35 (14 

cases and 21 controls)

Number of sites: 2

For cases:

Prematures with BW<1250 g

Admitted in the NICU s of UAH 

and RAH from 1990-1995

Diagnosis of candidemia: by at 

least one positive blood culture

Diagnosis of candidal meningitis:

By isolation of candida in the CSF 

or >45x10 6 WBCs in the CSF and 

candidemia.

For controls:

Prematures with BW <1250 g

Admitted to the same NICUs

during the same period without

candidal infection

Neonates with major 

congenital anomalies

Sample 1:

Premature infants <1250 

with candidemia and/ or 

candida

meningitis (25)

 Sample 2:

 Premature neonates 

with BW <1250 

matched with cases for 

BW, GA, sex and 

admission dates, 

with out candidal 

infection (25)

Retrospective

longitudinal 

comparative study with 

case control design and 

cases defined based on

exposure to candidemia

and matched controls

( f/up between 37 and 

70 mo CA)

Average age at

assessment: for cases

:31 ±19 mo, and for

controls: 28 ±20 mo 
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

240

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

DeReginer 

1997

98041177

Location: US

Years of Birth: 1987-1991

Mean GA (range), wk:

Sample 1: 28.0±1.5

Sample 2: 27.1±1.2

Sample 3: 27.5±1.7

Mean BW (range), g:

Sample 1: 1030±140

Sample 2: 1007±122

Sample 3: 1007±140

Male: ND

Race: ND

Enrolled: 174

Evaluated: 164

Number of sites: 2

BW =1500 g survived until 

Discharged

Able to match to a patient in other 

two respiratory groups

Presence of independent 

of chronic lung disease 

known to adversely 

affect 

neurodevelopment, 

sensory, or growth, i.e. 

severe intracranial 

abnormalities, 

congenital 

anomalies or viral 

infections, etc.

Unable to match to a 

patient in other groups

Died after discharged (6)

Lost to follow-up (4)

Sample 1: 

No chronic lung 

disease (58)

Sample 2:

Mild chronic lung 

disease (58)

Sample 3:

Severe chronic lung 

disease (58)

Retrospective chart 

review with marched 

subject group

(1 year of adjusted age)

Kurkinen-Raty 

1998

98387235

(All+Lung)

*sample from 

the same big 

population as 

20284814

Location: Finland

Years of Birth: 1990-1996

Mean GA (range), wk:

Cases: 28.2 (23.8- 37.2)

Controls: 28.4 (22.9-36.9)

Mean BW (range), g:

Cases: 1138.3±434

Controls: 1272.4±547.2

Male: ND

Race: ND

Enrolled: 78 (78 controls)

Evaluated: 78 (78)

Number of sites: 1

Preterm PROM between 17-30 

weeks gestation; singleton; 

delivered > 2 hr after rupture

Controls: preterm no PROM; 

spontaneous preterm delivery 

matched for GA and year of 

delivery.

Rupture unconfirmed or 

transient

Sample 2: Preterm 

rupture (78)

Sample 2: Preterm 

delivery no rupture 

(78)

Retrospective cohort

Kurkinen-Raty, 

2000

20284814

*sample from 

the same big 

population as 

98197235

Location: Finland

Years of Birth: 1990-1997

Mean GA (range), wk:

Cases: 30.5±2.1

Controls: 30.4±2.1

Mean BW (range), g:

Cases: 1294±469

Controls: 1605±427

Male: ND

Race: ND

Enrolled: 103 (103 controls)

Evaluated: 103 (103)

Number of sites: 1

Casarean delivered singleton, GA 

24-33 weeks

Controls: spontaneous delivered 

singleton after regular 

contractions and/or preterm 

rupture of the membranes no 

more than 24 hrs before. The 

mothers were matched one-toone by gestational age at 

delivery plus or minus 1 week.

ND Sample 1: Indicated 

preterm (i.e., preterm 

birth ‘indicated’ for 

maternal/fetal 

reasons (103)

Sample 2: Spontaneous 

preterm delivery due 

to preterm labor (103)

Retrospective cohort
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

241

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Northern 

Neonatal 

Nursing Initiative 

Trial Group

1996

96304894

Cardiovascular or Pulmonary 

Predictors: use of FFP or 

plasma substitute to expand 

vascular volume prophylactically

ND CNS Outcomes:

Motor delay

Cerebral palsy

Seizure disorder

Post hemorrhagic hydrocephalus

Ophthalmology:

Visual impairment

Blindness

Audiology Outcomes:

Hearing disorders

Speech

Other outcomes:

Blind, deaf, or unable to walk –

 combined outcome

No severe disability – combined 

 outcome

Overall developmental quotient –

 Griffith’s

Motor delay: Griffith’s gross motor 

quotient >350 below mean

Griffith’s quotient for speech + hearing 

>350 below mean

Hack

1996

97066007

General: Birth Weight 500-750 gm CNS: 

Cerebral palsy

Motor and cognitive delay

Ophthalmology: Blindness

Audiology: Deafness

Neurosensory status

BSID: MDI, PDI
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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242

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Hack

2000

20358826

General:

 1) Birth weight

 2)GA

 3) SGA/IUGR

 4) Antenatal steroids

 5) Jaundice

CNS:

1) Intracranial/Intraventricular 

Hemorrhage

2) Periventricular leukomalacia

3) Ventriculomegaly/ ventricular 

dilation

Cardiovascular/Pulmonary: 

Chronic lung disease

Gastrointestinal: Necrotizing 

“entroclitis”

Other:

 1) Infectious Disease

 2) Dexamethasone

 3) Perinatal factors 

(chorioamnionotis)

 4) Multiple birth

 5) C-section

 6) Social risk

 7) Male sex

ND CNS:

Cerebral palsy

Motor delay

Cognitive delay MDI score<70

Post hemorrhagic Hydrocephalus

Ophthalmology: Blindness

Audiology: Deafness

Neurologic abnormality - includes: 

CP, hypotonia, hypertonia 

Shunt-dependent hydrocephalus 
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

243

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Wood

2000

20373840

General:

1) GA

2) Gender

Other: Perinatal Factors‡

Multiple gestation

ND CNS: 

Motor delay

Cognitive delay

Seizure disorder

Overall development

Ophthalmology:

Visual impairment

Blindness

Audiology:

Hearing disorder

Deafness

Speech

Communication disorder

Other:

Severely disabled

Other disability

No disability

Disability of hearing, vision, or 

communication

Bayley scales 

Severe disability = need of physical 

assistance to perform daily activities. 

If disability did not fit into this category = 

“other disability”

Singer

1997

98049057

Singer

2001

21163669

Cardiovascular or pulmonary 

predictors: 

1) Bronchopulmonary 

dysplasia

General : BW, Neurologic risk

Other: Race, Socioeconomic 

status

BPD: preterm,<1500g BW, oxygen 

for >28 days with radiographic 

evidence of CLD

CNS outcomes:

Cerebral palsy

Cognitive delay

Mental retardation

Ophthalmology outcomes:

Visual impairment

Audiology outcomes:

Hearing disorders

Speech

Language

Communication disorder

Bayley scale of infant development

Language (speech/communication) 

measured by Battelle Developmental 

Communication Subscale Domain‡

receptive, expressive and total 

communication scores converted to 

DQ mean 100 and SD 15.
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

244

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Schmidt

2001

21298249

1) Prophylactic indomethacin 

administration : 0.1 mg/kg 

Q24 hrs X 3 days (vs NS 

placebo) in VLBW infants, 

during first 6 hrs of life

Nor further specified Primary outcomes at 18 months of 

age:

1) Composite outcome: death or 

impairment

2) Death before 18 mo corrected 

age

3) Cerebral palsy

4) Cognitive delay (MDI<70)

5) Hearing loss requiring 

amplification

6) Bilateral blindness

Secondary long term outcomes 

outcomes:

1) Hydrocephalus, necessitating 

the placement of shunt

2) Seizure disorders

3) Microcephaly (HC<3 d %)

1) Death before a corrected age of 18 

months or documentation in survivors of 

one of the following: CP, Cognitive 

delay, Hearing loss requiring 

amplification, B/L blindness

2) Cerebral palsy diagnosed if had 

nonprogressive motor impairment with 

abnormal muscle tone and decreased 

range or control of movements.

3) Cognitive delay: as MDI less than 

70 (2SD below the mean of 100) on the 

Bayley scale between 85-114: classified 

as normal, Scores below 70: marked 

cognitive delay.

4) Documentation of composite 

primary outcome: required 

documentation that the infant had died 

or had survived with one of the 4 types 

of impairment. A single missing 

component of the f/up assessment 

would result in designation of missing 

for primary outcome. A priori criteria for 

definitions of presence or absence of 

component of the primary outcome.

5) In cases it was difficult to obtain 

Audiologic test results, deafness 

requiring amplification was assumed to 

be absent if no such indication was 

present during the Bayley test. (n=27 )

6) Blindness: a corrected visual 

Acuity of less than 20/200. F/up 

evaluation around 18 mo: allowed range 

18-21 mo.

(Home visits were permitted when 

necessary)
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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245

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Battin

1998

99002694

General: 

1) GA (23-25 wks)

In comparative component with

historical control group

General:

1) Birth during a period with 

routine use of: antenatal 

steroids, surfactant and 

dexamethasone for BPD 

(vs birth in presurfactant, 

presteroid period)

ND CNS:

Neurodevelopmental outcome 

CP

Low MDI (below 2 SDs)

Ophthalmology- Audiology:

Blind, Deaf

Neurologic exam

Bayley scale: MDI, PDI

Formal hearing test

Ophthalmologic examination

Vohr

2000

20295211

General:

1) Birth weight

2) Maternal disease (HTN)

3) Antenatal steroids

CNS:

1) Intracranial/Intraventricular 

hemorrhage ( GR 3 to $ 

IVH/PVL)

Cardiovascular or Pulmonary:

1) Chronic lung disease 

(oxygen requirement at 36 

weeks)

2) Other: postnatal steroids

3) Other: Surfactant

Gastrointestinal:

1) Necrotizing “enterocolitis”

Other:

1) Other: male sex

2) Other: Race (white)

3) Other: sepsis (early and 

late onset)

4) Other: maternal education

GR 3 to 4 IVH. PVL undefined sepsis 

undefined

CNS :

Cerebral palsy

Neurodevelopmental:

Motor delay (sitting, walking, picer 

 grasp, feeding)

Seizure disorder

Post hemorrhagic Hydrocephalus 

 (PHH) and shunt

Other: Neurologic exam (normal; 

 abnormal)

Development (MDI and PDI by 

 Bayley II Scale) 

Ophthalmology :

Visual impairment (any)

Blindness (unilateral, bilateral)

Audiology:

Hearing disorders

“normal Neurologic exam”: no 

abnormalities on neurologic exams
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

246

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Piecuch

1997 

98012134

General predictors:

1) GA

CNS predictors:

1) intracranial/ intraventricular 

hemorrhage

2) periventricular leukomalacia

Cardiovascular or pulmonary 

predictors:

1) chronic lung disease

Other predictors:

1) social risk: economic

2) social risk: substance abuse

CLD - at 36 weeks PCA, requirement 

for supplemental O2

IVH grade 3 or 4 & PVL, according to 

sonogram

Social risk economic - maternal 

education <12 grade; complete 

unemployment in household; or 

government assistance for health 

insurance

Social risk substance abuse - positive 

toxicology screens or confirmed 

history of drug or alcohol abuse

CNS outcomes:

Cerebral palsy

Cognitive delay

Ophthalmology outcomes:

Visual impairment

Audiology outcomes:

Hearing disorders

Visual – Near point tests or Snellen eye 

charts

Audiologic - behavioral testing followed 

by BAER or pure tone audiometry.

Cognitive outcome - Bayley scales at 12 

and 18 months; Stanford-Binet at 

2.5-4 years; McCarthy scales at 4-6 

years.

Abnormal neurological outcome – CP, 

quadriplegia, dysplegia, hemiplegia

Suspicious neurological outcome -

clumsiness, tremors

Severe neurosensory abnormalities –

Bilateral hearing loss, blindness

Mild neurosensory abnormalities - high 

frequency hearing loss without 

hearing aids, visual deficit without 

glasses

Victorian Infant 

Collaborative 

study Group, 

1997 

97466059

Arch Dis Child

Other: time period of birth ND CNS:

Cerebral Palsy

Cognitive delay

Post Hemorrhagic Hydrocephalus 

(PHH) 

Ophthalmology: Blindness

Audiology: Deafness

Other:

Sensorineural disability: severe, 

mental, moderate, none.

CP neurologic exam 

Bayley MDI, PDI scores

Blindness-not stated

Deafness-not stated

Degrees of sensorineural delay are 

defined as an aggregate measure and 

are approximated. 

Victorian Infant 

Collaborative 

study Group, 

1997

98026322

General: BW

Other: period of time when born

Each sample were subdivided into 

BW=500-749 g and BW=750-999 g

1985-1987 vs. 1991-1992

CNS:

Cerebral palsy

Neurodevelopmental:

Cognitive and motor delay

Disability

Ophthalmology: Blindness

Audiology: Deafness or hearing aid

CP was not defined

Bayley Scales of Infant Development

DQ, using the published mean and SD

Disability: “Sever” – bilateral blindness, 

cerebral palsy with the child unlikely 

ever to walk, or a DQ score <-3SD; 

“Moderate” – bilateral sensorineural 

deafness requiring hearing aids, 

cerebral palsy in children not walking at 

2 but expected to walk, or a DQ score 

from –3SD to <-2 SD; “Mild” – cerebral 

palsy but walking at 2 , or a DQ score 

form –2 SD to <-1 SD.
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

247

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Ambalavanan

2000

21031370

General: BW, GA, Antenatal 

steroids, Apgar score

Other: Race, Gender Multiple 

gestation, Maternal education, 

Maternal age

CNS:

Intracranial hemorrhage

Periventricular/Ventricular 

Dilation

Bronchopulmonary dysplasia

GI: Necrotizing “entrocolitis” 

Interinal perforation, 

Chorioamnionitis

Multiple gestation

Maternal education

Maternal age

Extensive list of the 21 predictor 

variables

CNS:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

PHH

Neurologic exam

Major handicap

Ophthalmology:

Visual impairment

Blindness

Audiology:

Hearing disorders

Deafness

Bayley scales

Major handicap-presence of one or any 

poor outcome (i.e. CP, deadness, 

blindness). Mental retardation (MDI or

PDI <70), PHH requiring sheet

Cheung

1999

99146391

General predictors:

1) BW

2) GA

3) Apgar score

CNS predictors:

1) intracranial/ intraventricular 

hemorrhage

Cardiovascular or pulmonary 

predictors:

1) days of ventilation

2) days of O2 use

Other predictors:

1) frequency of apnea

2) mean desaturation of 

apnea

3) mean frequency of apnea

4) Blisten index 

(socioeconomic status)

ND CNS outcomes:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Seizure disorder

Neurodevelopmental disability

Ophthalmology outcomes:

Blindness

Audiology outcomes:

Hearing disorders

Growth outcomes:

Weight > 2 SD below the mean

Height > 2 SD below the mean

HC > 2 SD below the mean

Bayley scores

Stanford-Binet Intelligence Scale

Peabody Developmental Motor Scale

Neurodevelopmental disability: "children

with 1 or more of a) cerebral palsy b) 

legal blindness c) hearing loss d) 

convulsive disorder e) cognitive delay
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

248

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Doyle

2001

21326609

Victorian Infant 

Collaborative 

study Group, 

1997

97290716

*some 

subjects were 

overlapped 

with 20307288 

(stated in text)

*possibly 

overlapped 

with 98026322

General predictors:

1) GA

2) SGA/IUGR

3) antenatal steroids

4) gender (female)

5) postnatal age

CNS predictors:

1) intracranial/ intraventricular 

hemorrhage

2) periventricular leukomalacia

Cardiovascular or pulmonary 

predictors:

1) bronchopulmonary 

dysplasia

Other predictors:

1) dexamethasone

2) perinatal factors

a) multiple birth

b) cesarian section

3) socioeconomic variables

i) Asian mother

ii) higher SEC

iii) no Englishspeaking at home

4) surgery in primary hospital

5) patient with no adverse 

events

1) SGA/IUGR - BW ratio <0.8

2) intracranial/ intraventricular 

hemorrhage - Papille system

3) periventricular leukomalacia -

cystic lesions in PVWM dx < 

discharge

4) bronchopulmonary dysplasia -

ROS + O2 Rx after 28 days age

5) dexamethasone - postnatal 

steroid use

CNS:

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Ophthalmology outcomes:

Blindness

Audiology outcomes:

Hearing disorders

Deafness

Other:

Survival without major disability at 5 

 years age

Survival with major neurosensory 

 disability at 5 years age

1) motor delay, cognitive delay -

WPPSI-R and alternative IQ tests

2) cerebral palsy - not walking or 

walking with difficulty

3) mental retardation - IQ < 2 SD 

below mean for NBW group
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

249

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Corbet

1995

95264244

General:

1) Synthetic surfactant (single 

dose via ET tube of 5 

mg/kg vs air placebo)

Not further specified Growth:

Growth status at 1 yr:

1) Weight

2) Height, 

3) HC and percentiles distribution

Other: Health status at 1 yr:

1) Surgeries

2) Readmissions to hospital

3) CLD,Medications for CLD

4) Respiratory support on exam 

day

5) Medications for chronic 

neurologic disease

6) Asthma, Eczema

CNS: Neurodevelopmental outcome

1) MDI

2) PDI

3) Impairments: Present absent

4) Severity of impairment

5) Type of impairment (MDI<69, 

MDI 69-84)

6) CP

Audiology

1) B/L sensorineural deafness

2) Deafness not requiring 

amplification

Ophthalmology: (worst exam and 

last)

1) B/L blindness

2) Visual defect

3) No ROP, mild/moderate ROP, 

severe ROP)

4) Treatment for ROP (surgery, 

cryotherapy)

Assessment at 1 yr of corrected age

Not further specified
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

250

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Gerdes

1995

95264241

Cardiovascular or Pulmonary:

Surfactant use

ND CNS:

Cerebral palsy 

Cognitive delay

Mental retardation

Ophthalmology: Visual impairment, 

Blindness

Audiology: Hearing Disorder, 

Deafness

Pulmonary: 

1) Asthma

2)e/o CLD

3) respiratory support @ 1yr

Growth: Height, Weight, HC

Other: hospital re-admissions, h/o 

surgery

Mental retardation Bayley Scales 

MDI<69
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

251

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Marlow

2000

20150342

General: 1) Birth weight 

2) Apgar score 3) CRIB scores

CNS:

1) Maximum bilirubin level

2) Abnormal cerebral US scan

Audiology:

1) Sensorineural hearing loss

Cardiovascular/Pulomonary:

1) Duration of intubation, 

respiratory support, oxygen, 

pH<7.2, base excess 

2) Dopamine 3) Furosemide

4) Indomethacin use

Other:

5) Netilmicin 6) Vancomycin

7) Positive blood cultures

8) Bilirubin >200 ?mol/l

9) Bilirubin>GA x 10

10) Creatinine >60 mmol/l

11) Netilmicin 12) Vancomycin

Combination of the above:

1) Bili.200 + acidosis

2) Bili> 200 + sepsis

3) Bili >200+ netilmicin

4) Bili> 200+ vancomycin

5) Bili>200+ furosemide

6) Peak bil+ acidosis

7) Peak bili+ sepsis

8) Peak bili+ netilmicin

9) Peak bili+ furosemide

10) Creatinine>60+ netilmicin 

or vancomycin or furosemide

11) Netilmicin+furosemide

12) Vancomycin+ furosemide

Not further specified In case control component:

Audiology:

1) Sensorineural hearing loss 

(SNHL) of 50 dB within 9 months 

from birth

In Longitudinal component:

CNS:

1) Cerebral palsy at 12 months of 

age in the 2 groups (SNHL and 

control group)

Cases of SNHL were identified if the 

hearing loss had been identified within 3 

months of discharge home, (within 9 mo 

from birth); after excluding cases with 

conductive hearing loss, possible 

congenital cause, or had neonatal 

bacterial meningitis
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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252

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Lee

1998

98442293

General:

1) Candidemia and/or 

Candidal meningitis

Diagnosis of Candidemia: by at least 

one positive Blood Culture

Diagnosis of Candidal meningitis:

by isolation of Candida in the CSF or 

>45x10 6 WBCs in the CSF and 

candidemia.

CNS:

1) Neurodevelopmental disabilities 

(NDDs) 

2) Cognitive delay

3) Cerebral palsy 

Ophthalmology:

1) Legal blindness 

Audiology:

1) Hearing loss 

Growth:

1) Growth retardation

1) Bayley Scales of Infant 

development; MDI, PDI for ages < 

24 mo.

2) Stanford-Binet Intelligence Scale 

and Peabody Development Motor 

Scales for ages > 24 mo .

3) Scores obtained by psychologists, 

psychometricians, pediatricians 

specialized.

Neurodevelopmental Disabilities:

1) Cerebral palsy (all types and 

severity)

2) Legal blindness (corrected VA of 

the better eye<20/200)

3) Hearing loss (neurosensory 

hearing loss in the better ear > 30 

dB) (done by certified audiologist

4) And/or cognitive delay (MDI>3 

SDs below the mean)

Growth retardation: Weight, Height, HC 

> 2 SDs below the mean

(Between 3-6 yrs CA)

DeReginer 

1997

98041177

Cardiovascular/ Pulmonary: 

Chronic lung disease

Classification based on the duration

of supplemental oxygen 

requirements.

“No CLD” – breathing room air at 28 

days

“Mild CLD” – requiring supplemental 

oxygen at 28 days but not at 36 

weeks PMA

Sever CLD” – reqiring oxygen at 28 

days and 36 weeks PMA

General:

Motor and cognitive delay

Cerebral palsy

Opthalmology: 

Visual impairment

Blindness

Audiology: 

Hearing loss

Deafness

Growth: 

Weight Z score

Length Z score

Head circumference Z score

Other: any adverse outcome

Bayley PDI & MDI
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part II

253

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Kurkinen-Raty 

1998

98387235

*sample from 

the same big 

population as 

20284814

General : PROM Diagnose was through clinical 

assessment or with the use of a 

PROM-test, which detects insulin 

growth factor binding protein-1 in the 

cervico-vaginal secretions, or with the 

use of a nitrazine test.

CNS:

Motor delay

Cerebral delay

Ophthalmology: Visual Blindness

Audiology: Hearing disorders

Pulmonary: Chronic lung disease

Growth: weight percent

Other:

Days of re-hospitalization

Steroid therapy at followed up 

Neurologic exams

Diagnosis of CLD was made if infants 

required oxygen, continuous 

bronchodilator, or steroid tx because 

of respiratory signs and symptoms.

Diagnoses of RDS were made based on 

need for respiratory support, 

radiologic findings, and clinical 

assessments

Kurkinen-Raty, 

2000

20284814

*sample from 

the same big 

population as 

98197235

General predictors:

Birth weight

GA

Antenatal steroids

Cord pH

Bronchopulmonary dysphasia 

(BPD)

Other predictors: 

Indicated preterm delivery

Spontaneous perterm delivery

BPD diagnoses were based on 

radiologic finding

CNS: 

Motor delay

Cerebral palsy

Ophthalmology

Visual impairment

Audiology

Hearing disorder

Pulmonary

Chronic lung disease (CLD) at 1 year

Growth:

Wt, Ht, HC

Motor delay = abnormalities of tone or 

reflexes but functionally normal or 

borderline

CP = spastic diplegia or hemiplegia or 

spastictetraplegia

Diagnosis of CLD was made if infants 

required oxygen, continuous 

bronchodilator, or steroid tx because 

of respiratory signs and symptoms.
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Northern 

Neonatal 

Nursing Initiative 

Trial Group

1996

96304894

No significant differences by Griffith’s Developmental quotients, incidence of 

CP, seizures, hearing disorders. Initial demographics available in an earlier 

study.

Study was government and private 

funded

Hack

1996

97066007

Pediatrics

 MR (MDI<84) CP Blind Deaf Major Neurosensory abnormal

 +MDI<80

1982-1988 52% 10% 10% - 49%

1990-1992 34% 10% 2% 6% 35%

20-month Neurodevelopmental outcomes did not change appreciably between the 2 eras. 

20% of infants had subnormal cognitive function (MDI<70) and 10% had CP 

during 1990-1992 period. One third of infants with BW 500-750 gram had 

major neurosensory abnormalities and / or MDI<80. 

No data on funding source

Hack

2000

20358826

MDI Score < 70:

 CLD: 55% (49/89); 2.18 (1.20-3.94)

MDI Score<70 (multi stepwise logistic regression) 

 Male sex: 2.73 (1.52-4.92)

 Social risk: 1.48 (1.09-2.00)

 CLD: 2.18 (1.20-3.94)

OR adjusted for sex, social risk & BW:

 Gr III-IV IVH: 

 50% (16/32); 8.55 (3.52-20.76)

 50% (8/16); 4.45 (1.54-12.84)

 50% (17/34); 5.48 (2.41-12.47)

 CLD: 30% (27/89); 3.09 (1.51-6.35)

 Sepsis: 14% (13/93); 3.47 (1.16-10.36)

 Jaundice: 26% (6/23); 5.15 (1.63-16.22)

Mult. Stepwise Logistic regression:

 Male sex: 2.79 (1.02-7.62)

 Sepsis: 3.15 (1.05-9.48)

 Jaundice: 4.80 (1.46-15.73)

Predictors of neurologic abnormality were a severely abnormal finding on cerebral ultrasound (OR, 8,09; 95% CI 

3.69-17.71) and chronic lung disease (OR 2.46; 95% CI 1.12-5.40); predictors of deafness were male sex (OR 

2.79 95% CI 1.02-7.62), sepsis (OR 3.15 95 % CI 1.05-9.48), and jaundice (maximal bilirubin level >171)

The authors concluded that there is an 

urgent need for research into the 

etiology and prevention of neonatal 

morbidity.
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Wood

2000

20373840

Infants 22-25 weeks GA developmentally assessed at median 30 months

• 138/283 had disability 49%(64 met criteria for severe disability)

• 49% no disability

• 53/283 severely delayed 19%(Bayley below 3 SD)

• 32/283 2-3 below SD 11%

• 28 severe neuromotor disability 10%

• 7 blind or perceived light only 2%

• 8 hearing loss that was uncorrectable or required hearing aids 3%

 Survived without overall disability

 22 wks--------------0.7 %

 23 wks--------------5%

 24 wks--------------12%

 25 wks--------------23%

Severe disability at 30 months

 22 -------------------0.7%

 23 --------------------3%

 24---------------------6%

 25---------------------9%

• no relation between morbidity pattern and either gestational age &multiple birth 

• boys were likely to be disabled than girls

Severe disability common; children born 

extremely premature
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Singer

1997

98049057

Singer

2001

21163669

Evaluation at 36 months corrected age. VLBW, VLBW with BPD, full term (FT).

 Bayley MDI % with MDI below 70

VLBW 90 + 16 (38-126) 11%

VLBW w/ BPD 84 + 24 (10-116) 21%

FT 96 + 12 (57-127) 4%

P = 0.001 for VLBW vs. VLBW w/ BPD

 Bayley PDI % with PDI below 70

VLBW 98 + 20 (33-122) 9%

VLBW w/ BPD 84 + 29 (8-127) 9%

FT 103 + 15 (58-128) 1%

 P = 0.001 for VLBW vs. VLBW w/ BPD

At 3 years BPD predicted poorer motor outcome but not poorer mental outcome.

Receptive DQ: BPD < VLBW < Term, p < 05

Receptive DQ < 85: BPD 49%, VLBW 34%, Term 30%,

BPD < VLBW + Term p < .05

Expressive DQ: BPD < VLBW + Term, p < .05

Expressive DQ<85: BPD 44%, VLBW 25%, Term 25%

BPD < VLBW + Term p < .05

Communication DQ: BPD < VLBW + Term, p < .05

Communication DQ < 85: BPD 43%, VLBW 31%, Term 28%, NS

Rank order listing of risk factors in order of magnitude of effect and the number of communication DQ lowered by 

the risk factor: PDA lowered DQ by 13 points, Minority race by 6 points, lower socioeconomic status by 5 points, 

and higher neurologic risk by 5 points. p .001

Bayley Scales MDI:

BPD 83.7 ± 24, VLBW 90 ±16, Term 96.4 ± 12, BPD < VLBW < Term, p< 0.05

Bayley Scales PDI:

BPD 84.1 28, VLBW 97.4 19, Term 102.8 14

BPD < VLBW + Term, p< .05

ROP: BPD 43%, VLBW 4%, p= .001

Seizures: BPD 7%, 

Neurologic score: BPD 1.3 ± 2, VLBW 58 ± 1, p < .001

Single region, but at least it is a region

Unclear if examiners were blinded to 

groups status

Study was government funded
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Schmidt

2001

21298249

1) There was no difference in primary outcomes between the 2 groups at 18 months of age.

2) Among the 574 infants who were assigned to prophylaxis with indomethacin, 271 (47%) died or survived with 

impairment as compared with 261 of 569 infants (46%) assigned to placebo (OR: 1.1; 95% Confidence intervals; 

0.8-1.4)

3) In VLBW infants, prophylaxis with indomethacine does not improve the rate of survival without neurosensory 

impairments at 18 months of age

4) There was no difference in any of the secondary outcomes between the 2 groups, at 18 months of age.

Primary: Composite / CNS Outcomes: Indomethacin vs. Placebo

• Death or impairment 271/574(47%) vs. 261/569 (46%)

• Death before 18 mo 121/595 (21%) vs 111/594 (19%)

• Cerebral palsy 58/467 (12%) vs 55/477 (12%)

• Cognitive delay (MDI<70 by Bayley scale 118 /444 (27%) vs 117/457 (26%)

Audiology outcome:

• Hearing loss requiring amplification 10/456 (2%) vs 10/466 (2%)

Ophthalmology outcome:

• Bilateral blindness 9/456 (2%) vs 7/472 (1%)

(Odds ratios adjusted for BW stratum and Center)

Secondary CNS outcomes were not affected by indomethacin administration:

• Hydrocephalus requiring shunt 15/470 (3%) vs 9/480 (2%)

• Seizure disorder 8/470 (2%) vs 7/483 (1%)

• Microcephaly 49/461 (11%) v s 54/475 (11%)

Kaplan Meier estimates of survival in the 2 groups:

• 0 months n=601 vs 601

• 6 months n=479 (80%) vs 490 (82%)

• 12 months n=473 (79%) vs 487 (81%)

• 18 months n=470 (78%) vs 483 (80%)

1) By using the Bayley test at 18 mo 

the authors found that more than 

one quarter of all surviving infants 

had moderate to severe cognitive 

delays, defined by MDIs< 70. The 

validity of the MDI score at this age 

as a predictor of later intellectual 

functioning remains to be 

determined.

2) At a post hoc calculation the study 

had a 90% power to detect a 20% 

reduction in risk, had it existed

3) Authors report that the outcome 

assessments were done blindly by 

investigators unaware of treatment 

groups assignments

4) Authors report that they had almost 

complete ascertainment for the 

primary outcome at 2 yrs of age.
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Battin

1998

99002694

CNS outcomes:

Major impairment was present in 36% of infants born at 23-25 wks GA, during 1991-1993 (N=44)

1) Cerebral palsy 9/44 (20%)

2) Low MDI 8/44 (18%)

Ophthalmology outcome:

1) Blind 4/44 (9%)

Audiology outcome:

1) Deaf 4/44 (9%)

Combined outcome:

1) Overall impaired 16/44 (36%)

2) Multiple handicaps 6/16 (38%)

Analysis of only 24-25 wks GA infants (N=43):

Major handicaps: 15/44 (34%)

The percentage of infants with major impairments and/ or multiple handicaps, for the 23-25 wks GA group, was 

the same in 1991-1993 and 1983-1989 periods 

(However, no data on the number of infants from this cohort that were actually followed up at 18 mo of age)

1) During 1991-93 period there is no 

concurrent control group for the 

comparative assessment of 

neurodevelopmental outcome 

2) Group of infants of 23-25 wks GA, 

born during 1991-1993, was not 

matched to the historical control 

group born during 1983-1989. 

Possibility of confounders cannot 

be excluded.

3) No data were given on the number 

of infants in the historical control 

group that had f/up at 18 mo of 

age.

No data on source of funding

Vohr

2000

20295211

Studied effect of early IVH at 5 to 11 hours of age on IQ distribution and presence of cerebral palsy (CP). 

Assessed at 36 months CA.

 Early IVH present Early IVH absent P value

 N 29 249

Binet IQ 78.7 (25) 87.5 (20) 0.09

Binet IQ < 70 38% 19% 0.03

PPVT-R 76.6 (28) 86.0 (21) 0.15

CP at 36 months 25% 8% 0.01

Later IVH had effect on Binet IQ similar to early IVH.

IVH rates seems high

No data on funding source
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Piecuch

1997 

98012134

Mean age at follow-up was 32 months. Bayley exams were done at 18 months.

Neurologic abnormalities and CP did not differ significantly across the gestational ages of 24 to 26 weeks.

Between 67% and 89% were normal in each gestational age group.

Significant differences (P = 0.036) related to gestational age were found in 18 month Bayley exam scores when 

group as normal borderline or deficient

 Normal Deficient

24 wk 28% 39%

25 wk 47% 30%

26 wk 71% 11%

Significant differences (P = 0.008) related to gestational age were found in the combined end point of CP or an 

abnormal Bayley exam score:

 Neither One Both

24 wk 28% 39% 33%

25 wk 47% 23% 30%

26 wk 63% 34% 3%

All inborn infants

No data on funding source

Victorian Infant 

Collaborative 

study Group, 

1997 

97466059

All children born outside the level III perinatal centers. Assessment at 2 years corrected age. 

 1985-1987 1991-1992

 n 19 16

Cerebral Palsy 19.1% 12.5%

Cognitive delay 19.1% 18.8%

Blind 5.6% 6.2%

Deaf 0 0

Sensorineural disability

Mild 15.8% 6.2%

Moderate 0 0

 Severe 5.3% 12.5%

Incomplete reporting of demographic 

data, methods and results.

Study was government funded
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Victorian Infant 

Collaborative 

study Group, 

1997

98026322

Birth weight < 1000g; assessed at 2 years corrected age.

Cohort n DQ < -3 SD DQ –3 to –2 SD DQ –2 to –1 SD DQ> -1 SD

‘91-’92 237 5.9% 6.3% 13.9% 73.4%

‘85-’87 211 6.2% 4.3% 14.2% 75.4%

Cohort n Mild CP Mod. CP Severe CP Any CP Blindness Deaf

‘91-’92 237 3.8% 1.7% 3.8% 9.3% 2.1% 0.8%

‘85-’87 211 NS NS NS 6.6% 4.3% 0.5%

Cohort No disability Mild Disability Moderate disability Severe disability

‘91-92 71.3% 14.8% 7.2% 6.8%

n = 237

‘85-’87 71.6% 15.6% 6.2% 6.6%

n = 211

Incomplete reporting of demographic

data, methods and results.

Study was government funded
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Ambalavanan

2000

21031370

ELBW:

MDI<68 : 12%

PDI<68: 20%

Major handicap: 28%

CP:28%

MR 16%

Post-hemorrhagic hydrocephalus: 5%

Deaf 1.4%

Blindness 1%

Predictors of major handicap (Low MDI and/or PDI): Grade of IVH, PVL, absence of chorio (in this population, not 

in most others), NEC>II; race; multiple gestation, BPD, maternal education

For ELBW infants without IVH, the prevalence of major handicap, low MDI, and Low PDI was 25%, 17%, 16%, 

respectively.

For ELBW infants with grade III IVH, the prevalence of major handicap, low MDI, and Low PDI was 33%, 29%, 

24% respectively.

For ELBW infants with grade IV IVH, the prevalence of major handicap, low MDI, and Low PDI was 69%, 44%, 

63% respectively.

This study identifies major determinants of adverse neurodevelopmental outcome (i.e. major handicaps, low MDI, 

low PDI) of ELBW (<1 kg) infants born 1990-1994. Grade of IVH is strong predictor of adverse outcome. But 

note large % of ELBW without IVH who had major handicap, low MDI, and Low PDI. BPD was a significant 

determinant of low MDI and PDI. Mat education level was significant determinant of neurodevelopmental 

outcome. NEC, race, multiple gestation, PVL independently contributed to poor outcome in ELBW infant. Lower 

BW predicted low PDI.

Retrospective, relatively small sample 

size (218).

No data on funding source

Cheung

1999

99146391

Mental score:

 Days of ventilation: (N=64) <0.0001 

Motor Score:

 Days of ventilation: (N=164) <0.004

Mental Score:

 Grade of IVH: (N=164) 0.003

Motor Score:

 Grade of IVH: (N=164) <0.0001

Mental Score:

 Infants <1250g with gr. 3 or 4 IVH: (N=50) <0.001 

Motor Score:

 Infants <1250g with gr. 3 or 4 IVH: (N=50) <0.001

No data on funding source
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Doyle

2001

21326609

Victorian Infant 

Collaborative 

study Group, 

1997

97290716

*some 

subjects were 

overlapped 

with 20307288 

(stated in text)

*possibly 

overlapped 

with 98026322

Evaluation at 5 years corrected age:

CP : 23-27 wk survivors (11.3%) 25/221 Blindness : 23-27 wk (1.8%) 4/221

 FT controls (0%) FT control 0%

Deafness : 23-27 wk (0.9%) 2/221

FT control 0%

IQ <-2 SD: 23-27 wk (15.4%) 34/221

 Major neurosensory disability 

23 –27 wk (19.6%) 44/225 FT control (4.1%) 10/245

Major disability among survivors

 23 wk GA: 2/5 (40%) 24 wk GA: 7/21 (33%)

 25 wk GA: 13/51 (25%) 26 wk GA: 17/71 (24%)

 27 wk GA: 5/79 (6%) Overall 23-27 wk: 19%

OR for survival with major disability at 5 years:

OR each 1 wk increase in GA = 0.59 (95% CI 0.43, 0.8)

Prognostic factors with major disability at 5 years: IVH, cystic PVL, surgery during primary hospitalization, 

postnatal steroid treatment.

Rates of survival free of major disability for surviving PT infants: 

None 96/103 =93% One 59/71 =83 % 

Two 23/43 =53 % Three 3/9 =33%

Four 0/1 = 0

Evaluation at 2 years corrected age. Data shown are for births in 1991-1992.

Gestational age Sensorineural disability (% of survivors)

 n Severe Moderate Mild None

23 weeks 5 29% 20% 40% 20%

24 weeks 21 14.3% 19% 33.3% 33.3%

25 weeks 51 5.9% 21.6% 25% 47%

26 weeks 68 8.8% 11.8% 20.6% 58.8%

27 weeks 74 1.4% 10.8% 23% 64.9%

Overall 219 6.4% 14.6% 24.2% 54.8%

Decrease in disability with increase in gestational age was significant, p = 0.014.

Also showed significant fall in severe disability with increase in gestational age, Odds ratio = 0.58 (0.36-0.94)

Comparison of cohorts born in 1985-1987 vs. 1991: 1992 did not demonstrate any difference between cohorts.

Perinatal data lacking on some infants, 

Especially outborn (in level II or I)

Different methods of testing IQ

Different times of assessing 

Neurodevelopmental outcome

Some children not evaluated at 5 years 

(evaluated at 2 years)

210/401 preterm infants were assessed 

at both 2 and 5 years

The classification of disability or no 

disability was the same at both 2 and 

5 years (90.5% agreement; k=0.691)

Inadequate discussion of study 

population demographics 

Also various surrogate data

Study was government funded
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Corbet

1995

95264244

Growth AT 1 YR: Mean measurements of Height (74 cm), weight (9.1 kg) and HC (46 cm) and growth percentiles 

were equivalent in the 2 groups.

Health Status AT 1 YR: No difference in parameters between 2 groups

1) Surgeries (33% vs 34%) 2) Readmission to hospital (45% vs 39%)

2) CLD (11% vs 10%) 4) Medications for CLD (14% vs 14%)

3) Respiratory support (4% vs 2%)

4) Med. for chronic neurologic problems (1% vs 2%)

5) Asthma (this only was s/s : 9% vs 3%) 8) Eczema (2% vs 1%)

Neurodevelopmental Outcome: No difference in the outcomes between the 2 groups in these parameters.

1) Mean MDI (values <50= 49): 2) Mean MDI (only children with MDI>69)

2) Number of children with MDI<69: 4) Number of children with PDI<69

3) Mean PDI (values<50=49) 6) Mean PDI (only children with PDI>69)

CNS Impairment: No difference in any impairments between 2 groups

1) Present: 43% vs 37% 2) Absent: 57% vs 63%

2) Mild/moderate: 20% vs 14% 4) Severe:23% vs 23%

3) MDI<69: 17% vs 16% 6) MDI: 69-84: 18% vs 14%

4) CP mild: 8% vs 7% 8) CP moderate/severe: 7% vs 7%

Audiology:

1) B/L sensorineural hearing deafness: 0% vs 1% 

2) Deafness not needing amplification: 0% vs 1%

Ophthalmology:

1) B/L blindness: 3% vs 2% 2) Visual defect: 8% vs 8%

Worst examination

2) No ROP: 30% vs 33% 2) Mild/moderate ROP: 53% vs 52%

3) Severe ROP: 17% vs 15% 4) Surgical treatment for ROP:10% vs 12%

4) Cryotherapy for ROP: 5% vs 6%

Last examination

5) No ROP: 69% vs 72% 2) Mild/moderate ROP: 26% vs 22%

6) Severe ROP: 5% vs 6% 4) Surgical treatment for ROP: 4% vs 4%

7) Cryotherapy for ROP: 2% vs 3%

Infants who survived after treatment at birth with single dose synthetic surfactant fare as well in terms of growth, 

development and late morbidities as infants who survive without treatment. No difference in medical history during 

first year of life, growth, incidence of visual or auditory defects, CP, neurodevelopmental delay at 1 yr adjusted 

age.

The incidence of severe impairment in 

the 19% of infants who did not return 

for evaluation at the age of 1 yr may 

be higher than in those who were 

evaluated.

Source of funding not reported.

The neurodevelopmental evaluation of 

infants at 1 yr may not be absolutely 

reliable for the estimation of later 

outcome.

The estimated mental retardation is 

likely to be low, and the estimated CP 

is likely to be high, compared to 

estimates at 2 and 3 yrs.
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Gerdes

1995

95264241

Severe ROP:

 1 dose: 47(16) 3 dose: 35(11)

Physical evidence of CLD:

 1 dose: 43(18) 3 dose: 40(15)

Medication for CLD:

 1 dose: 35(14) 3 dose: 30(11)

Medication for chronic neurologic disease:

 1 dose: 12(5) 3 dose: 3(1)

Index<2 SD (%):

 1 dose: 29(15) 3 dose: 30(13)

Impairment present:

 1 dose: 106(44) 3 dose: 92(35)

No impairment:

 1 dose: 123(51) 3 dose: 155(59)

Severity of impairment:

 Mild/moderate:

 1 dose: 40(17) 3 dose: 39(15)

 Serious:

 1 dose: 66(27) 3 dose: 53(20)

Types of impairments:

 MDI<69:

 1 dose: 40(16) 3 dose: 38(14)

 Moderate/severe CP:

 1 dose: 22(9) 3 dose: 16(6)

 Bilateral sensorineural deafness:

 1 dose: 5(2) 3 dose: 10(2)

 Deafness not requiring amplification:

 1 dose: 5(2) 3 dose: 2(1)

 Bilateral blindness: 

 1 dose: 10(4) 3 dose: 4(2)

 Visual defect: 

 1 dose: 24(10) 3 dose: 22(8)

25% loss to follow up, equal in both 

groups; 1 year follow-up does not 

predict long-term outcome from all 

infants

No data on funding source

“Prenatal and postantal 

exclusion criteria were 

identical to those used in an 

earlier prophylactic trial of 

this synthetic surfactant”

Died by 1-year adjusted age 

Lost to follow-up
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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265

Author, Year Associations found Potential Biases

Marlow

2000

20150342

Pulmonary and Other predictors evaluation for Audiology outcome.

Children with sensorineural hearing loss [15] as compared to control group[30] had longer periods of:

1) Intubation, (14 ds vs 2 ds)

2) Ventilation (34 ds vs 6 ds)

3) Oxygen therapy (57 ds vs 10 ds) 

4) Acidosis (12 ds vs 0.5 ds), and 

5) More treatments with dopamine (33% vs 7%)or

6) Furosemide (87% vs 53%)

7) Neither P/T of aminoglycosides 

8) nor duration of jaundice 

9) or level of bilirubin varied between the 2 groups. 

SNHL was more likely when :

1) netilmicin use coexisted with the peak of bilirubin (87% vs 14%)_

2) when acidosis occurred when bilirubin was over 200 ?mol/l, (31% vs 4%)

3) when furosemide was used in the face of high creatinine levels (64% vs 27%)

4) when furosemide was used with netilmicin (67% vs 37%)

CNS outcome at 12 mo:

At 12 months of age evidence of cerebral palsy was present in 7/15 (47%) of children with SNHL vs 2/30 (7%) of 

children without SNHL.(p=0.022)

1) Very small sample size (cases 

with SNHL only 15)

2) Analyzed too many predictors 

and combination thereof, for very 

few outcomes. Very wide 

confidence intervals; and even 

those predictors found to be 

associated with the SNHL this 

may have been due to chance.

3) The association found between 

SNHL and cerebral palsy was not

based on an adjusted analyses for 

possible confounders; 

4) The 2 groups were different in 

many factors that were associated 

with both SNHL and CP

Not reported source of funding
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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Author, Year Associations found Potential Biases

Lee

1998

98442293

Growth, CNS and Audiology, and 

ophthalmology outcomes for 

prematures<1250 g with candidemia/candida 

meningitis 

Growth:

1) No difference in Growth retardation: 

CNS:

1) No difference in MDIs of survivors

2) Lower PDIs in survivors

3) No difference in overall 

Neurodevelopmental disabilities (NDDs)

4) Cerebral palsy

Ophthalmology:

1) Vision loss

Audiology:

1) Hearing loss

(All the children with NDDs had Cerebral palsy 

with or without visual or hearing deficit)

Prematures<1250 g with candidemia/candida 

meningitis had: Higher Combined mortality and 

NDDs

Cases

7/14 survivors(50%)

83 ±20

71 ±21

4/14 (29%)

4/14 (29%)

2/14 (14%)

2/14 (14%)

60% 

(OR=3.9; 1.2-12.6)

Controls

11/21 survivors (50%)

90 ±20 (p>0.05)

87±18 (p<0.05)

3/21 (14%) (p>0.05)

3/21 (14%)

1/21 (5%)

1/21 (5%)

28% (p< 0.05)

Cannot exclude missed association due 

to the small number of patients 

analyzed n both groups
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

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267

Author, Year Associations found Potential Biases

DeReginer 

1997

98041177

Chronic lung disease 

Any adverse outcome:

 2/54 

 12/54 P<0.001

 18/56

Sensorineural hearing loss:

 0/54 

 0/54 P<0.05

 3/56

Low MDI<2 SD from mean:

 0/54 

 4/54 P<0.05

 5/56

Low PDI<2 SD from mean:

 1/54 

 4/54 P<0.05

 7/56

Weight Z-score:

 No numbers given <0.05

Chronic lung disease and cerebral palsy, unilateral blindness, length Z-score,

head circumference Z-score are not significant.

Matching scheme used is likely to be 

ineffective

Large proportion of study population 

excluded by their matching strategy: 

subjects excluded were: 

329/387=85% with no chronic lung 

disease; 53/111=47.7% with mild 

chronic lung disease; 122/180=68% 

with severe chronic lung disease

No data on funding source

Kurkinen-Raty 

1998

98387235

*sample from 

the same big 

population as 

20284814

Retrospective controlled cohort study of early PROM between 17 and 30 weeks of gestation. Assements at one 

year corrected age. N = 55 for early PROM and 56 for control.

Outcome Early PROM Control OR (CI)

Cerebral palsy 18% 16% 1.2 (0.4, 3.1)

Delayed motor

Development 9% 16% 0.5 (0.2, 1.7)

Visual disability 4% 4% 1.0 (0.1, 7.5)

Hearing loss 7% 9% 0.8 (0.2, 3.2)

Good nuerosensory

development 67% 61% 1.2 (0.6, 2.2)

Early PROM seems to be a major obstetric and neonatal problem with pulmonary ramifications extending beyond 

the neonatal period. However, most of these infants can be saved.

No data on funding source
Evidence Table 5B. Studies Evaluating Association of LBW to Audiology Outcomes

Part III

268

Author, Year Associations found Potential Biases

Kurkinen-Raty, 

2000

20284814

*sample from 

the same big 

population as 

98197235

CLD at 1 year age: 

Indicated PT delivery: (81) 12/81 (15%)

Spontaneous PT delivery: (94) 3/94 (3%)

RR 4.6 (1.4, 1.6)

Growth: 

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94) 

Weight RR =0.03 (-5.3, 0.3)

L RR = 0.002

HC RR = 0.03

CP:

Indicated PT delivery: (81) 5/81 (6%)

Spontaneous PT delivery: (94) 10/94 (11%)

RR=0.6 (0.25-1.6)

Delayed motor:

Indicated PT delivery: (81) 8/81 (6%)

Spontaneous PT delivery: (94) 8/94 (9%)

RR 1.2 (0.5-3.0)

Visual disability:

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94)

RR =1.9 (0.5, 7.8)

Hearing loss:

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94)

RR =1.9 (0.5, 7.8)

This study demonstrated that premature infants who were born due to ‘indicated maternal/fetal reasons’ vs. 

spontaneous preterm delivered infants had worse pulmonary outcome a 1 yr age. More infants in ‘indicated’ 

group were SGA and were significantly smaller than control group at 1 yr in Wt, HT, and HC. There was no 

difference between groups in neurosensory outcomes.

Outcome not well defined

Difficult to know if lack of difference 

between 

groups is due to sample size or event 

rate. 

No data on funding source
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part I

269

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Nadeau

2001

21163667

Location: Canada

Years of Birth: 1987-1990

Median GA (range), wk:

Cases: 27.4±1.1

Control: 39.8±1.6

Median BW (range), g:

Cases: 1024.3±204.2

Control: 3453.4±497.8

Male: 

Cases: 51%

Control: 50%

Race: ND

Enrolled: 129

Evaluated: 86 ? 61 (50 controls)

Number of sites: 1

Cases: GA<29 weeks, BW<1500 g

Controls: Normal BW children , 

born at the same hospital during 

the same time period

Cases:

Lost to follow-up at 5 years 

9 months: families had 

moved away (33), 

parents’ refusal (10)

Lost to follow-up at age 7: 

families had moved 

away (10), parents’ or 

school’s refusal (13)

Cases: EP/VLBW 

infants (86? 61)

Prospective cohort 

(at 18 months, 5 years 

9 months, and age 7)

Robson

1997

9055145

Location: Canada

Years of Birth: ND

Mean GA (range), wk: 32.6±3.4

Mean BW (range), g: 

1758.7±521.7

Male: 36%

Race: ND

Enrolled: 132

Evaluated: 85

Number of sites: 2

LBW cohort: ≤ 2500 g

Admitted to neonatal intensive 

care units at 2 hospitals in a 

mid-sized Canadian city.

English-speaking mothers.

Families lived within 100 km of 

either hospital.

Assessments at 7 mos and 12 

mos of age.

Significant visual or motor 

impairments or any 

other gross neurological 

or physical anomalies.

Cases:

85 LBW infants

No control group 

Prospective single-arm 

cohort study
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part I

270

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Breslau

1996

8836807

Location: US

Years of Birth: 1983-1985

Mean GA (range), wk: ND

Mean BW (range), g:

Urban LBW: 14.7%<1500 g, 

21.4% 1501-2000 g, 63.9% 2001-

2500 g.

Suburban LBW: 17.4%<1500 g, 

17.9% 1501-2000 g, 64.7% 2001-

2500 g.

 Urban NBW: ND 

 Suburban NBW: ND 

Male:

 Urban LBW: 42%

 Suburban LBW: 52%

 Urban NBW: 48%

 Suburban NBW: 54%

Race (% African-American):

 Urban LBW: 80%

 Suburban LBW: 11%

 Urban NBW: 48%

 Suburban NBW: 3%

Enrolled: 1095

Evaluated: 823

 Urban LBW: 238

 Suburban LBW: 235

 Urban NBW: 176

 Suburban NBW: 174

Number of sites: 2

LBW cohort: ≤ 2500 g

NBW cohort: > 2500 g

Born between 1983-85, 6- 7 yrs 

old during 1990-92 when the 

fieldwork took place.

From 2 major hospitals in

 southeast Michigan: one urban 

and one suburban.

 (In each hospital, random

 samples of LBW and NBW

 children were drawn).

From the target sample:

 Children with severe 

neurologic impairment: 

severe mental 

retardation, severe 

cerebral palsy, 

blindness. 

At 6 yrs (823):

Cases:

 LBW 473:

 Urban LBW (238)

 Suburban LBW (235)

Controls:

 NBW 350:

 Urban NBW (176)

 Suburban NBW (174)

Nonrandomized 

comparison study 

(6 years)
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part I

271

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Breslau

2000

20298367

Location: US

Years of Birth: 1983-1985

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race (% African-American):

 Urban LBW: 80%

 Suburban LBW: 11%

 Urban NBW: 74%

 Suburban NBW: 3%

Enrolled: 1095

Evaluated: 823→717

Number of sites: ND

LBW cohort: ≤ 2500 g

NBW cohort: > 2500 g

Born between 1983-85, 6- 7 yrs 

old during 1990-92; when the 

initial assessment took place. 

Follow-up assessment at age 11 

(1995-1997).

From 2 major hospitals in

 southeast Michigan: one urban 

and one suburban.

 (in each hospital, random

 samples of LBW and NBW 

children were drawn).

From the target sample:

 Children with severe 

neurologic impairment: 

severe mental 

retardation, severe 

cerebral palsy, 

blindness. 

At 11 yrs (717):

Cases:

 LBW 411:

 Urban LBW (217)

 Suburban LBW (194 )

Controls:

 NBW 306:

 Urban NBW (164)

 Suburban NBW (142)

Nonrandomized 

comparison study 

(11 years)
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part I

272

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Hille

2001

21319264

Location: US, Canada, Germany, 

Netherlands

Years of Birth:

US: 1984-1987

Canada: 1977-1982

Germany: 1985-1986

Netherlands: 1983

Mean GA (range), wk:

US: 27±2.3

Canada: 27±2.3

Germany: 29±2.0

Netherlands: 29±2.3

Mean BW (range), g: 

US: 853±114

Canada: 834±126

Germany: 888±101

Netherlands: 882±105

Male: 

US: 40%

Canada: 45%

Germany: 45%

Netherlands: 42%

Race: White 93%

Enrolled: 523

Evaluated: 408

Number of sites: 1

Survivors from 4 population based 

cohorts of ELBW infants in 4 

countries:

US – the neonatal brainhemorrhage cohort (NBH): 

BW<2000 g

Canada – McMaster ELBW cohort 

(McM): BW<1000 g

Germany – Bavarian longitudinal 

study of children at biological 

risk (BLS): BW<1500 g and 

GA<32 weeks

Netherlands – the project on 

preterm and small for 

gestational age infants (POPS): 

BW<1500 g and GA<32 weeks

No assessments of CBCL 

at age 8-19

Cases:

ELBW infants from 4 

population based 

cohorts in 4 countries 

(108):

USA (80)

Canada (150)

Germany (78)

Netherlands (100)

Controls/Normative 

Samples:

USA had 1200 4 – 11 

year old normative 

controls.

Netherlands had 1172 

11 year old normative 

controls.

Canada had 145 fullterm controls

Germany had 335 fullterm controls.

Prospective single-arm 

cohort study
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part I

273

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Katz

1996

97145056

Location: UK

Years of Birth: 5/83- 4/85

Median GA (range), wk: 29.2+2.5 

(26-34)

Mean BW (range), g: 1227.5+341.4 

(740-2240)

Male: 

Cases: 52%

Controls: 55%

Race: 

Cases: 75% White, 19% Black, 

6% Asian

Controls: 75% White, 12.5% 

Black, 12.5% Asian

Enrolled: 212

Evaluated: 64 (40 controls)

Number of sites: 2

<34 weeks, no major congenital 

anomaly, 3 cranial u/s in first 

week of life 

Lost to follow-up

Too impair due to multiple 

cognitive, sensory, or 

motor disabilities, to 

complete testing

Cases: Preterm infants 

(64)

Controls: Full-term 

comparison sample 

(40)

Prospective cohort 

(6-8 years)

Sajaniemi

1998

99041674

Location: Finland

Years of Birth: 1989-1991

Mean GA:

 Sample 1: 28.9 (23-35)

 Sample 2: 39.4 (36-43)

Mean BW:

 Sample 1: 1205 (560-2360)

 Sample 2: 3461 (2510-5360)

Male: ND

Race: ND

Enrolled: ND

Evaluated : 160

Number of sites: 1

For Preterm Group (sample 1):

GA: 23-34 wks

Mother referred to University 

Central Hospital of Helsinki for 

threatened preterm delivery

Born between 1989-1991

For Full term group (Sample 2):

Born in Metropolitan Helsinki

Visiting pediatric services in 

Helsinki for acute infectious 

diseases

For Preterm group

If mothers had 

chorioamnionitis

If mother had insulin 

dependent diabetes

Children with congenital 

anomalies, by U/S

For Full term group

Chronic diseases

Developmental delay

Sample 1:

Preterm infants

( 80)

Sample 2

Full term enrolled at:

20-28 mo of age (80)

Retrospective

comparative study

( 24 mo CA)
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part II

274

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Nadeau

2001

21163667

General: GA

Other: Family adversity Index

Evaluated at 5 years 9 months, was 

developed using SES data such as 

the family status (two-parent, singleparent, blended), age of each parent, 

their respective levels of education, 

and professional occupations. 0=low 

~ 7=high

CNS:

Neurodevelopmental:

Motor function

Cognitive delay

Behavioral disorders

Behavior

Neuromotor development index: 

Huttenlocher neurological task test

McCarthy Scales of Children’s Abilities

Behaviors wre assessed by peers, 

teachers, and parents: RCP, TRF, 

parent’s CBCL

Robson

1997

9055145

Developmental status

Quality of home environment

Early Medical risk

Infant temperament

Development measured by The 

Bayley Scales of Infant 

Development

Quality of Home environment at 7 

and 12 mos of age: The HOME 

Inventory, paternal education, The 

Blishen Index, preschool version of 

the HOME Inventory in early 

childhood

Early Medial Risk measured by the 

Morbidity Scale

Infant Temperament and 

Development: The Carey Infant 

Temperament Questionnaire when 

the infants are 7 months of age 

corrected for prematurity.

Behavior at 5.5 years of age:

Inattention

Impulsivity

McCarthy Scales of Children’s Abilities 

by the examiner

Parental report from the Child Behavior 

Checklist

Task performance test, vigilance tasks

Matching Familiar Figures Test

Breslau

1996

8836807

General:

1) LBW (vs Normal BW= 

NBW)

2) Urban (vs suburban 

setting)

3) Maternal smoking during 

pregnancy

BW <2500g

Racial composition, whether mothers 

completed high school, marital 

status, maternal smoking during 

pregnancy, maternal substance 

abuse/dependence during 

pregnancy.

ADHD (attention deficit hyperactivity 

disorder)

Separation anxiety disorder

Simple phobia

Overanxious disorder

Oppositional defiant disorder

The National Institute of Mental Health 

Diagnostic Interview Schedule for 

Children-Parent

Teacher Report Form
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part II

275

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Breslau

2000

20298367

General:

4) LBW (vs Normal BW= 

NBW)

5) Urban (vs suburban 

setting)

6) Maternal smoking during 

pregnancy

BW <2500g

Racial composition, whether mothers 

completed high school, marital 

status, maternal smoking during 

pregnancy, maternal substance 

abuse/dependence during 

pregnancy.

Behavior assessment at 11 yrs of 

age. (Assessment at 6 yrs: reported 

in 1996 publication)

1) Behavioral problems in 3 

domains: Attention, Externalizing 

behaviors, Internalizing 

behaviors

2) Severe attention problems 

(above a cutoff point of 67)

Mother’s rating was done with:

Child Behavior Checklist (CBCL)

Teacher’s rating was done with Teacher 

Report Form (TRF)

(teachers were blind to the BW 

information of the child)

Assessments at 11 yrs were conducted 

blindly to the results of assessments 

at 6 yrs (reported in another 

publication)

1) Attention problem subscale; 20 

items

2) Externalization problem subscale: 

2 subclasses

3) Internalization problem subscale: 3 

subclasses

Hille

2001

21319264

Birth weight ND Behavior 

Attention

CBCL – Parents: Total problem score 

Internalizing behavior (anxious, 

Socratic), Externalizing behavior 

(aggressive and delinquent), Social, 

thought, attention problems 

Katz

1996

97145056

General: GA

CNS: 

1) Intracranial/ Intraventicular 

hemorrhage

2) Periventricular leukomalacia 

(cystic PVD)

3) PVD (if unilateral or bilateral 

periventicular echogenic 

lesions present on at least 3 

scans)

IA IVH: no lesion= consistently NC 

scans. 

Mild lesion = germinal hem or small 

IVH or PVD or mild vent dilation 

without hem.

Severe lesion: blood distends the 

vents or in parenchyma, or 

multicystic PVC.

CNS:

Neurodevelopmental:

Attention

IQ 

Measured by CPT test (Continuous 

Performance Test), measuring errors 

of omission or commission. 

Is also measured by CBCC (Child 

Behavior Check List): parents check 

off behavior related to attention and 

hyperactivity.

Measured by British Abilities Scale
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part II

276

Author, Year

UI# Predictors Predictor Measures Outcomes Outcome Measures

Sajaniemi

1998

99041674

General:

1) Prematurity per se

2) Premature with BW< 1000 

g vs premature with BW > 

1000 g 

3) Preeclampsia

4) SGA

5) Duration of NICU stay

CNS:

1) PVL

2) IVH

Pulmonary:

1) Duration of ventilation

Not further specified CNS:

Neurologic outcome

Developmental outcome

Temperament profile

Behavioral profile

Neurologic outcome:

1) Cerebral palsy

2) Free of major disabilities

Developmental outcome:

1) Bayley Scales of Infant 

Development

2) Mental Development Index (MDI)

Temperament: Toddler Temperament 

questionnaire (TTQ) (contains 97 

statements) 9 temperament dimensions:

1) Activity

2) Rhythmicity

3) Approach

4) Adaptability

5) Intensity

6) Mood Persistence

7) Distractability

8) Threshold

Behavior: Infant Behavior Record:

1) Social responsiveness

2) Attention

3) Affect

4) Energy level

5) Goal directedness during the test

( 24 mo CA)
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part III

277

Author, Year Associations found Potential Biases

Nadeau

2001

21163667

EP/ VLBW, n = 61 and controls, n = 44. 

 EP/ VLBW Control Significance

Normal neuromotor function 67% 97% NS

Abnormal neuromotor function 33% 3% 

McCarthy IQ [mean (SD)] 100.3 (19.1) 112.8 (16.2) P < 0.01

Behavioral ratings at 7 years age:

Peers rated EP/ VLBW’s as significantly more sensitive/ isolated than controls

Teachers rated EP/ VLBW’s as significantly more inattentive than controls

Parents rated EP/ VLBW’s as more hyperactive than controls

Significantly = P < 0.01

No data on funding source

Data on neuromotor and intellectual 

functioning only collected once

Data on behavior collected once

Robson

1997

9055145

• Developmental status and the quality of the home environment correlate with hyperactivity.

• Medical risk, infant temperament, quality of home environment and developmental status correlate with 

attention.

• A nurturing home environment fosters development of self-regulating behaviors in LBW.

Internal validity B

Breslau

1996

8836807

• LBW was significantly associated with ADHD but not with separation anxiety disorder, simple phobia, 

overanxious disorder, or oppositional defiant disorder.

• Both the mothers’ and teachers’ ratings significantly correlated with increased ADHD in LBW infants and this 

relationship is stronger in urban than in suburban communities.

• LBW children with the lowest IQ have highest incidence of ADHD.

• The urban group was primarily black, more mothers had not completed high school and more were single. 

However, maternal marital status, history of substance abuse/dependence and smoking during pregnancy 

were not associated with ADHD.

Parent ratings, 

questionnaire 

results are 

biased but 

corroborated by 

teachers who 

are blinded to 

BW of children 

helps to 

corroborate.

Internal validity B
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part III

278

Author, Year Associations found Potential Biases

Breslau

2000

20298367

1) Information from mothers and teachers on children’s behavior problems at age 11 revealed that the effect of 

LBW on attention problems differed between urban and suburban settings.

2) LBW children had an excess of attention problems in the urban disadvantaged communities and not in the 

suburban middle class communities.

3) LBW infants in the urban setting had twice as high incidence of attention problems than in urban NBW.

4) In suburban setting there was no difference in severe attention problems between LBW and NBW children.

5) LBW children had externalizing problems both in the urban and suburban settings (however this effect was 

mainly accounted for by maternal smoking in pregnancy).

6) No LBW effect was observed with respect to internalizing problems

7) Regardless of LBW status, maternal smoking during pregnancy was associated with an increase in 

externalizing problems

8) No association found between maternal smoking during pregnancy and internalizing or attention problems

OVERALL SCORES Attention scores Internalizing Externalizing

MOTHER’S SCORES 

Urban

• LBW (n=217) 58.8 52.7 52.2

• NBW (n=164) 55.8 51.5 50.4

Suburban

• LBW (n=194) 55.1 50.4 48.4

• NBW (n=142) 53.8 48.6 46.3

TEACHER’S SCORES

Urban

• LBW (n=186) 56.9 50.3 53.9

• NBW (n=151) 54.7 48.8 48.5

Suburban

• LBW (n=180) 53.7 49.0 48.5

• NBW (n=135) 54.0 48.7 48.3

1) Recollection bias: The Hx of 

maternal smo king during 

pregnancy was elicited when the 

child was 6 yrs old. This bias would 

have resulted in underestimation of 

the confounding effect of smoking 

during pregnancy.

2) Diagnosis bias: Although there 

was correspondence of the 

findings of teachers reports (who 

were blind to the LBW status of 

children) and the mothers reports, 

mothers report could have 

definitely been biased (worse 

scores from mothers of LBW 

infants)

Hille

2001

21319264

ELBW vs. Controls

 Total problem score: 

Boys: 3.3-9.8 points higher in ELBW vs. norm/ control

Girls: 3.7-5.9 points higher in ELBW vs. norm/ control

Social, thought, and attention difficulty scales were 0.5-1.2 SD higher in ELBW children vs. norm/control

Internalizing and externalizing behavior scores: no difference for all 4 groups (except for one cohort for 

internalizing scores)

ELBW children had higher total problem scores than normative/control children (statistical significance in European 

countries). Study identified similar types of behavioral problems in all 4 countries in ELBW infants. This 

suggests that problems with attention, social, and thought problems are a function of experiences of children 

who were born ELBW, and not to cultural differences.

(None) Study was 

privately funded
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part III

279

Author, Year Associations found Potential Biases

Katz

1996

97145056

Attention deficit is measured by the CPT test (error of omission). Hyperactivity and impulsivity is measured by the 

CPT test (error of commission).

There were no differences among the preterm infants with mild, moderate and severe intracranial lesions. 

However, there was a significant increase in both errors of commission and omission in preterm with mild lesions 

compared to full term infants as well as in preterm with severe lesions compared to full term infants. With 

increasing severity of lesions in preterm infants, increasing percentage in each group commit errors of 

commission. Even in the absence of detectable intracranial lesions, preterm infants are still at higher risk for 

developing attention deficits than full term infants.

Exactly how FT 

controls were 

selected in an 

unbiased way 

is not 

described.

No data on 

funding 

source

This study does 

not explore 

relationship of 

attention 

deficits 

identified with 

CPT test with 

actual school 

performance 

and 

achievement 

in this group 

of preterm 

infants.

This study 

includes older 

preterm 26-34 

weeks and 

does not 

include the 

extremely 

preterm 24-25 

wk infants.
Evidence Table 6A. Studies Evaluating Association of LBW to Behavioral Disorders

Part III

280

Author, Year Associations found Potential Biases

Sajaniemi

1998

99041674

The neurological outcome of preterm infants was:

For Cerebral palsy: Free from major disabilities MDI

1) All prematures: 17.5% 82.5% 103

2) Prematures < 1000 gs: 23.5% 23.5% 98

3) Prematures > 1000 gs: 13.5% 85.6% 107

The developmental outcome: Preterm infants had significantly lower MDI scores when compared to full terms (Full 

terms 124 )

When temperament was considered: the premature children were significantly less active; more adaptive; less 

intensive; more positive in mood and had lower sensory threshold than the healthy control term children. When 

behavior was assessed (Infant’s Behavior Records): the preterms were significantly less goal directed; less 

attentive, and had lower endurance than the controls.

When Bayley neurodevelomental was assessed:

1) the preterms performed significantly less well than the controls.

2) Low Bayley scores correlated with temperament scores of high rhythmicity, positive mood, low persistence 

and high threshold

3) Low Bayley scores correlated with IBR scores

4) No strong relationship between temperament characteristics and cognitive performance. Preterm infants had 

significantly lower MDI compared to full terms:

• Preterm infants were different in 5/9 items of temperament profile compared to full terms: less active 

(p<0.008), more adaptive (p<0.02), less intense (p<0.01), more positive in mood (p<0.0004), lower in threshold to 

respond (p<0.0003)

• Preterm infants were different in 3/5 items in IBR profile when compared to full terms: less goal directed, less 

attentive, lower in endurance

Predictors evaluation:

• From the perinatal risk factors: preeclampsia, SGA, PVL and IVH were not associated with developmental 

outcome or temperament profiles.

• PVL, IVH were associated with shorter attention span (1/5 items in IBR profile); when preterms compared to 

full terms.

• Duration of NICU stay was not associated with Bayley score

• Duration of ventilation was not associated with Bayley score

• Duration of ventilation and days in NICU were associated with the 5 items of IBR profile; Duration of 

ventilation was associated with 1/9 items of temperament profile

• Post hoc multiple comparisons 

were done between preterms and 

full terms for the multiple individual 

items of the tests used.

• Cannot exclude selection bias

• No matching between groups 

cannot exclude the presence of 

confounders.

• Interactions between

• Predictor may have masked some 

real associations; Possible 

interactions were not formally 

tested 

• Cannot exclude

Diagnosis bias, as no information is 

given on the blinding of the personnel 

doing the outcome evaluation, of the 

child’s PMHx.
Evidence Table 6B. Studies Evaluating Association of LBW to School Performance and Learning Disabilities

Part I

281

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Hille

1994

8071753

Location: Netherlands

Year of birth:1983

Description of group: VLBW

Mean GA (range), wk: <32 weeks

Mean BW (range), g: <1500 g

Male: ND

Race: ND

Enrolled: 1338

Evaluated: 813

Number of sites: 1

Cases: Participants of the Project 

on Preterm and Small for 

Gestational Age Infants, a 

nationwide collaborative study 2) 

Perinatal data collection and 

follow-up until 2 years of age 

and assessments at 5 and 9 

years 3) VLBW (very preterm) 

GA< 32 weeks at birth

 BW<1500 g.

ND Cases:

VLBW (or very 

preterm): 813

No control group

Prospective (single 

arm) cohort 

Stathis

1999

99325758

Location: Australia

Years of Birth: :1977-1986

Median GA (range), wk: 27.7(27.3-

28.1)

Mean BW (range), g: 860 (837-

833)

Male: 36%

Race: ND

Enrolled: 124

Evaluated: 87

Number of sites: 1

BW 500-999g survived to 

discharge

Cared for in study NICU

Enrolled in follow-up programs

ND ELBW survived infants 

(87)

Prospective cohort 

(followed at 4, 8, 12, 

months)

CherkesJulkowski

1998

98262696

Location: ND

Years of Birth: ND

Mean GA (range), wk: ND

Mean BW (range):

Cases: 4.14±1.87 lbs

Controls: 7.30±1.87 lbs

Male: 

Cases: 61%

Controls: 50%

Race: ND

SES: “middle class”

Enrolled: 48

Evaluated: 28 (20 controls)

Number of sites: 1

Preterm: 

<38 wks, BW<5 lbs, no 

congenital disorders, no 

retrolenteal fibroplasia, 

discharge from hospital prior to 

42 wks conceptional age, mother 

willing to participate

Controls: participats were enrolled 

in a longitudinal sudy before 

their second month of age

ND Preterms (28)

Controls: full term 

infants (20)

Retrospective cohort
Evidence Table 6B. Studies Evaluating Association of LBW to School Performance and Learning Disabilities

Part I

282

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Marlow

1993

8466264

Location: UK

Years of birth:1980-1981

Description of group: VLBW

Mean GA (range), wk: ND

Mean BW (range), g: ≤1250 g

Male: ND

Race: ND

Enrolled: 72 

Evaluated: 51

Controls: 59

Number of sites: 1

Cases: VLBW ≤1250g at birth and 

without cerebral palsy at 6 years.

Controls: 1) Control group (full 

term) matched for age, race, and 

sex, and school-matched. 

Major disabilities (CP or 

major sensory impairment)

Cases: VLBW: 51

Controls: Full term/ 

controls: 59

Nonrandomized 

comparison trial
Evidence Table 6B. Studies Evaluating Association of LBW to School Performance and Learning Disabilities

Part II

283

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Hille

1994

8071753

General predictors: 

1. BW

2. GA

3. Gender

4. Perinatal factors: congenital 

malformations, Apgar 

scores, intracranial 

hemorrhage, septicemia, 

assisted ventilation >7 

days, serum bilirubin, 

thyroxine levels.

5. Socioeconomics

6. Performance at 5 years of 

age: Development, 

neuromotor function, 

speech/language, 

hyperactivity and school 

performance.

Assessment at 5 years of age:

1. Neurologic examination 

according to Touwen

2. Dutch test of speech and 

language development

3. Visual fields, acuity

4. Audiometry

5. Groningen Neurobehavioral 

concentration test

6. Child Behavior Checklist

7. Handedness

8. Kind of school

9. School results

At 9 years of age :

School performance

Special education

Questionnaire: kind of school 

(mainstream or special education), 

grade and need for extra help from 

teachers, remedial teaching, or 

speech therapy.

Stathis

1999

99325758

CNS Predictors

1) Other: head circumference 

category 

2) Head growth velocity

Self-explanatory CNS:

Neurodevelopmental:

Cognitive delay

Behavioral disorders-ADHD 

School problems

Learning disabilities

Academic problems--Answer 

questionnaires given to teacher

ADHD--Dr. Paul rating scale

McCarthy’s scales

CherkesJulkowski

1998

98262696

General: GA

Other: Mother perception of child 

competence

ND CNS:

Cognitive delay

Neurodevelopmental 

School problem

Neurological Impairment (NI)

Attention Deficit Disorder (ADD)

Audiology: 

Language 

Cognitive delay, measured by StanfordBinet

School programs (school concerns = 

SC)

Learning disabilities (LD)

Neurological Impairment (NI)

Attention deficit Disorder (ADD)

Language impairment = LI – dx made 

by speech and language clinician
Evidence Table 6B. Studies Evaluating Association of LBW to School Performance and Learning Disabilities

Part II

284

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Marlow

1993

8466264

General predictors: VLBW BW ≤ 1250g At 8 years of age:

School performance

Behavior disorder

School performance: mathematics test 

(NFER Nelson), Schonell S1 graded 

word spelling test, Suffolk reading test, 

handwriting, fine motor skills.

Behavior Measurements: parental 

questionnaire Rutter A(2), and teacher 

questionnaire using Rutter B(2) and 

Connors hyperactivity scale.
Evidence Table 6B. Studies Evaluating Association of LBW to School Performance and Learning Disabilities

Part III

285

Author, Year Associations found Potential Biases Comments

Hille

1994

8071753

• School performance at 9 years of age is best predicted by performance at 

5 years of age.

• At 9 year of age, 19% were in special education and 81% in mainstream 

education.

• At 9 years of age, only 44% of the nondisabled prematurely born children 

were in mainstream education at an age-appropriate level without special 

assistance.

• GA <28 wks, BW < 1250 g, male gender and socioeconomics were 

significantly related to education outcome. Neonatal illnesses were not 

associated with school outcome at 9 years of age.

• Majority of children having difficulty in school at 5 years of age had 

difficulty in school at 9 years of age.

Children labeled as having difficulty in school 

early in education (i.e. at 5 years of age) 

may continue to be treated as such within 

the system. Therefore independent 

evaluation of these children’s performance 

at 9 years of age may reveal more useful 

information.

Internal validity A

According to this study, 

early school problems 

are not transient.

Stathis

1999

99325758

Head circumference category at 8 months corrected age related to learning 

delay greater than one year when assessed at 6 years:

HC Category n % with delay

< 3rd percentile 23 61% (39, 80)

3

rd to 10th 13 77% (46, 95) P = 0.004

> 10th 40 30% (17, 47)

Head circumference category at 12 months CA did predict McCarthy General 

Cognitive index at six years, but head circumference category at 24 months 

CA did not significantly predict McCarthy CGI at 6 years.

Head circumference and head growth velocity was not shown to have a 

relationship with attention deficit hyperactivity disorder.

Head circumference category < 10th vs. greater than 10th percentile at four and 

8 months corrected age were significantly associated with McCarthy CGI at 

6 years age

One nursery

High rate of patients lost to follow-up (30%)

Small numbers: limited ability to detect small 

differences; high chances of type 2 error

Study was privately 

funded

Marlow

1993

8466264

• Even in the presence of normal IQ, premature children are more likely to 

underachieve in school compared to full-term peers.

• Forty -eight percent in preterm group had difficulty in one or more subjects 

compared with 19% in full term group.

• Both teachers and parents report behavior problems of restlessness, 

hyperactivity, inattention, unresponsive/apathetic, fearful/afraid of new 

situations.

• Motor difficulties and mathematics test best correlate with later school 

performance problems.

Internal validity B
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part I

286

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Page

1993

94051493

Location: Canada

Years of Birth: 1986-1987

Mean GA (range), wk: 27±1.8 (23-

32)

Mean BW (range), g: 942±197 

(400-1250)

Male: 38%

Race: White 100%

Enrolled: 138

Evaluated: 110 ? 50

Number of sites: 1

BW<1250 g admitted to Toronto’s 

Hospital for sick children

Survived the neonatal periods and 

had at least one eye examination 

between 28 and 42 of life that 

documented the severity of ROP

No 12-month follow-up 

reports 

VLBW infants at 12-

month follow-up (110)

VLBW infants at 24-

months follow-up (50)

Retrospective cohort 

(12, 24 months)

Cryo-ROP

1994

94304375

*The original 

large 

population of 

CRYO-ROP

Location: US

Years of Birth: 1/1986 to 11/1987

Mean GA (range), wk: 26.0±1.9 to 

29.6±2.1

Mean BW (range), g: 781±156 to 

1061±144

Male: 48%

Race: White 56%, Black 35%, 

Hispanic 6%, Other 3%

Enrolled: 4099

Evaluated: 2759 

Number of sites: 23

BW < 1251 g

Survived at least 28 days

No serious ocular anomaly, such 

as cataract, glaucoma, or 

chorioretinitis, and no major 

systemic malformations

Parental consent

Initial eye examination by a studycertified ophthalmologist by 49 

days after birth

Death <28 days; serious 

ocular anomaly or 

systemic malformations, 

lack of consent; first eyes 

exam with 4 qd

Death (264)

Lost to follow-up (1076)

Zone and Stage of 

ROP (2759):

Zone I (46)

Zone II, stage 3+, 9-

12 sectors (139)

Zone II, stage 3+, 5-

8 sectors (64)

Zone II, stage 3+, 1-

4 sectors (47)

Zone II, stage 3 

(241)

Zone II, stage 2 

(484)

Zone II, stage 1 

(500)

Zone III (319)

Other ROP (22)

No ROP (896)

Prospective cohort 

(1 year)
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part I

287

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Keith

1995

95288128

Location: UK

Years of Birth: 1977-1992

Mean GA (range), wk: 

Sample 1: 26.0±2.3

Sample 2: 26.1±2.2

Mean BW (range), g:

Sample 1: 783±136

Sample 2: 786±133

Male: ND

Race: ND

Enrolled: 457

Evaluated: 434

Number of sites: 1

ELBW infants, BW < 1000g

Survival to hospital discharge

Eye exams done

ND

Not seen by the 

ophthalmologist: 

transferred to another 

level-3 center for ongoing 

care (17); unknown 

reasons (6)

Sample 1: ELBW 

survivors born 

1977-1984 (145)

Sample 2: ELBW 

survivors born 

1985-1992 (312)

Prospective cohort 

(16 years)

Foreman

1997

97271716

Location: UK

Years of Birth: 4/1994-4/1996

Mean GA (range), wk: 

Cases: 29.38

Controls: 39.88

Mean BW (range), g:

Cases: 1413±302

Controls: 3437±625

Male: 63%

Race: ND

Enrolled: 114

Evaluated: 16 (16 controls)

Number of sites: 1

Healthy preterm infants

GA 27 –32 weeks; weight within 

the normal range for GA

Normal on all criteria of 

Standard child health 

surveillance program from 7.5 

to 48 months

Each could be matched with FT 

control on gender, post-natal 

age at testing, and on SEC. 

Healthy controls from School 

population

Controls: children drawn from a 

school population who were 

known to have been full-term, 

normal delivered and whose 

uneventful medical and 

developmental histories were 

confirmed by parents, general 

practitioners, and teachers

ND Healthy preterm infants 

(16)

Controls: Matched full 

term controls (16)

Prospective cohort 

(6.1 years)
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part I

288

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Tin

1998

99046171

*also in CNS 

table

Location: North of England

Years of Birth: 1983, 1990-1991

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 1983 (230); 1990-1 (566)

Evaluated: 1983 (230); 1990-1 

(566)

Number of sites: 5

GA 23-31 weeks ND 1983 cohort (230):

Child reviewed without 

difficulty (204)

Child traced with 

difficulty (14)

Child seen with 

difficulty after child 

was traced (12)

1990 to 1991 (566):

Child reviewed without 

difficulty (505)

Child traced with 

difficulty (26)

Child seen with 

difficulty after child 

was traced (35)

Prospective cohort

*2 Cohorts of different 

time periods

Dogru

1999

99168711

Location: Japan

Years of Birth: 4/1994-4/1996

Mean GA (range), wk: 

Sample 1: 27.6±2.9

Sample 2: 26.9±1.4

Sample 3: 26.3±3.1

Controls: 29.6±2.6

Mean BW (range), g:

Sample 1: 1016±207

Sample 2: 836±178

Sample 3: 874±218

Controls: 1193±241

Male: 49%

Race: ND

Enrolled: 144

Evaluated: 78 (66 controls)

Number of sites: 1

Premature infants (BW < 1500 g, 

GA < 37 weeks) with ROP

Controls: randomly selected 

premature subjects with no ROP

Physical and mental 

disabilities or any CNS 

and ocular disorder

Premature infants:

(Sample 1, 2, and 3): 

Premature infants 

with ROP (78)

Sample 1: ROP 

stage 1 (53)

Sample 2: ROP 

stage 2 (11)

Sample 3: ROP 

stage 3 (14)

Controls: Premature 

infants without ROP 

(66)

Prospective cohort 

(18-24 months)
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part I

289

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Pennefather

1999

20002011

Pennefather

2000

20217908

* This study 

also should be 

mentioned in 

multiple 

outcome and 

CNS table

Location: UK

Years of Birth: 1/1/90-12/31/91

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 566

Evaluated: 558

Number of sites: ND

All surviving children <32wk GA 

born in geographically deprived 

region in Northern UK

Survived to 2 years old

No examined at age 2 

years old

Preterm infants (558) Prospective cohort and 

retrospective review of 

patient records (2-3 

years)

Tin

2001

21143595

*1990-1991 

sample is same 

as 99046171

Location: North of England

Years of Birth: 1990-1994

Median GA (range), wk: 23-27

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 1990-1 (781); 1992-1994 

(ND)

Evaluated: 249 (for current review)

Number of sites: ND

GA < 28 weeks

Surviving (born 1990-1991) when 

2 years old

Surviving (born 1992-1994) when

18 months 

Assessed for CP and ophthalmic

For current review, only SpO2 88-

98% and SpO2 70-90% groups 

were included

ND Sample 1: Preterm 

infants, SpO2 88-

98% (123)

Sample 2: Preterm 

infants, SpO2 70-

90% (126)

Prospective cohort
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part II

290

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Page

1993

94051493

General predictors:

1) Birth weight

2) GA

CNS predictors:

1) Intracranial/ Intraventricular 

hemorrhage

2) Periventricular 

leukomalacia

Ophthalmology predictors:

1) Retinopathy of prematurity

2) Myopic at 12 months postterm

Cardiovascular or pulmonary 

predictors:

1) PDA

2) Days ventilated

3) Days in O2

ROP - ICROP

Others not defined

Myopic - >0.25 D

Ophthalmology outcomes:

Visual impairment

Strabismus

Refractive error

 Myopia

 Astigmatism

Myopia - spherical equivalent of ? 0.25 

diopters

High Myopia - spherical equivalent of ? 

4.0 diopters

Astigmatism - > 1 diopter in any 

meridian or cycloplegic refraction

Anisometropia - spherical equivalent >2 

D between eyes (both refracted)

Cryo-ROP

1994

94304375

*The original 

large 

population of 

CRYO-ROP

Ophthalmology predictors:

Retinopathy of prematurity

ROP defined by examination 

according to the ICROP

Ophthalmology:

Visual impairment

Structural outcome

ROP outcomes (structural):

I. Only peripheral changes, no 

mascular distortion

II. Mascular displacement

III. Retinal fold involving 

macula

IV. Retrolental opacity entotal 

retinal detachment and/or 

total pupillary occlusion to 

retinal detachment

Functional outcome:

a. Normal fixation

b. Presence/absence of 

nystagmus

c. Strabismus

d. Refractive error (spherical 

equivalence)
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part II

291

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Keith

1995

95288128

General predictors:

Birth cohort: 1977-1984 vs. 

1985-1999

ND Ophthalmology outcomes:

1) blindness

2) severe ROP

Eye exam with ICROP classification.

Sheridan-Gardner test - visual outcome.

Snellen's eye chart - visual outcome.

Foreman

1997

97271716

GA 28-32 week prematurity 

vs. full term controls

CNS

Attention skill

Ophthalmology

Visual-perceptual skills

Visual-motor skills

Point-to-Target test

Complex visual search test

Cartoon comparison test

Overlapping figures

Goillin incomplete figures

Tin

1998

99046171

*also in CNS 

table

General: GA (23-31 wks) ND CNS: CP

Neurodevelopmental:

Mental retardation (IQ < 75)

Other; disability (severe, sever 

 sensorimotor)

Other: development - assessed by 

Griffith’s mental and developmental 

 scales

Ophthalmology

Visual impairment

Blindness

Other: Severe ROP with 

Cryotherapy 

Definition of "severe disability” and 

"severe sensorimotor disability" 

were not given in this article . They 

referred to the wrong reference for 

these definitions, therefore, I am 

unable to find the definitions. 

Reference population for Griffith’s 

scales were "preterm babies in the 

study S serious sensorimotor 

disability"

Dogru

1999

99168711

ROP Staging of retinopathy was based on 

International Classification of 

Retinopathy of Prematurity (The 

Committee for the Classification of 

Retinopathy of Prematurity, 1984)

Ophthalmology:

Visual acuity

Preferential looking method
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part II

292

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Pennefather

1999

20002011

Pennefather

2000

20217908

* This study 

also should be 

mentioned in 

multiple 

outcome and 

CNS table

General Predictor: GA

CNS:

1) IVH

2) Periventricular leukomalacia

3) Ventriculomegaly/Ventricular 

Dilation

Ophthalmology: 

1) ROP

2) Refractive error

Other: Family Hxg strabismus, 

Developmental disability, CP

ND CNS:

Cerebral palsy

Ophthalmology:

Visual impairment (cortical)(CVI)

Cicatricial ROP

Strabismus

Retrospective review of patient records

Visual acuity, visual fields

Tin

2001

21143595

*1990-1991 

sample is same 

as 99046171

General predictors:

GA

Other predictors:

SpO2 policies (88-98% vs.70-

90%)

SpO2 policies were obtained 

retrospectively

CNS:

Cerebral palsy

Ophthalmology:

Blindness

Severe ROP Rx with cryotherapy

Threshold ROP: (Cryo-ROP definition) 

stage 3 plus acute ROP extensive 

permanent cicatricial retinal 

scanning
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part III

293

Author, Year Associations found Potential Biases Comments

Page

1993

94051493

Outcome: Incidence of myopia at 12 mo postterm age:

 Overall incidence of myopia in cohort (BW<1251 g) was 15% (4.5% severe 

myopia)

At 12 months age:

Increased severity of ROP predicted increased severity of myopia (p=0.001)

 Overall, 16% of infants had myopia, and 4.5% had severe myopia at 12 

months age.

To show incidence of myopia according to severity of ROP:

 10% of infants with No or Stage 1 ROP had myopia

 54% of infants with Stage 3 ROP had myopia

 23% of infants with Stage 3 ROP had severe myopia

The likelihood of myopia at 12 months age doubled with each increment in 

ROP stage.

- At 24 months age: 80% of 50 children showed deteriorating vision.

- 13 of 16 (81%) showed worsening of their myopia after 12 months age.

Overall, the incidence of myopia and severe myopia increased among 50 

infants followed to 2 years: 38% had myopia 0.25-4 Diopters; 

24% had myopia >4 Diopters.

BW was negatively associated with incidence of myopia (p=0.002).

 BW<750 g 3.2 fold odds of myopia vs. 751-1000 g.

- BW <750 g 10 fold odds of myopia vs. 1001-1250 g. 

Incidence of strabismus was positively associated with severity of ROP 

(e.g. no ROP 6% vs. Strabismus at 12 mo in infants who had Stage 3 

ROP 38%). There was further increased diagnosis of strabismus at 24 

months age. 

Months of age in infants who had had Stage 3 ROP (38% to 62%). 100% of 

infants who had Grade III or IV IVH had strabismus

Retrospective NB and ophthalmic chart review

36% eye reports available at 24 months. Also 

24 month sample was biased toward children 

at greatest risk of myopia. Children with 

normal eye results at 12 months age were 

discharged from further follow-up at 18

 months post-term age. This may have led to 

underdiagnosis of myopia due to lack of 

detection of progressive myopia.

Infants born 1986-1987 (not a bias, but a 

limitation)

Used other pop reference figures for norms

No data on funding source

This study demonstrates 

the importance of low birth 

weight, ROP severity, and 

IVH in the development of 

myopia and strabismus.
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part III

294

Author, Year Associations found Potential Biases Comments

Cryo-ROP

1994

94304375

*The original 

large 

population of 

CRYO-ROP

The more posterior the zone of ROP and /or the greater the extent of Stage 3+ 

ROP, the worse the structural and functional ophthalmic outcomes. Zone II 

without plus disease, Zone III, or no ROP was associated with low rate of 

unfavorable outcome. CNS injury may affect ophthalmic function (e.g. 

nystagmus and strabismus).

Visual function by ROP Classification

ICROP Abnl.Fixation %Nystagmus %Strabismus

Zone I ...................44% ...............6%...............25% 

Zone II 

 Stage 3, 9-12 sectors 57%............39%...............33%

Zone II, 

 Stage 1..................2%.............1%.................10%

No ROP...................1% .............1%..................6%

% of Eyes with refractive error (≥2 diopters myopia) by ROP severity

No or Stage 1 ROP (<5%)

Zone II, Stage3+, 9-12 sectors (62%)

Zone I (40%)

(None) Study was government 

and privately funded

Biweekly or weekly eye 

exams until fully 

vascularized or until 

threshold ROP (>5 

contiguous or 8 

cumulative clock hours) 

stage 3 with plus disease.

Only data from eyes that 

served as controls 

(untreated) are included in 

this segment.

Keith

1995

95288128

Any ROP:

Birth Cohort

1977 –1984 (141) 68/141 48.2 % 

1985-1992 (293) 105/293 35.6% OR=0.60 (0.40-0.90) P<0.02

Severe ROP:

1977 –1984 (141) 36/141 25.4 % 

1985-1992 (293) 52/293 17.4% OR=0.62 (0.38-1.02) NS

Blindness:

1977 –1984 (141) 2/141 1.4 % 

1985-1992 (293) 2/293 0.6% OR=0.43 (0.05-3.5) NS

Data are from care center

No outborn infants in either cohort so data are 

not generalizable to outborn ELBW infants

Twenty -three surviving ELBW's could not be 

located to determine ROP status.

No data on funding source

16 year study; 1001 

ELBW infants; 457 

survived to discharge; 434 

seen by same 

ophthalmologist. Twenty 

children not seen by 

ophthalmologist.
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part III

295

Author, Year Associations found Potential Biases Comments

Foreman

1997

97271716

Visual-motor coordination: 

PT v. FT NS diff

Visual-spatial attention skill: Significant difference between Preterm and 

Full term in complex visual search scores (failure to find figure and latency to 

find) and cartoon comparisons

PT 2.94 FT 0.81 P<0.05

Visual-form perception: NS difference between Preterm and full term in 

latency to respond to overlapping figure and Gollin incomplete figure tests.

PT 22.2% FT 21.9% NS diff

Compared to matched, FT controls, the PT school age group performed 

poorly on 2 measures visual-motor tests. Thus in the absence of detectable 

disability, prematurity is associated with visual-motor and attentional 

impairments that persist through 16 years age.

Small sample size

Incomplete data analysis 

No data on funding source

Tin

1998

99046171

*also in CNS 

table

Result of 1983 cohort at 6 years:

Severe disability:

Sample 1: 4.4%, Sample 2 : 2.1%, Sample 3: 50%

IQ < 75 without sensorimotor disability:

Sample 1 : 4.9%, Sample 2 : 0, Sample 3 : 25%

Severe sensorimotor disability:

Sample 1 : 5.9%, Sample 2 : 21.4%, Sample 3 : 41.7%

Severe sensorimotor or cognitive disability:

Sample 1 : 8.4% (5 - 13.1%, 95% CI)

Sample 2 : 21.4% ( 4.7-50.8%)

Sample 3: 41.7% (15.2-72.3%)

Result of 1990 cohort at 2 years:

Severe disability:

Sample 1: 7.9%, Sample 2: 15.4%, Sample 3: 57.1%

High f/u rate is critical because it may underestimate incidence of the 

outcome.

No definitions of outcome, incomplete 

methods description, wrong reference

Study was privately 

funded

Dogru

1999

99168711

Stage 3 ROP had significantly lower visual acuity scores compared to stage 1-

2 or no ROP at 18-24 months (P<0.0001)

(None) No data on funding source
Evidence Table 7. Studies Evaluating Association of LBW to Ophthalmologic Outcomes

Part III

296

Author, Year Associations found Potential Biases Comments

Pennefather

1999

20002011

Pennefather

2000

20217908

* This study 

also should be 

mentioned in 

multiple 

outcome and 

CNS table

Strabismus in 70/558 (12.5%) infants GA<32 week .

The incidence of strabismus increased with decreasing GA (p=0.0004), 

increasing severity of ROP (p=0.0001), and decreasing general 

developmental quotient (GMDS) (p<0.0001).

Stabismus present in 28 (52%) of patients with CP (P< 0.001)

OR (95% CI) of Strabismus if following predictor was present:

Cicatricial ROP: 4.94 (1.1-22.12), p0.037

Fam Hx of Strabismus: 4.15 (2.19-7.88), p<0.00005

Refractive Error: 2.71 (1.3-5.66), p=0.008

GMDS 78-100: 3.34 (1.46-7.64), p =0.004

GMDS <77: 46.2 (17.1-125), p<0.00005

This study confirms findings of other studies that strabismus is increased in 

premature infants with decreasing GA and is increased with increasing 

severity of ROP and CP. Independent factors related to strabismus are 

cicatricial ROP, refractive error, family hx of strabismus, and developmental 

delay (especially delayed hand-eye coordination)

Prospective evaluation but retrospective 

collection of neonatal data; therefore, 

probable incomplete collection of variable 

reason for present and absent data

No demographic data was report (the cohort 

was described elsewhere)

No data on funding source

Tin

2001

21143595

*1990-1991 

sample is same 

as 99046171

Premature infants who had oxygen saturation range (SpO2) between 88-98% 

for at least first 8 weeks of life developed severe ROP requiring treatment 

with cryotherapy four times greater than infants who had SpO2 range 

between 70-90. 

Incidence of severe ROP with Cryotherapy (SpO2 range 88-98%)=28%

Incidence of severe ROP with Cryotherapy (SpO2 range 70-80%)= 6%

Incidence of Blindness in the two study groups:

Premature infants with SpO2 range 88-98%: 4 / 65

Premature infants with SpO2 range 70-80%: 0 / 65

Incidence of CP in the two study groups:

Premature infants with SpO2 range 88-98%: 17%

Premature infants with SpO2 range 70-80% 15%

The lower SpO2 range was not associated with difference in CP.

Differences in SpO2 policies (70-90% vs. 88-98%) did have a major impact on 

the proportion who developed severe ROP, but had no effect on survival or 

on incidence of CP among premature survivors.

Different pulse oximeters

No attempt to document real SpO2 or how 

often SpO2 fell outside recommended 

ranges (or vice versa). Narrow limits 

broached often > wider limits.

ROP screening conformed 

to national guidelines
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part I

297

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Cryo-ROP, 

1990, 1996, and 

2001 (x3)

91024693, 

96180078, 

21375786,

21375787,

21375788

Repka

1998

98426775

*sample from 

the large

population of 

94304375 

(CRYO-ROP)

Location: US

Years of Birth: from 1/1986 to 

11/1987

Mean GA (range), wk: 

1 yr follow-up: 26.3±1.8

5.5 yr follow-up: 26.3±1.7 

(bilateral threshold ROP; 

26.3±1.8 (asymmetric threshold 

ROP)

10 yr follow-up: 26.3±1.8

Mean BW (range), g: 

1 yr follow-up: 800±165

5 yr follow-up: 801±165 (bilateral 

threshold ROP; 800±165 

(asymmetric threshold ROP)

10 yr follow-up: 800±165

Male: ND

Race: ND

Enrolled: 291

Evaluated: 246 (at 1-year exam), 

234 (at 5.5-year exam), 247 (at 

10-year exam)

Number of sites: 23

BW < 1251 g

Survived at least 28 days

Diagnosis of threshold ROP

ND

{(At 1-year follow-up:

Died before the 1-year 

follow-up (36)

Unable to follow-up for the 

1-year exam (14)

At 5.5-year & 10-year 

follow-up:

Died before the 5.5-year & 

10-year exam (36)}

Lost to follow-up for the 

10-year exam (8)

At 1-year exam: VLBW 

infants with ROP 

(241) 

At 5.5-year exam: 

VLBW infants with 

ROP (234) –

bilateral threshold 

ROP (191); 

asymmetric 

threshold ROP (43)

At 10-year exam:

VLBW infants with 

ROP (234)

Randomized controlled 

trial 

(1, 5.5, 10 years) 

Cryotherapy for 

Retinopathy of 

Prematurity 

Group

1993

93191597

Location: US

Years of Birth: 1986-1987

Mean GA (range), wk: 26.3±1.8

Mean BW (range), g: 800±165

Male: ND

Race: ND

Enrolled: 236

Evaluated: 236

Number of sites: 23

All infants <1251g, who 

participated in CRYO-ROP 

Multicenter trial and had 

threshold (severe) ROP.

See original study Infants with threshold 

ROP (236)

3.5 years
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part I

298

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Algawi

1994

95001766

Location: UK

Years of Birth:

Sample 1: 2/1992-11/1992

Sample 2: 1/1987-2/1992

Mean GA (range), wk: 

Sample 1: 24-32

Sample 2: 25-30

Mean BW (range), g: 

Sample 1:700-1200 

Sample 2: 620-1500

Male: 53%

Race: ND

Enrolled: 32

Evaluated: 32

Number of sites: 1

Premature infants with threshold 

ROP (stage 3+ disease of 5 or 

more contiguous clock hours [30° 

sector] or 8 cumulative clock 

hours) or more

ND Sample 1: Laser 

Treatment (12)

Sample 2: Cryotherapy 

Treatment (20)

Prospective cohort

Ling

1995

95391616

Location: UK

Years of Birth: 1992-1993

Median GA (range), wk: 25.5 

(24-27)

Median BW (range), g: 725 

(589-887)

Male: 38%

Race: White 100%

Enrolled: 13

Evaluated: 13

Number of sites: 1

All premature infants in 1 unit who

developed threshold ROP and 

treated with diode laser therapy

ND Infants with ROP 

treated with Diode 

laser (13)

Before and after trial 

(6, 12, and 18 months)
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part I

299

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Connolly

1998

984267776

Location: US

Years of Birth: 11/1989-5/1992

Mean GA (range), wk: 25.4 (23-32)

Mean BW (range), g: 731 (440-

1318)

Male: 44%

Race: ND

Enrolled: 52

Evaluated: 25

Number of sites: 1

Premature infants with symmetric 

threshold ROP underwent bilateral 

treatment

ND

(Stage 4 or 5 ROP in one 

or both eyes

Refused to cooperate with 

monocular occlusion 

during Snellen testing

Limited cognitive ability 

that precluded Snellen 

or illiterate e-chart acuity 

testing)

Sample 1: Laser 

Treatment (21 eyes)

Sample 2: Cryotherapy 

Treatment (21 eyes)

RCT and follow-up 

(5.8 [4.3-7.6] years)

Shalev

2001

21331013

Location: US

Years of Birth: 1991-1992

Mean GA (range), wk: 24.8

(23.4-27.0)

Mean BW (range), g: 631

 (540-846)

Male: 60%

Race: 30%

Enrolled: 19

Evaluated: 10

Number of sites: 1

Threshold ROP treated with laser 

or cryotherapy

ND

Lost to follow-up (2)

Died at 4 months of age 

(2)

Refusal (3)

Infants with threshold 

ROP (10)

RCT with prospective 

follow-up 

(7 years and 6 months)

O’Connor

2002

21635822

Location: UK

Years of birth: 1985-1987

Mean GA (range), wk: 31.06±3.09

Mean BW (range), g: 1400 (iqr 

1150, 1562)

Male: ND

Race: ND

Enrolled: 505

Evaluated: 505

Number of sites: 5

All infants <1701g, who survived 3 

weeks. Born to mothers who 

were residents in the study 

areas, admitted to one of 5 

NICUs.

ND Premature infants 

(254)

Control (169)

10-12 years
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part II

300

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Cryo-ROP, 

1990, 1996, and 

2001 (x3)

91024693, 

96180078, 

21375786,

21375787,

21375788

Repka

1998

98426775

*sample from 

the large 

population of 

94304375 

(CRYO-ROP)

Ophthalmology predictors:

Threshold retinopathy of 

prematurity

At 5.5-year & 10-year follow-up:

Cryotherapy vs. No Cryotherapy

At least 5 contiguous clock hours or 8 

cumulative clock hours of stage 3 

ROP in zone 1 or 2 in the presence 

of "plus disease" (dilation and 

tortuosity of the posterior retinal 

vessels)

Monocular visual acuity (using log of 

minimal angle of resolution visual 

acuity chart)

Ophthalmology:

Visual impairment (visual acuity)

Structural outcome

Blindness

Distance snellen acuity

Near snellen acuity

Visual field

Medical and surgical ophthalmologic 

 interventions

Cerebrospinal fluid shunting surgery

Visual acuity -

• "normal": ?1.6 cycles per degree

• "below normal": 8.0 to <1.6 cycles 

per degree

• "poor": <0.8 cycles per degree

• "blind": eyes judged to have no 

light perception, eyes for which the 

tester was unable to estimate 

acuity, which were judged by a 

physician to have total retinal 

detachment

Structural outcome -

• Posterior retinal fold

• Retinal detachment involving zone 

1 of the posterior pole

• Retrolental tissue or "mass" 

obscuring the view of the posterior 

pole

Favorable Functional outcome:

Favorable visual acuity: better than 

20/200

Unfavorable visual acuity: worse than 

20/200 or blind

Goldmann perinmetry to measure visual 

field extent along 8 meridian using 

V4e and III 4 e stimuli

Cryotherapy for 

Retinopathy of 

Prematurity 

Group

1993

93191597

Retinopathy of Prematurity

(ROP) (Specifically threshold 

ROP treated with cryotherapy or 

no cryotherapy)

Threshold ROP as per CRYO-ROP 

definition.

Visual impairment

Blindness

Visual acuity (HOTV, Grating)

Unfavorable outcome (HOTV 20/200 or 

worse, Grating <6.4 cycles per 

degree; blind): this outcome is 

combination of poor + blind

Myopia:≥2 <6 diopters; ≥6 diopters
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part II

301

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Algawi

1994

95001766

Ophthalmology

Retinopathy

ND Ophthalmology:

Visual impairment:

Refractive error

Visual fixation

Preferential looking

Visual functions were assessed by 

either fixation pattern or preferential 

looking technique

Ling

1995

95391616

ROP Threshold as for Cryo-ROP trial Ophthalmology 

Visual function 

Favorable outcome (anatomical) 

defined as a normal posterior funus on 

BIO exam performed by observer who 

had not done Rx. Functional outcomes 

assessed using Keeler preferential 

looking cords acuity greater or equal to 

0.8 cycles per degger defined 1 yr. Age

.

Connolly

1998

984267776

ROP Threshold as for Cryorop trial - 5 or 

more contiguous or 8 cumulative 

clock-hours of stage 3 ROP in zone I 

or II in the presence of “plus” disease

Ophthalmology Outcomes:

Visual impairment

Refractive error

Visual acuity 

Visual acuity 20/50 or better =good

Visual acuity 20/60 or worse = poor

Shalev

2001

21331013

ROP Threshold as for Cryorop trial Ophthalmology 

Visual function outcome

Structural outcome

Favorable outcome = normal posterior 

fundus.

Refraction by retinoscopy

Functional outcomes: Keeper 

preferential looking cards . Favorable 

function was grating acuity greater than 

or equal to 0.8 cycles/degree (as per 

CRYO ROP study at 1 year)
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part II

302

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

O’Connor

2002

21635822

Birth weight

ROP

BW self-explanatory (grams)

ROP not stated, but c/w ICROP

Visual impairment

Blindness

Visual acuity: Normal (20/20); 

≥Moderately reduced = worse than 

20/40.

Contrast sensitivity (Pelli Robson chart)

Steroacuity (TNO plates)

Perimetry (visual fields) (Damato 

campimeter)

Color vision (desaturated D15 test)

Strabismus (cover test and prism test)

Refractive error (cycloplegic refraction)

Eye size and dimensions of its 

components (N.D.)
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part III

303

Author, Year Associations found Potential Biases Comments

Cryo-ROP, 

1990, 1996, and 

2001 (x3)

91024693, 

96180078, 

21375786,

21375787,

21375788

Repka

1998

98426775

*sample from 

the large 

population of 

94304375 

(CRYO-ROP)

At 1-year follow-up:

Fundus photography: Unfavorable posterior pole outcome at 1 yr

Cryotherapy Rx 191 eyes 25.7%

Control 194 eyes 47.4% P<0.001

Unfavorable structural outcome (retinal detachment, macular fold, etc) at 1 yr

Cryotherapy Rx 208 eyes 49%

Control 203 eyes 66%

Unfavorable functional (Teller Visual Acuity) outcome at 1 yr

Cryotherapy Rx 160 35%

Control 158 56.3%

At 5.5-year follow-up:

Visual acuity Unfavorable outcome:

Threshold ROP (control: no cryotherapy) 62%

Threshold ROP CRYOtherapy 47% 

Greater reduction in unfavorable visual acuity outcome in cryo group (P<0.005)

Unfavorable structural outcome

Threshold ROP (control: no cryotherapy) 45%

Threshold ROP CRYOtherapy 27% 

Greater reduction in unfavorable structural outcome in cryotherapy group (P<0.001)

Blindness

Threshold ROP (control: no cryotherapy) 48%

Threshold ROP CRYOtherapy 32% 

Greater reduction in blindness in cryotherapy group (P<0.001)

Visual acuity 20/40 or better

Threshold ROP (control: no cryotherapy) 17%

Thresdhold ROP CRYOtherapy 13% 

No significant difference between groups with respect to proporation of infants with 

visual acuity 20/40 or better (P=0.19).

Among children who had Threshold ROP treated with cryotherapy: 226 / 257 had 

ocular intervention in addition to cryotherapy (0.9% interventions per child)

Vitrectomy 26% (66/257); Scleral buckling 3% (8/257); Lensectomy 18%; Glaucoma 

medical treatment 4%; Glucoma surgery 2%; amblopia treatment 20%; Strabismus 

surgery 10%; Cataract surgery 2%; Enucleation 2%; Ventriculoperitoneal shunt 

(VPS) 11% Among children in the Natural History Cohort with variable ROP: 239 

ocular interventions (0.4% interventions per child) Strabismus 6%; Amblyopia Rx 

7% (3% if no ROP); VPS 3%

(None) Study was government and 

private funded 5 1⁄2 year followup of preterm infants with BW 

<1251 g with Threshold ROP 

randomized to cryotherapy vs. 

no cryotherapy groups. Both had 

high incidence of blindness, 

impaired visual acuity, and 

unfavorable outcome. 

Unfavorable outcomes were 

significantly less in cryotherapy 

group vs. control group.

Excellent long-term (10 yr) 

ophthalmic follow-up of PT 

infants with severe ROP. 

Cryotherapy assoc with 

significantly less unfavorable 

visual function outcome and less 

unfavorable structural outcome. 

>44% of cryo Rx eyes have 

unfavorable visual outcome and 

62% have unfavorable structural 

outcome. Threshold ROP with 

or without Rx is high for adverse 

long-term outcome. Infants with 

BW<1251 g with ROP 

underwent a large number of 

ophthalmic interventions through 

the first 5.5 years of life. Longterm costs of extreme 

prematurity and ROP include 

initial ablative therapy for ROP 

and societal loss due to visual 

impairment or blindness and 

ongoing costs for caring for eye 

problems.
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part III

304

Author, Year Associations found Potential Biases Comments

Cryo-ROP, 

1990, 1996, and 

2001 (x3)

91024693, 

96180078, 

21375786,

21375787,

21375788

Repka

1998

98426775

Continued

At 10-year follow-up:

Unfavorable Visual outcomes (functional) in Threshold ROP. Comparison of 

Threshold ROP eyes treated with CRYO vs. Control.

Distance Snellen Acuity (≥20/200)

 CRYO Rx 44%

 Control 62%

Near Snellen Acuity

CRYO Rx 43%

 Control 62%

Blindness

 CRYO Rx 33%

 Control 50%

Unfavorable Visual Acuity

Zone I/Threshold ROP/ CRYO Rx 94%

Zone I/Threshold ROP/Control 94%

Unfavorable structural outcome

Zone I/Threshold ROP/ CRYO Rx 88%

Zone I/Threshold ROP/Control 94%

Although cryotherapy was beneficial in reducing unfavorable structural and 

functional outcome vs. no treatment in Threshold ROP eyes, infants with 

threshold ROP still were at high risk for unfavorable outcome even with 

cryotherapy, especially infants with Threshold Zone 1 ROP.Vii

Visual fields at 10 years age in children enrolled in the CRYO ROP trial who had 

history of Threshold ROP (cryotherapy vs. control). Visual fields (with or without 

cryotherapy) were significantly smaller with severe ROP Visual fields in treated 

eyes were reduced by 30-37% vs. no ROP. Visual fields in control eyes were 

reduced by 27-33% compared to no ROP. Cryotherapy vs. control preserved 

sight and visual field in infants with severe ROP. Visual field area was 24 to 26% 

larger in CRYO Rx eyes vs. Control. Comparison of sighted treated eyes vs. 

sighted control eyes revealed that cryotherapy reduced visual field by small 

amount (5%).
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part III

305

Author, Year Associations found Potential Biases Comments

Predictors/

Conditions N

Outcome Category

Outcome of 

Interest/ 

Instruments 

used

% with Outcome

Methods of 

Correlation

Cryotherapy 203 vision Unfavorable 

outcome

HOTV acuity

47%

No 

Cryotherapy 

203 vision Unfavorable 

outcome

HOTV acuity

58%

unfavorable 

outcome

Cryo group had 19% 

reduction in 

unfavorable 

outcome for HOTV 

(p<0.01)

Cryotherapy 193 vision Unfavorable 

outcome

Grating acuity

52%

No 

Cryotherapy 

193 vision Unfavorable 

outcome

Grating acuity

66%

Cryo group had 20% 

reduction in 

unfavorable 

outcome for grating 

(p<0.01)

Cryotherapy vision Myopia :32 

<6 diopters

20%

No 

Cryotherapy 

vision Myopia :32 

<6 diopters

15.5%

Cryotherapy vision Myopia 36 

diopters

37.7%

Cryotherapy for 

Retinopathy of 

Prematurity 

Group

1993

93191597

No 

Cryotherapy 

vision Myopia : 36 

diopters

27.2%

More treated eyes 

had myopia than 

control eyes.

Data not shown is 

that more control 

eyes could not be 

refracted. 
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part III

306

Author, Year Associations found Potential Biases Comments

Algawi

1994

95001766

Myopia

Treat with Laser 6/15 (40%) (Spher Equiv −1.5 to −3.5 D)

Treat with Cryotherapy 23/25 (92%) (Spher Equiv −0.5 to −8.0 D)

Significantly more myopia in cryotherapy vs. laser group (P=0.0006)

Hypermetropia <+3.0 Diopters

Treat with Laser 9/15 (60%)

Treat with Cryotherapy 2/25 (8%)

Clinical significant astigmatism (no significant difference between groups (P=0.4).

Treat with Laser 5/15 

Treat with Cryotherapy 5/25 

Small sample size

Cohorts treated at different time, 

not concurrent and not 

randomized

No data on funding source

There is a high incidence 

of myopia following 

treatment for threshold 

ROP. Myopia occurred 

less often in the laser

treated group vs. 

cryotherapy treated group. 

Ling

1995

95391616

Visual outcome of Threshold ROP treated with diode laser: Structural 

Outcome (as defined by Cryotherapy Multicenter Trial) at 19.5 months age 

(range 9.7-25.5. mo) was favorable in all 13 patients (25 eyes). Functional 

outcome at the same follow-up (n=13): 3 with strabismus; 1 myopic; grating 

visual acuity (Keeler preferential looking cards) ranged 2.9-14.5 cycles per 

degree. 7 uniocular and 6 binocular acuity assessments fell within the CRYOROP definition of favorable acuity at 1 year of age (>0.8 cycles per degree 

uniocular)

(None) No data on funding source
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part III

307

Author, Year Associations found Potential Biases Comments

Connolly

1998

984267776

 Laser Treated Cryotherapy Treated Total

Threshold ROP Threshold ROP

Visual Acuity 20/50 or better 17 8 25

Visual Acuity 20/60 or worse 4 13 17

Total 21 21 42

81% of laser-treated vs. 38 % of cryotherapy treated Threshold ROP had good 

visual acuity outcome (VA 20/50 or better). The odds that a laser treated eye had 

a good visual outcome were 6.91 greater than threshold ROP eyes treated with 

cyrotherapy (95% CI 1.7- 28). 

Refractive Error: On average, 23 cryotherapy eyes had a mean spherical equivalent 

of – −5.08 Diopters vs. −3.05 Diopters for 23 laser treated eyes P=0.0072). Thus, 

cryotherapy eyes had greater amount of myopia than laser treated eyes. 

Summary: The odds that eyes treated with laser therapy would have best-corrected 

visual acuity of 20/50 or better was almost 7 times greater than cryotherapy 

treated eyes. Also, laser treated eyes had less myopia than cryotherapy treated 

eyes. Thus, the results suggest that laser photocoagulation for threshold ROP 

was more likely to result in good visual outcome with less myopia compared to 

cryotherapy treatment. 

Excluded large numbers of 

subjects

No data on funding source

Shalev

2001

21331013

Associations:

All 10 Laser treated eyes had favorable structural outcome; 2 of 8 cryotherapy eyes 

had unfavorable structural outcome. 

Laser-treated vs. cryotherapy treated threshold eyes had more favorable outcome.

Laser Cryotherapy P

Geometric visual acuity 20/33 20/133 0.03

Range (20/20-20/70) (20/25 to phthisis)

Mean refractive error(D) -6.5 -8.25 0.27

Conclude: Laser therapy for threshold ROP may have long-term visual 

function advantages over cryotherapy.

Small numbers for randomized 

comparison.

It is not clear how similar were the 

groups in terms of original 

threshold ROP (zone I vs. II)

No data on funding source
Evidence Table 8. Studies of Treatment Effects for LBW Infants with Retinopathy of Prematurity (ROP)

Part III

308

Author, Year Associations found Potential Biases Comments Predictors/C onditions

N

Outcome CategoryOutcome of Interest/ Instruments used% with OutcomeMethods of Correlation

Full

term

Control 169 Visual 

function

Distance 

Acuity (Left 

eye)

-0.08 (-

0.1,0.01)

BW

<1701

all

Premature 

cohort

254 Visual 

function

Distance 

Acuity (Left 

eye)

0.0 (-

0.08,0.1)

No 

ROP

Premature 

cohort

126 Visual 

function

Distance 

Acuity (Left 

eye)

0.0(-

0.08,0.04)

Stage 

3 or 4 

ROP

Premature 

cohort

7 Visual 

function

Distance 

Acuity (Left 

eye)

0.34(0.21,0.6

05)

Full

term

Control 169 Visual 

function

Binocular 

Distance 

Acuity

Normal 93%

≥Moderately 

reduced 0%

P<0.001 

between 

control vs. 

premature 

cohort

O’Connor

2002

21635822

BW

<1701

all

Premature 

cohort

254 Visual 

function

Binocular 

Distance 

Acuity

Normal 76%

≥Moderately 

Reduced 

3.5%
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcome

309

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Als

1994

94358983

(CNS+ 

Pulmonary)

Location: US

Years of Birth: ND

Median GA (range), wk:

Experiment: 27.1±1.6

Control: 26.5±1.4

Median BW (range), g:

Experiment: 827±173

Control: : 862±145

Male: 

Experiment: 45%

Control: 61%

Race: Black

Experiment: 40%

Control: 17%

SES I, II/III/IV, and V:

Experiment: 45%, 20%, 35%

Control: 56%, 17%, 27%

Enrolled: 43

Evaluated: 38

Number of sites: 1

BW < 1250 g

GA < 30 weeks and more than 24 

weeks of estimated GA at birth

Mechanical ventilation starting 

within the first 3 hrs after birth 

and lasting longer than 24 hrs in 

the first 48 hrs

Alive at 48 hrs

Absence of chromosomal or other 

major genetic anomalies, 

congenital infections, and known 

fetal exposure to drugs of 

addiction

Singleton

At least one family member with 

some English-language facility

Telephone access

Living within the greater Boston 

area

ND Experiment: VLBW 

infants participated 

in individualized 

developmental care 

(20)

Controls: VLBW infants 

received standard 

care (18)

Randomized controlled 

trial 

(2 weeks and 9 months)

Chye

1995

95314864

Location: Australia

Years of Birth: 1989 to 1990

Mean GA (range), wk: 

Cases: 28±1.58

Controls: 28.63±1.26

Mean BW (range), g: 

Cases: 1055± 234

Controls: 1077±215

Male: 56%

Race: ND

Enrolled: 80

Evaluated: 78 (78 controls)

Number of sites: 1

Cases: 26-33 week GA infants 

with BPD and discharged home

Controls: 26-32 week GA infants 

without BPD admitted to the 

hospital within 1 year of the 

cases, matched for BW with the 

cases in broad categories 

(<1000 g, 1000-1499 g and 

=1500 g)

Cases: Trisomy 21 (2) Cases: Preterm infants 

with BDP (78)

Sample 2: Preterm 

infants without BPD 

(78)

Subgroups of cases at

12 months corrected 

age follow-up:

Sample 1: BPD no 

Home O2 (58)

Sample 2: BPD with 

Home O2 (20)

Case-control study
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcome

310

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Kraybill

1995

95264242

Location: USA

Years of Birth: 1986-1989

Mean GA: (F/up at 1 year)

 Sample 1: 28.2 ±1.9

 Sample 2: 28.1 ±2.0

Mean BW: 

 Sample 1: 1022 ±177

 Sample 2: 1028 ±184

Male:

 Sample 1: 51%

 Sample 2: 52%

Race:

 Sample 1: White: 21%, Black: 

53%, Hispanic: 23%, Other; 4%

Sample 2: White: 34%, Black: 

42%, Hispanic: 22%, Other: 2%

Enrolled: 323 (survivors at 1 yr)

Evaluated: 258 (at 1 yr f/up)

Mean GA (F/up at 2 years of age)

 Sample 1: 28.3 ±1.8

 Sample 2: 28.1 ±1.8

Mean BW:

 Sample 1: 1043 ±165

 Sample 2: 1005 ±184

Male:

 Sample 1: 49%

 Sample 2: 43%

Race:

 Sample 1: White: 35%, Black: 

60%, Other:5%

 Sample 2: White: 43%, Black: 

54%, Other: 3%

Enrolled: 136 (survivors at 2 yrs)

Evaluated: 118

Number of sites: 2 

Premature VLBW: 700-1350 g

(Detailed description available in 

another article)

ND At 1 yr f/up 

Sample 1:

Synthetic Surfactant at

Birth via ET tube: 5

ml/kg (136)

Sample 2:

Air placebo via ET

tube at birth (122)

At 2 yr F/up:

Sample 1:

Synthetic surfactant at 

birth (57)

Sample 2:

Air placbo (61)

Randomized placebocontrolled double blind 

trial 

(at 1 year and at 2 years 

CA) 
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcome

311

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Santuz

1995

96023205

Location: Italy

Years of Birth: 1981-1987

Mean GA (range), wk: 

Cases: 30±2 (27-32)

Controls: 39±1 (37-40)

Mean BW (range), g: 

Cases: 1400±335 (890-1900)

Controls: 3335±418 (2800-4100)

Male: 

Cases: 75%

Controls: 69%

Race: ND

Enrolled: 12 (16 controls)

Evaluated: 12 (16)

Number of sites: 1

Cases: Premature, RDS with 

mechanical vent > 7 days; met 

criteria for BPD; agreed to 

cooperate 

Control: healthy term school 

children matched for age, height, 

weight, habitual level of physical 

activity

Cerebral palsy; too young 

to cooperate

Cases: Preterm infants 

with BPD (12)

Controls: Healthy term 

infants (16)

Case-control study 

(6-12 years)

Iles

1997

97280982

Location: UK

Years of Birth: ND

Mean GA (range), wk: ND

Median BW (range), g: 900 (589-

1891)

Male: ND

Race: ND

Enrolled: 40

Evaluated: 33

Number of sites: 1

Premature birth

Continuous supplemental O2 for 

28 days after birth

Refused consent

Returned to referring 

hospital

Premature infants with 

CLD (33)

Prospective cohort

Cheung

1998

99059896

Location: Canada

Years of Birth: 12/93-10/97

Mean GA (range), wk: 25 (24-30)

Median BW (range), g: 860 (340-

1460)

Male: 67%

Race: ND

Enrolled: 24

Evaluated: 10

Number of sites: 1

VLBW survivors, BW < 1500 g, 

requiring inhaled nitrous oxide 

(INO) (continues to be hypoxenic 

at >90% O2 and MAP 15 ± 2)

Mosaic trisomy 18

Potter’s syndrome

survived to 1 year of 

chronological age

VLBW infants treated 

with INO (10)

Prospective cohort 
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcome

312

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Gross

1998

98375435

Location: US

Years of Birth: 1985-1986

Mean GA (range), wk: 

Sample 1: 28.2±2.1

Sample 2: 28.4±2.0

Controls: 40±1.1

Mean BW (range), g: 

Sample 1: 1173±345

Sample 2: 1179±354

Controls: 3565±427

Male:

Sample 1: 53%

Sample 2: 51%

Controls: 57%

Race: White

Sample 1: 86%

Sample 2: 85%

Controls: 89%

Enrolled: 133 (125 controls)

Evaluated: 96 (108)

Number of sites: 1

All live-born babies 24-31 wk 

gestation cared for at Crouse 

Memorial Hospital, survived to 

discharge

Controls: FT AGA, 38-42 wk GA.

PT matched to FT for sex, mat. 

Race, mat. Educa. and marital 

status (sociodemographic 

factors).

ND (Sample 1&2): Preterm 

infants (96)

Sample 1: Preterm 

infants with BPD 

(43)

Sample 2: Preterm 

infants without BPD 

(53)

Controls: Full term 

infants (108)

Prospective cohort (7 

years)

Cases: 8 died after 

discharge because of 

complications of 

chronic lung disease 

(2), pneumonia (2), 

nonrespiratory 

conditions (4), lost to 

follow-up (6), and 

neurodevelopmental 

delays (23)

Controls: lost to followup (12), 

neurodevelopmental 

delays (5)

Kurkinen-Raty

1998

98387235

(All+Lung)

*sample from 

the same big 

population as 

20284814

Location: Finland

Years of Birth: 1990-1996

Mean GA (range), wk:

Cases: 28.2 (23.8- 37.2)

Controls: 28.4 (22.9-36.9)

Mean BW (range), g:

Cases: 1138.3±434

Controls: 1272.4±547.2

Male: ND

Race: ND

Enrolled: 78 (78 controls)

Evaluated: 78 (78)

Number of sites: 1

Preterm PROM between 17-30 

weeks gestation; singleton; 

delivered > 2 hr after rupture

Controls: preterm no PROM; 

spontaneous preterm delivery 

matched for GA and year of 

delivery.

Rupture unconfirmed or 

transient

Sample 2: Preterm 

rupture (78)

Sample 2: Preterm 

delivery no rupture 

(78)

Retrospective cohort
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcome

313

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Subhedar

1999

20257096

Location: UK

Years of Birth: 6/1995-5/1999

Mean GA (range), wk: 

Sample 1: 28 (24-34)

Sample 2: 30 (26-34)

Mean BW (range), g: 

Sample 1: 1055 (510-2310)

Sample 2: 1420 (840-2150)

Male: 

Sample 1: 52%

Sample 2: 52%

Race: ND

Enrolled: 98

Evaluated: 98

Number of sites: 1

Sample 1: Preterm infants with 

CLD 

Sample 2: Preterm infants without 

CLD received mechanical 

ventilation <24 hours + 02< 72 

hours

ND Sample 1: Preterm 

infants with CLD 

(54)

Sample 2: Healthy 

preterm infants (44)

Prospective cohort 

Kurkinen-Raty

2000

20284814

*sample from 

the same big 

population as 

98197235

Location: Finland

Years of Birth: 1990-1997

Mean GA (range), wk:

Cases: 30.5±2.1

Controls: 30.4±2.1

Mean BW (range), g:

Cases: 1294±469

Controls: 1605±427

Male: ND

Race: ND

Enrolled: 103 (103 controls)

Evaluated: 103 (103)

Number of sites: 1

Cesarean delivered singleton, GA 

24-33 weeks

Controls: spontaneously delivered 

singleton after regular 

contractions and/or preterm 

rupture of the membranes no 

more than 24 hrs before. The 

mothers were matched one-toone by gestational age at 

delivery plu7s or mines 1 week.

ND Sample 1: Indicated 

preterm I.e. preterm 

birth ‘indicated’ for 

maternal/fetal 

reasons (103)

Sample 2: 

Spontaneous 

preterm delivery 

due to preterm labor 

(103)

Retrospective cohort
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcome

314

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Brooks

2001

21153125

Location: US

Years of Birth: 1988

Mean GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: 8071

Evaluated: 8071

Number of sites: 1

< 4 year old selected from 

randomized, systematic population 

based sample, weighted to be 

nationally representative of 

sampling of African-American and 

LBW infants who had initial (1988) 

and follow-up (1991) surveys and 

asthma reports

ND VLBW infants 

(<1500g), MLBW 

(1500-2499g); NBW 

(=2500) infants from 

NMIHS population 

(8071)

Prospective cohort 

Follow-up 3 years

1988-1991

Doyle

2001

21064379

*overlapped 

sample with 

Ford, 2000

20380862 in 

growth table

Location: Australia

Years of Birth: 1/1977 to 3/1982

Mean GA (range), wk: 

Sample 1: 27.5 ±2.3

Sample 2: 29.6 ±1.5

Controls: 39.9 ±1.0

Mean BW (range), g:

Sample 1: 859±100

Sample 2: 1248±145

Controls: 3420±427

Male: 

Sample 1: 45%

Sample 2: 54%

Controls: 62%

Race: ND

Enrolled: 210 (60 controls)

Evaluated: 180 (42 controls)

Number of sites: 1

Sample 1: 86 consecutive ELBW 

survivors (BW 500-999g) born 

during the 63 months from 

1/1/1977

Sample 2: 124 consecutive ELBW 

survivors (BW 1000-1500g) born 

during the 18 months from 

1/10/1980

Control: 60 randomly selected 

term infants with BW>2499g 

born within the Royal Women’s 

Hospital during the last 6 months 

of the recruitment phase

ND Sample 1: Preterm 

ELBW infants, BW 

500-999g (78)

Sample 2: Preterm 

ELBW infants, BW 

1000-1500g (102)

Control: Term infants, 

BW >2499g (42)

Prospective cohort 

(14 years)
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part II

315

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Als

1994

94358983

Other:

Participation in individualized 

developmental care staffing by 

specially educated nurses

The psychologist and clinical nurse 

specialist provided ongoing support 

for the care teams and parents of 

the infants in the experimental 

group in jointly planning and 

implementing individually 

supportive care and environments.

CNS:

Neurodevelopmental:

Cognitive delay

Pulmonary:

BPD severity

Baley Scale of Infant Development at 9 

months of age

Assessed by double-blind review of 

cranial US scans by a consultant 

senior radiologist

Chye

1995

95314864

Bronchopulmonary dysplasia

BPD with Home O2

BPD without Home O2

Diagnoses of BPD was based on 

Bancalari’s BPD definition

Home oxygen therapy program –

infants who were well, feeding 

satisfactorily and gaining weight, but 

were unable to maintain adequate 

oxygenation (93-97% saturation) in 

room air, and were therefore 

discharged from hospital under the 

home oxygen therapy

Growth 

Re-hospitalization

Growth was based on sex-specific 

National Center of Health Statistics 

growth chart
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part II

316

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Kraybill

1995

95264242

General:

Surfactant (single dose 5 ml/kg 

given via ET tube at birth)

As soon as after birth, infants were 

treated either with 5 ml/kg of 

surfactant or air placebo, via ET 

tube.

At 1 yr assessment (NCMH and 

HCHD cohort):

General:

Overall survival

Pulmonary:

Need for O2 via Nasal canula

Need for O2 via CPAP

CLD

At 2 yr assessment (NCMH cohort)

General:

Overall survival

Hospitalization for respiratory illness

Pulmonary:

Bronchodilator regular use

Tracheostomy

At 1 and 2 yr assessment:

Growth:

Height for age

Weight for age

HC for age

Mean MDI score 

MDI scores < 2 SDs

Mean PSI score

PDI scores < 2 SDs

Severity of impairments

Types of Impairments

Any surgery (between 28 ds-1 yr or 

 1yr to 2 yr)

Assessment between 28 ds-12mo:

Ophthalmology:

ROP (No ROP, Mild/moderate, 

 Severe)

Tx for ROP( surgery or cryotherapy)

ROP presence at latest exam

Severe ROP

No further specifications given, except 

for the followings:

Oxygen via Nasal canula : providing 

alveolar O2 concentrations of : 26%-

40%, based on NC flow and NC O2 

concentration

Bayley Scale of Infant Development:

• MDI= Mental Development Index 

Score

• PDI: Psychomotor Development 

Index Score

ROP : (not further definitions)

• No ROP,

• Mild/moderate

• Severe

CP (no further definitions)

• Mild

• Moderate/Severe

Severity of impairments:

• Severe

• Mild/Moderate

Types of impairments:

• MDI<69

• MDI: 69-84

• Moderate/severe CP

• Mild CP

• Bilateral sensorineural deafness

• Deafness not requiring 

amplification

• Bilateral blindness

• Visual defect

(1 yr and 2 yr CA)
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part II

317

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Santuz

1995

96023205

General Predictor: GA

Cardiovascular

1) Chronic Lung Diseases

2) Other: duration of 

supplemental oxygen

Chronic Lung Disease defined as 

oxygen dependency for at least 28 

days and beyond 36 postmenstrual 

weeks in association with an 

abnormal chest radiograph.

Other Outcomes:

Cardiovascular: pulmonary 

hypertension

Measured as AT/RVET ratio = Doppler 

derived acceleration time to right 

ventricular ejection time ratio

Iles

1997

97280982

Cardiovascular or Pulmonary 

Predictors:

Bronchopulmonary dysplasia

Other Predictors:

ECG with RVH

DaAO2 in 50% O2

PaCO2

PFT testing to determining Vmax FRC

Pulmonary:

Requirement for supplemental O2 at 

one year CA; alternately phrased 

by authors as SaO2 < 90% in RA

Other outcomes:

Hospital readmission

ND

Cheung

1998

99059896

Cardiovascular or Pulmonary 

Predictors:

Inhaled nitric oxide (INO)

ND Pulmonary:

BPD or CLD (with or without meds)

Aspiration pneumonia

PDI + MDI of Bayley Scales of Infant 

Developmental Index were used.

"Neurodevelopmental" outcomes:

Disability: one of more of:

1. CP (all types or severity)

2. Legal blindness (corrected visual 

acuity of the better eye <20/200

3. Hearing loss (sensorineural 

hearing loss of >30 dB in the better 

ear)

4. Severe mental retardation (MDI >3 

SD below the mean)

Delay: does not have disability and 

either MDI or PDI was >2 SD below 

the mean.

Normal: free of disability or delay 

and MDI and PDI were within 2 SD 

of the mean.
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part II

318

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Gregoire

1998

95264241

Cardiovascular/Pulmonary: 

1) Chronic Lung Disease

2) Bronchopulmonary 

dysplasia

Compared O2 dependence at 28

days with O2 dependence at 36 

wk

N ND CNS: 

Cerebral palsy

Motor and cognitive delay

Audiology: Hearing Disorders‡

Free field audiograms 

Pulmonary: 

Respiratory readmissions

PICU admissions

Growth: Weight, height, head 

circumference

Other: Health Outcomes

Giffith’s Mental Development Scales 

Neurologic examinations

Gross

1998

98375435

General: GA

Cardiovascular: 

Bronchopulmonary dysplasia 

@ 30 wk

Other: social data, health data

PT 24-31 wk GA

BPD if infants were dependent on 

supplemental oxygen @ 35 wk 

PMA

Pulmonary:

Respiratory symptoms (wheeze, 

 chronic cough, chest congestion)

Restriction in activity, 

Use of respiratory medicines,

7-year pulmonary function studies

Bronchodilator responsivness

Other:

Re-hospitalization

Metabolic measures

Lung function testing was performed on 

SensorMedics 2200 (SensorMedics, 

Anaheim, Calif) by investigators 

blinded to children’s GA and medical 

histories

Kurkinen-Raty

1998

98197235

General : PROM Diagnose was through clinical 

assessment or with the use of a 

PROM-test, which detects insulin 

growth factor binding protein-1 in the 

cervico-vaginal secretions, or with the 

use of a nitrazine test.

CNS:

Motor delay

Cerebral delay

Ophthalmology: Visual Blindness

Audiology: Hearing disorders

Pulmonary: Chronic lung disease

Growth: weight percent

Other:

Days of re-hospitalization

Steroid therapy at follow-up 

Neurologic exams

Diagnosis of CLD was made if infants 

required oxygen, continuous 

bronchodilator, or steroid tx because 

of respiratory signs and symptoms.

Diagnoses of RDS were made based on 

need for respiratory support, 

radiologic findings, and clinical 

assessments
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part II

319

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Subhedar

1999

20257096

Cardiovascular/Pulmonary:

Chronic lung disease

CLD was defined as oxygen 

dependency for at least 28 days 

and beyond 36 PMA in association 

with an abnormal chest radiograph

Pulmonary:

 1) Pulmonary function-forced vital 

capacity

 2) Minor ventilation forced expiratory 

volume, forced expiratory flow

Other: Heat rate during exercise 

Measures OR aerobic power: a) 

maximum O2 consumption b) max O2 

consumption at anaerobic threshold 

C) running time

Kurkinen-Raty

2000

20284814

General predictors:

Birth weight

GA

Antenatal steroids

Cord pH

Bronchopulmonary dysphasia 

(BPD)

Other predictors: 

Indicated preterm delivery

Spontaneous preterm delivery

BPD diagnoses were based on 

radiologic finding

CNS: 

Motor delay

Cerebral palsy

Ophthalmology

Visual impairment

Audiology

Hearing disorder

Pulmonary

Chronic lung disease (CLD) at 1 year

Growth:

Wt, Ht, HC

Motor delay = abnormalities of tone or 

reflexes but functionally normal or 

borderline

CP = spastic diplegia or hemiplegia or 

spastictetraplegia

Diagnosis of CLD was made if infants 

required oxygen, continuous 

bronchodilator, or steroid tx because 

of respiratory signs and symptoms.

Brooks

2001

21153125

General:

Birth weight

Sex

Other:

SEC factors (mat age, race, 

education, SEC status, mat wt 

gain, mat smoking, poverty 

status variable)

Prenatal history

Developmental outcomes

Predictors self-explanatory. Poverty 

variable based on family income and 

number of household members, 

categorized by standard national 

poverty levels. 

Pulmonary:

M.D. diagnosed asthma in 1st 3 

years of life

Diagnosis of asthma based on

 response of parent to question, “Have 

you been told by a MD/ RN/other health 

provider that your child has asthma?”

Doyle

2001

21064379

*overlapped 

sample with 

20380862

General: Birth weight

Cardiovascular/Pulmonary: 

Bronchopulmonary

ND Pulmonary:

 1) Asthma

 2) Lung function testing

 3) readmission to hospital for asthma 

or pneumonia

Growth: height

Other: hospital readmission 

Lung function testing, Jaeger 

Bodyscreen II-Bodybox (Jaeger, 

Germany), with Masterlab (ML3) 

software
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

320

Author, Year Associations found Potential Biases Comments

Als

1994

94358983

Studied effect of an individualized developmental care plan on Bayley score at 

9 months age and occurrence and severity of BPD.

Experimental group Controls P value

N 20 18

Bayley MDI 118.30 (17.35) 94.38 (23.31) < 0.001

Bayley PDI 100.6 (20.19) 83.56 (17.97) < 0.01

No BPD 2/20 3/18

Mild BPD 13/20 7/18

Moderate BPD 5/20 2/18

Severe BPD 0 6/18 0.03

Small number of babies studied

Only one NICU

Only one neurodevelopmental assessment at 

9 months of age

Reported timing of IVH different from many 

other studies

High potential for contamination

Study was government 

funded
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

321

Author, Year Associations found Potential Biases Comments

Chye

1995

95314864

Rehospitalization rate (overall)

BPD (78) 58%

Control (75) 35% RR 1.7 (1.2-2.4)

Rehospitalization for respiratory illness

BPD (78) 39%

Control (75) 20% RR 1.9 (1.1- 3.2)

Rehospitalization for poor growth

BPD (78) 14%

Control (75) 1% RR=1.4 (1.7-82)

Rehospitalization for failure to thrive

BPD on home O2 (20) 30%

Control no home O2 (58) 9% RR=3.3 (1.2-8.9)

Growth (wt in kg) : NS diff between BPD and control 

BPD M 9.08 F 8.4

Control M 9.37 F 8.82 

Growth (Ht in cm): NS diff

BPD M 73.0 F 72.1

Control M 74.4 F 72.6 

Growth (HC in cm): NS diff

BPD M 46.7 F 46.0

Control M 47.0 F 454. 

There was a significant increase in any rehospitalization in 1st year of life in 

preterm infants with BPD vs. preterm infants with no BPD.

There was a significant increase (2-fold) in rehospitalization for respiratory 

illness in the 1st year of life in preterm infants with BPD vs. preterm infants 

with no BPD. 

BPD infants with Home O2 (N=20) had ~3 fold increased re-hospitalization for 

failure to thrive. 

Growth failure was common in both preterm groups (i.e. in infants with no BPD 

and with BPD <10% in weight at 1 yr age). Re-hospitalization was high in 

both preterm groups (with and without BPD).

(None) Study was privately 

funded
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

322

Author, Year Associations found Potential Biases Comments

Kraybill

1995

95264242

Single dose Surfactant tx at birth was not associated with the physical and 

neurodevelopmental status of VLBW premature infants at 1 yr of corrected 

age Placebo group vs Surfactant group, at 1 yr of age:

1. Overall survival at 1 yr: 

2. Oxygen via NC

3. Oxygen via CPAP: 

4. CLD

5. Distribution of pts in both groups across different percentiles:

Ht/age, Weight/age and HC/age: were not s/s different across the two groups.

6. Mean MDI score:

7. MDI scores< 2SDs 

8. Mean PDI score:

9. PDI scores < 2 SDs: 

10. No impairment: 

11. Impairment present (total )

12. Severe impairment: 

13. Mild/Moderate impairment: 

14. Types of impairment:

 MDI<69: MDI: 69-84: 

 Moderate/severe CP: Mild CP: 

 Bilateral sensorineural deafness: Deafness not requiring amplification 

 Bilateral blindness: Visual defect: 

Assessment from 28ds-12 mo:

• No ROP: 

• Present ROP overall: 

• Mild/Moderate ROP: 

• Severe ROP: 

• Treatment for ROP overall: 

Surgery: 

 Cryotherapy: 

In the NCMH cohort there was no difference in impairments, the severity of 

impairments and the types of impairments at the 1yr of age assessment
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

323

Author, Year Associations found Potential Biases Comments

Santuz

1995

96023205

Forced vital capacity (FVC):

 BPD: (N=12) 87+10 

 Without BPD: (N=16) 96+8 

 <0.05

Forced expiratory volume(1 sec)(FEV1):

 BPD: 83+12 

 Without BPD: 100+8 

 <0.01

FEF 25-75 (forced expiratory flow between 15-7520 vc):

 BPD: 77+30 

 Without BPD: 110+14 

 <0.01

Oxygen consumption (ml/?/?):

 BPD: 25.2+10.3 

 Without BPD: 37.1+10.4 

 <0.01

Running time (minutes):

 BPD: 6.1+1.3 

 Without BPD: 7.9+2.6 

 <0.05

Minute ventilation:

 BPD: 20+9.4 

 Without BPD: 30.7+9 

 <0.01

Max heat rate during exercise:

 BPD: 192+7.9 

 Without BPD: 194+8 

 Not significant

Running time:

 BPD: 6.1+1.3 

 Without BPD: 7.9+2.6 

 P <0.05

Small study

Far from comprehensive; likely substantial 

section bias

Compares prematures with BPD to term infants 

without BPO; unclear if results are due to 

BPD or prematurity

No data on funding source
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

324

Author, Year Associations found Potential Biases Comments

Iles

1997

97280982

Study of chronic lung disease (CLD) leading to a persistent requirement for 

supplemental oxygen at one year of age.

 N % requiring oxygen at one year age

Supplemental O2 at discharge 6 50%

RVH on ECG 3 100%

Alveolar arterial oxygen gradient > 29 kPa in 50% hood oxygen at 35 to 40 

weeks PCA predicted need for supplemental oxygen at one year with 

sensitivity 0.85 and specificity 0.88. PaCO2 greater than 7 kPa at 35 to 40 

weeks PCA predicted supplemental oxygen requirement at one year with 

sensitivity 0.78 and specificity 0.88.

Small number of infants

No information regarding early neonatal 

course

No control groups of preterms without CLD

Study was privately 

funded

Cheung

1998

99059896

Mean MDI 81 ± 21, PDI 64 ± 22

Normal development 31%

Neurodevelopmental delay 20%

Disabled 50%

Severe mental retardation 10%

Spastic diplegic CP 30%

Hemiplegic CP 10%

<3rd %ile for weight 20%

<3rd%ile for height 40%

<3rd%ile HC 30%

BPD 80%

Need bronchodilators for CLD 10%

Recurrent wheezing but did not need meds 40%

Grade 4 IVH 20%

Grade 3 IVH 20%

VP shunt 30%

PVL 10%

Sensorineural hearing loss 10%

Very small sample size

Descriptive study with no control group for 

comparison

No data on funding source
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

325

Author, Year Associations found Potential Biases Comments

Gross

1998

98375435

Rehospitalization during 1st 2 years: 

PT with BPD 23/43 (53%)

PT without BPD 14/53 (26%)

FT 3/108 (3%) 

Respiratory symptoms in PT with BPD were greater than symptoms in PT 

without BPD, and both were greater than FT group

Pulmonary function Tests: Multiple tests revealed significantly worse PFTs in 

PT with BPD at rest and after exercise compared to either PT without BPD 

or FT group. 

Exercise results:

No difference in baseline HR, VO2, RQ, Max VO2, 

Max RQ, endurance among groups

Asthma: 

PT with BPD 20/43 (47%)

PT without BPD 13/53 (25%)

FT 23/108 (21%) 

PT with BPD vs. FT: P<0.001

School age children who were former preterm infants with BPD demonstrated 

abnormal pulmonary function at 7 years age in contrast to school age 

children who were preterm infants without BPD or FT AGA control. The 

children who were preterm infants without BPD had similar pulmonary 

function as children who were FT AGA controls.

(None) No data on funding source
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

326

Author, Year Associations found Potential Biases Comments

Kurkinen-Raty

1998

98387235

Retrospective controlled cohort study of early PROM between 17 and 30 

weeks of gestation. Assements at one year corrected age. N = 55 for early 

PROM and 56 for control.

Outcome Early PROM Control OR (CI)

Cerebral palsy 18% 16% 1.2 (0.4, 3.1)

Delayed motor

Development 9% 16% 0.5 (0.2, 1.7)

Visual disability 4% 4% 1.0 (0.1, 7.5)

Hearing loss 7% 9% 0.8 (0.2, 3.2)

Good nuerosensory

development 67% 61% 1.2 (0.6, 2.2)

Early PROM seems to be a major obstetric and neonatal problem with 

pulmonary ramifications extending beyond the neonatal period. However, most 

of these infants can be saved.

(None) No data on funding source

Subhedar

1999

20257096

AT/RVET ratio much lower in CLD group p< 0.01.

Pulmonary arterial pressure remains persistently elevated in CLD infants until 

the end of first year of life.

Does not state whether the Doppler evaluators 

were blinded to the groups

Study was private funded
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

327

Author, Year Associations found Potential Biases Comments

Kurkinen-Raty

2000

20284814

CLD at 1 year age: 

Indicated PT delivery: (81) 12/81 (15%)

Spontaneous PT delivery: (94) 3/94 (3%)

RR 4.6 (1.4, 1.6)

Growth: 

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94) 

Weight RR =0.03 (-5.3, 0.3)

L RR = 0.002

HC RR = 0.03

CP:

Indicated PT delivery: (81) 5/81 (6%)

Spontaneous PT delivery: (94) 10/94 (11%)

RR=0.6 (0.25-1.6)

Delayed motor:

Indicated PT delivery: (81) 8/81 (6%)

Spontaneous PT delivery: (94) 8/94 (9%)

RR 1.2 (0.5-3.0)

Visual disability:

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94)

RR =1.9 (0.5, 7.8)

Hearing loss:

Indicated PT delivery: (81) 

Spontaneous PT delivery: (94)

RR =1.9 (0.5, 7.8)

This study demonstrated that premature infants who were born due to 

‘indicated maternal/fetal reasons’ vs. spontaneous preterm delivered infants 

had worse pulmonary outcome a 1 yr age. More infants in ‘indicated’ group 

were SGA and were significantly smaller than control group at 1 yr in Wt, 

HT, and HC. There was no difference between groups in neurosensory 

outcomes.

Outcome not well-defined

Difficult to know if lack of difference between 

groups is due to sample size or event rate. 

No data on funding source
Evidence Table 9. Studies Evaluating Association of LBW and Pulmonary Outcomes

Part III

328

Author, Year Associations found Potential Biases Comments

Brooks

2001

21153125

Diagnosis asthma by age 3 years

BW ≥ 2500 gm 6.7%

BW≥1500-2499gm 10.9% OR=1.4 (1.1-1.8)

BW < 1500 (VLBW) 21.9% OR=2.9 (2.3-3.6)

African-American 12% OR=1.9 (1.6-2.4)

VLBW/African-American OR 2.5 (2.0-3.3)

VLBW/white OR=3.1 9 ( 2.2-4.3)

Chronic lung disease (8058) 20.4% OR 3.4 (2.4-4.8)

68% attributable risk for asthma in VLBW children was due to birth weight. 

Retrospective classification of BPD may have 

been limited compared to prospective 

classification.

Potential for selection bias

a. identifying asthma children based on 

parental report of physician-diagnosed 

asthma. (Evidence of high specificity and 

PPV)

b. defining asthma may vary by physician 

practice

Study was government 

funded

Objective of study was to 

estimate the 

independent 

contribution of BW to 

asthma prevalence 

among children <4 

years age. This study 

found a strong, 

independent 

association between 

low birth weight and 

asthma. 

Doyle

2001

216464379

*overlapped 

sample with 

20380862

Respiratory health and lung function in these preterm children <1501g were 

mostly normal and comparable with normal control term infants at 14 years

(None) Study was privately 

funded
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part I

329

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Forslund

1992

93044002

Location: Sweden

Years of Birth: ND

Median GA (range), wk: ND

Mean BW (range), g: ND

Male: ND

Race: ND

Enrolled: ND

Evaluated: 41 (24 controls)

Number of sites: ND

ND ND Cases: Preterms (41)

Controls: Term infants 

(24)

Unclear (the study 

design was described 

in detail in previous 

papers)

Chye

1995

95314864

Location: Australia

Years of Birth: 1989 to 1990

Mean GA (range), wk: 

Cases: 28±1.58

Controls: 28.63±1.26

Mean BW (range), g: 

Cases: 1055± 234

Controls: 1077±215

Male: 56%

Race: ND

Enrolled: 80

Evaluated: 78 (78 controls)

Number of sites: 1

Cases: 26-33 week GA infants 

with BPD and discharged home

Controls: 26-32 week GA infants 

without BPD admitted to the 

hospital within 1 year of the 

cases, matched for BW with the 

cases in broad categories 

(<1000 g, 1000-1499 g and 

=1500 g)

Cases: Trisomy 21 (2) Cases: Preterm infants 

with BDP (78)

Sample 2: Preterm 

infants without BPD 

(78)

Subgroups of cases at 

12 months corrected 

age follow-up:

Sample 1: BPD no 

Home O2 (58)

Sample 2: BPD with 

Home O2 (20)

Case-control study

DeReignier

1997

98041177

Location: Netherlands

Years of Birth: 1/1/1987-12/31-

1991

Median GA (range), wk: 27.5

Mean BW (range), g: 1015

Male: 48%

Race: 38% Black

Enrolled: 678

Evaluated: 174

Number of sites: 1

VLBW infants , BW < 1500 g, 

survived until discharge

Matched sever CLD and no CLD 

infants to mild CLD infants for 

BW, race, and sex.

Condition independent of 

CLD known to adversely 

affect neurosensory 

status, development, 

growth; significant 

congenital anomalies; 

congenital viral 

infections; SGA; NEC 

requiring enterostomy

Matched VLBW infants 

(89):

No CLD (58)

Mild CLD (58)

Severe CLD (58)

Retrospective cohort 

(followed until 1 year 

adjusted age)
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part I

330

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Gosch

1997

97379896

Location: US

Years of Birth: 1989 to 1994

Mean GA (range), wk: 

Cases: 27.6 (26-29)

Controls: 39 (36-40)

Mean BW (range), g:

Cases: 880

Controls: 3466

Male: 50%

Race: ND

Enrolled: 5 (5 controls)

Evaluated: 5 (5)

Number of sites: 1

Participants in a early intervention 

and family care for blind infants 

and preschoolers

Blind children

ND Cases: Blind children 

born preterm (5)

Controls: Blind children 

born full term (5)

Retrospective cohort 

(24, 36, 48, and 58 

months)

Ladd

1998

98357452

Location: US

Years of Birth: 1980-1995

Mean GA (range), wk: 30 (23-42)

Mean BW (range), g: 1500 (272-

4840)

Male: 53%

Race: ND

Enrolled: 249

Evaluated: 249

Number of sites: 1

249 babies with NEC who had 

their initial surgical care at the 

James Whitcomb Riley Hospital 

for Children Indiana University 

Medical Center campus, with the 

diagnosis of NEC from 1/1/1908-

12/31/1995 were included in the 

study

Infants with focal, isolated 

perforations of the ileum 

were excluded 

 Infants with NEC (249) Retrospective cohort 

(16 years)
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part I

331

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Wang

1998

98244087

Location: Canada

Years of Birth: 1/1977 to 5/1992

Mean GA (range), wk: 27.7±2.3

Mean BW (range), g: 954.6±185.9

Male: 48%

Race: Caucasian 88.5%

SES: low SES category (Blishen 

index=40) 47.2%

Enrolled: 1007

Evaluated: 514

Number of sites: 1

VLBW infants, BW<1250g, 

survived to NICU D/C

Missing more than one 

measurement

VLBW infants (514) Prospective cohort 

(36 months)

Connors

1999

99250892

Location: Australia

Years of Birth: 1/1987 to 12/1992

Mean GA (range), wk: 27±2.2

Mean BW (range), g: 822.8 ±125

Male: 45%

Race: ND

Enrolled: 226

Evaluated: 198

Number of sites: 1

ELBW survived infants, BW <1000 

g 

Died by 2 years corrected 

age (1)

Lost to follow-up (12)

Transferred interstate and 

limited information was 

available (4)

ELBW infants (198):

Sample 1: ELBW 

with low perinatal 

risk factors (128)

Sample 2: ELBW 

with high perinatal 

risk factors (70)

Prospective cohort 

(2 year CA)
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part I

332

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

French

1999

99115141

(CNS + Growth+

All)

Location: Australia

Years of Birth: 1990-1992

Median GA (range), wk:

Sample 1: 30 (26-32)

Sample 2: 29 (27-31)

Sample 3: 30 (28.5-31.5)

Sample 4: 31 (29-32)

Mean BW (range), g:

Sample 1: 1435 (905-1810)

Sample 2: 1345 (1000-1735)

Sample 3: 1517.5 (1210-1660)

Sample 4: 1455 (1080-1715)

Male: total 57%

Race: ND

Enrolled: 652

Evaluated: 477

Number of sites: 1

Singleton live-born infants GA <33 

weeks

ND Sample 1: Antenatal 

steroids x 0 course 

(311)

Sample 2: Antenatal 

steroids x 1 course 

(123)

Sample 3: Antenatal 

steroids x 2 courses 

(20)

Sample 4: Antenatal 

steroids x > 3 

courses (23)

Prospective cohort (3 

years)

Ford

2000

20380862

*overlapped 

sample with 

Doyle, 2001

21064379 in 

Lung table

Location: Australia

Years of Birth: 1/1977 to 3/1982

Mean GA (range), wk: 

Sample 1: 27.5 ±2.3

Sample 2: 29.6 ±1.5

Controls: 39.9 ±1.0

Mean BW (range), g:

Sample 1: 859±100

Sample 2: 1248±145

Controls: 3420±427

Male: 56%

Race: ND

Enrolled: 206 (60 controls)

Evaluated: 179 (42 controls)

Number of sites: 1

Cases: Preterm ELBW infants 

(<1500g) who survived to 

discharge

Control: Full term NBW 

(BW>2499g) infants group who 

survived to discharge

Children with CP at age 14 

years

Lost to follow-up

At 14-year follow-up:

Cases (Sample 1&2): 

Preterm ELBW 

infants (179)

Sample 1: Preterm 

infants, BW<1000g 

(79)

Sample 2: Preterm 

infants, BW 1000-

1499g (100)

Control: Full term NBW 

infants (42)

Prospective cohort 

(14 years)
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part I

333

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Morley

2000

20167446

Location:UK

Centers:5

Enrollment period: ND

Age at assessement:7.5-8 yrs

Trial 1: conducted in 3 centers

Total enrolled in trial 1 and 2:

N=926 infants with BW< 1850 g

Long term f/up at 7.5-8 yrs of age:

 N=781 of 833 (94%) survivors 

Premature

BW< 1850 g

Survivors of participants in the two

RCTs with 2 parallel arms each ( 

assessing effect of different 

neonatal diets of growth)

Age 7.5-8 yrs

ND GroupA:

Prematures/ fed 

banked breast milk 

until weight 2000 g 

or discharge from 

the NICU

N=207

Mean BW: 1397±297

Mean GA:31.1

% of SGA:30%

Males: 53%

Group B:

Prematures/ preterm 

formula

N=213

Mean BW:1387 ±278

Mean GA:31

% of SGAs:35%

Males:52%

(both groups included 

2 parallel arms with or 

without

supplementation with 

mother’s own milk )

Two Randomized clinical 

trials

Trial 1 and 2, with 2 

parallel arms in each 

trial

(The results for each trial 

are presented for the 

combination of the 2 

parallel arms)

Trial 1 had :

Follow up 

At 9 mo

At 18 mo

At 7.5-8 yrs
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part I

334

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Avila-Diaz

2001

21334039

Location: Mexico

Years of Birth: ND

Mean GA (range), wk: 

Sample 1: 39±0.9

Sample 2: 30±2.6

Mean BW (range), g: 

Sample 1: 3195±323

Sample 2: 1294±167

Male: 51%

Race: ND

Enrolled: 82

Evaluated: 82

Number of sites: 1

Informed consent

48 full-term “healthy” infants and 

34 pre-term infants who were 

predominantly breast-fed

ND Sample 1: Full term 

infants (48)

Sample 2: Preterm 

infants (34)

Prospective cohort 

(6 

months)
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part II

335

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Forslund

1992

93044002

General: GA Not given, resulted from previous 

papers of study with same group

CNS:

Neurodevelopmental

Motor delay

Growth in height, weight and head 

circumference

Motor performance was tested by a 

physiotherapist: used TMI ( test of 

motor impairment)

Measurement of height

Weight and head circumference by an 

experienced RN.

Chye

1995

95314864

Bronchopulmonary dysplasia

BPD with Home O2

BPD without Home O2

Diagnoses of BPD was based on 

Bancalari’ BPD definition

Home oxygen therapy program –

infants who were well, feeding 

satisfactorily and gaining weight, 

but were unable to maintain 

adequate oxygenation (93-97% 

saturation) in room air, and were 

therefore discharged from hospital 

under the home oxygen therapy

Growth 

Re-hospitalization

Growth was based on sex-specific 

National Center of Health Statistics 

growth chart

DeReignier

1997

98041177

General: GA

Cardiovascular/Pulmonary: 

Chronic lung disease

Gastrointestinal: Necrotizing 

“enterocolitis”

Other: Osteomalcia = 

Socioeconomic status

No CLD- room air at 28 days

Mild CLD- requiring 02 at 28 days but 

not at 36 wks PCA.

Severe CLD- requiring 02 at 28 days 

and 36 wks PCA 

Not included in CLD if 02 used only 

for prevention of apnea

CNS: 

Motor delay

Cerebral palsy

Cognitive delay

Mental retardation

Growth:

Weight

Height

Head circumference 

Other : Hospital readmissions 

Motor and cognitive delay: corrected 

MDI or PDI scores were >2SD below 

mean (ie correct score <68)

Mental retardation

Growth: Weight, Length, Head 

circumference

Development: Pediatrician & physical 

therapist agreed on presence of 

definitely abnormal position & 

posture from impaired neuromotor 

function

Hospital readmission in 1st year
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part II

336

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Gosch

1997

97379896

Ophthalmology 

1) Other: Blind ELBW

2) Other: blind Term (term 

control)

Other Predictors 

1) Nutrition/Growth-lead 

circumference(cm)

2) Other: days spent in 

hospital after delivery

Self-explanatory CNS:

Other: BDTB (Bielefeld 

developmental test for blind infants 

and pre-schoolers at age 18-48 

months)

Growth:

Weight

Height

Head circumference

Body mass index

The scales of BDTB including numbers 

of items and maximum scores listed on 

table 1

Ladd

1998

98357452

Gastrointestinal: 

 1) Short gut

 2) Necrotizing “enterocolitis” 

 3) Presence of ileocecal valve

 4) Length of bowel reserve

ND Growth predictors: growth ND

Wang

1998

98244087

BW VLBW = 1250 g Growth

Weight

Height

At the specified age and reference

Connors

1999

99250892

Birth weight (i.e. 

ELBW=BW <1 kg)

Postnatal Nutrition Growth: 

<3%tile, 3-9%tile, ≥10%tile)

High perinatal risk: PVH>Grade 2 + 

ventriculomegaly, NEC, Home O2.

Low perinatal risk: none of the above 

risk factors

CNS: CP

Other adverse neurodevelopmental 

outcome

Neurological Exam

Neurodevelopmental outcome assessed 

by Griffith’s Developmental Scales, 

Motor outcome assessed by 

Neurosensory Motor Developmental 

Assessment [NMDA].

French

1999

99115141

(CNS + Growth+

All)

Other: Number of courses of 

antenatal steroids

ND CNS:

Neurodevelopmental

CP

Growth: 

Weight ratio

Height ratio 

Head circumference ratio

Disability

ND

Weight, height, or HC compared to 

national standard

“Any disability” = cerebral palsy, IQ< 85, 

deafness, or visual acuity worse 

than 6/60
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part II

337

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Ford

2000

20380862

*overlapped 

sample with 

Doyle, 2001

21064379 in 

Lung table

Birth weight VLBW < 1500g (<1kg and 1-1.5 kg) 

vs Normal BW (>2.4 kg)

Growth outcome:

Height

Weight

Head circumference

Pubertal development

Growth scores and variables

Morley

2000

20167446

Trial 1:

Type of diet in early neonatal 

period: 

• Banked donor breast milk 

vs Preterm formula (with or 

without supplementation 

with its mother’s milk)

Trial 2:

• Preterm formula vs term 

formula (with or without 

supplementation with 

mother’s milk)

Not further specified Trial 1:

Growth:

Assessment at 9 and 18 months 

post-term:

• Weight (kg)

• Length (cm)

• HC

• Subscapular skinfold thickness

• Body mass index

Assessment at 7.5 –8 yrs:

• All of the above 

• Also weight to hip ratio

Trial 2: 

• Growth at 18 mo

• Growth at 7.5-8 yrs

Not further specified 

Avila-Diaz

2001

21334039

General predictors:

1) birth weight

2) preterm vs. full-term

ND Other outcomes:

1) bone mineral contents (BMC)

2) bone area

3) changes in bone mineral content 

over time

BMC was measured monthly for fullterm infants during the first 5 months 

of extrauterine life and bimonthly for 

pre-term infants during the first 6 

months of extrauterine life
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part III

338

Author, Year Associations found Potential Biases Comments

Forslund

1992

93044002

Growth and motor performance assessed in preterm children at 8 years of life.

• Differences for mean values for weight, height and head circumference not 

significant

• Relationship exists between findings in TMI (test of motor impairment at 4 and 8 

years) suggests possibility of identifying motor problems before school age.

A specific population in a certain are 

that has been studied before

Lack of data regarding the 

population, stated birth weight 

significant but not listed 

anywhere

Study was privately 

 funded

Cannot generalize, 

general lack of data

The population studied 

and the study design 

have been described 

in detail in previous 

paper
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part III

339

Author, Year Associations found Potential Biases Comments

Chye

1995

95314864

Rehospitalization rate (overall)

BPD (78) 58%

Control (75) 35% RR 1.7 (1.2-2.4)

Rehospitalization for respiratory illness

BPD (78) 39%

Control (75) 20% RR 1.9 (1.1- 3.2)

Rehospitalization for poor growth

BPD (78) 14%

Control (75) 1% RR=1.4 (1.7-82)

Rehospitalization for failure to thrive

BPD on home O2 (20) 30%

Control no home O2 (58) 9% RR=3.3 (1.2-8.9)

Growth (wt in kg) : NS diff between BPD and control 

BPD M 9.08 F 8.4

Control M 9.37 F 8.82 

Growth (Ht in cm): NS diff

BPD M 73.0 F 72.1

Control M 74.4 F 72.6 

Growth (HC in cm): NS diff

BPD M 46.7 F 46.0

Control M 47.0 F 454. 

There was a significant increase in any rehospitalization in 1st year of life in preterm 

infants with BPD vs. preterm infants with no BPD.

There was a significant increase (2-fold) in rehospitalization for respiratory illness in 

the 1st year of life in preterm infants with BPD vs. preterm infants with no BPD. 

BPD infants with Home O2 (N=20) had ~3 fold increased re-hospitalization for failure to 

thrive. 

Growth failure was common in both preterm groups (i.e. in infants with no BPD and with 

BPD <10% in weight at 1 yr age). Re-hospitalization was high in both preterm groups 

(with and without BPD).

(None) Study was privately 

funded
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part III

340

Author, Year Associations found Potential Biases Comments

DeReignier

1997

98041177

Sensorineural Hearing Loss:

 CLD: No:0

 Mild:0

 Severe: 3 P<0.05

Low MDI (Bayley Scale):

 CLD: No: 0

 Mild:4

 Severe:5 P<0.05

Low PDI (Bayley Scale):

 CLD: No: 1

 Mild:4

 Severe:7 P<0.05

Cerebral Palsy

 No CLD vs Any CLD:

 Odds ratios: 6.4

 95% CI: (1.05-139.8)

Weight 2-Score:

 CLD: No: 2 score

 Severe: signify lower weight

HC+ Length 2-Score:

 No, Mild, Severe: No significant difference

(None) No data on funding source

Gosch

1997

97379896

Blind ELBW infants have developmental delay of 1.5 to 2 years that of term blind 

controls.

At 48 mos, ELBW blind vs Term blind BDTB scores: Overall score: 169.4±62.4 vs 

270.6±50.7, p <0.05

Neuromotor skills: not significant

Social maturity: 42± 13.4, 67.4± 10.1, p < 0.05

Cognition: 16.8 ±22.5, 47.5 ±19.7, p< 0.05

Linguistic abilities: 11.2± 11.7, 29.2 ±12.5, p< 0.05

Socioemotional behavior:33±9.6, 44.8±6.3, NS

Orientation and mobility: 35.6 ±10.7, 50.8± 5.9, p< 0.05

ELBW blind infants had significantly lower weight, height, head circumference and 

body-mass index than term blind infants.

Extremely small number of subjects 

only 5, so statistics not reliable

Validity of BDTB scale still in question

Does not state whether the evaluators 

were blinded to the groups or 

whether they were the same 

throughout the length of study.

No data on funding source
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part III

341

Author, Year Associations found Potential Biases Comments

Ladd

1998

98357452

Death rate of children with NEC was 49%

148 subjects with follow-up more than 2 years was evaluated for the impact of the ICV 

on severe growth retardation (<10 %tile) found that no association between length of 

bowel resected or status of the ICV, and sever growth retardation.

Extraordinary poor study

Populations at follow-up times not 

described or compared

Time of follow-up given only for 1 

outcome 

Massive Bias

Results not interpretable

No data on funding source

Wang

1998

98244087

More VLBW infants were classified as “subnormal growth” based on chronologic age vs. 

adjusted age through 36 months. The % of VLBW children with subnormal growth is 

therefore affected by adjustment for corrected age through 36 months and varies 

according to growth references (especially at younger ages 4-8 months). Regardless 

of adjusted or chronologic age or growth reference, the mean weight and mean 

height were significantly lower in VLBW (<1250 gm) than term infants at 4 through 36 

months age. As infants approach 18 and 36 months age, the deviation from full term 

infants is less.

Large number of infants were not 

included in the analyses. They were 

slightly differed from the study 

sample in that they had higher BW 

and GA and less BPD and CP in 

follow-up

Study was privately 

funded

Connors

1999

99250892

Weight percentile was strongly associated with lower general growth quotient and lower 

motor abilities in ELBW infants.

Low weight percentile at 2 year was related to adverse developmental outcome in ELBW 

infants at high perinatal risk or with neurological impairment. 

There was minimal association between postnatal low weight percentile and adverse 

neurodevelopmental outcome in ELBW infants who were at low perinatal risk and who 

had normal neurological exam. 

This study confirms strong association between low postnatal weight and adverse 

neurodevelopmental outcome. This association is stronger in infants with high 

perinatal risk factors and in infants with CNS impairment

(None) No data on funding source

French

1999

99115141

(CNS + Growth+

All)

No significant association between antenatal corticosteroids and cerebral palsy, weight 

ratio at 3 years (median, IQR), height ratio median (IQR), head circumference ratio 

(median, IQR), and any disability (number, %)

Differential loss to follow-up not 

assessed

Small number in severe group 

No data on funding source
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part III

342

Author, Year Associations found Potential Biases Comments

Ford

2000

20380862

*overlapped 

sample with 

Doyle, 2001

21064379 in 

Lung table

Pubertal development was similar in VLBW and Normal BW infants. At all ages (2,5,8,14 

yrs) the children who were VLBW were significantly smaller Wt/ Ht/ HC than normal 

BW children.

Differences in Ht/ Wt/ improved over time, between VLBW and NBW, but VLBW 

remained smaller than Normal BW.

(None) No data on funding source

Trial 1

There was no association between the 

neonatal diet (banked donor milk vs preterm 

formula ) and the 6 anthropometrics at any 

follow up point ( 9 mo, 18 mo and 7.5-8 yrs)

(Growth at 9 mo)

(Growth at 18 months)

(Growth at 7.5-8 yrs)

Group A: Fed 

Banked donor milk 

(with or without 

supplementation 

with mother’s milk)

N=195

N=221

N=206

Group B: Fed 

preterm 

formula:(with or 

without 

supplementation 

with mothers’ milk)

N=174

N=217

N=214

Morley

2000

20167446

Trial 2

There was no association between neonatal 

diet (term vs preterm formula) and the 

Weight, Height, HC and skinfold thicknesses 

at any follow up point (18 mo and 7.5 yrs)

Except for a significantly lower waist to hip 

ratio at 7.5 yrs in infants fed preterm vs term 

formula solely (without supplementation with 

mother’s milk) (0.86 vs 0.89, p<0.001)

(Growth at 18 mo)

(Growth at 7.5-8 yrs)

N= 168

N=181

N=166

N=178
Evidence Table 10. Studies Evaluating Association of LBW and Bone and Growth Outcomes

Part III

343

Author, Year Associations found Potential Biases Comments

Avila-Diaz

2001

21334039

Study of bone mineral density using DEXA scan. Outcomes at 5 to 6 months; well 

preterms vs. fullterm.

Full term infants (n = 16) had significantly higher ( P < 0.05) bone mineral content and 

bone area in comparison to preterm infants (n = 26). Preterm infants had a 

significantly higher rate of increase in bone mineral content per day than full term 

infants suggesting incomplete “catch-up”.

Only "healthy" premature infants 

enrolled

Short duration of follow-up - six 

months

Not clear that all preterms were 

VLBW

Study was government 

funded

A study of bone 

mineralization in 

preterm vs. full-terms. 

Not clear if all preterms 

were less than 1500 g.
Evidence Table 11. Randomized Controlled Trials in LBW Neonates for Growth Outcomes 

Part I

344

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Wauben

1998

98387708

Location: Canada

Years of Birth: ND

Mean GA (range), wk: 

Sample 1: 29.9+1.9

Sample 2: 30.1+1.5

Sample 3: 29.7+1.7

Mean BW (range), g:

Sample 1: 1400±200

Sample 2: 1300±200

Controls: 1200±200

Male: ND

Race: ND

Enrolled: 37

Evaluated: 37

Number of sites: 1

BWT<1800

AGA

>1 week old

Full feed 5x5d

Established weight gain

No GI disease 

No long malformation

ND Sample 1: Milk + 

Fortifier (12)

Sample 2: Milk + 

Calcium 

phosphorus (13)

Sample 3: Preterm 

formula-fed (12)

Randomized controlled 

trial (3 and 6 months)
Evidence Table 11. Randomized Controlled Trials in LBW Neonates for Growth Outcomes 

Part I

345

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Morley

2000

20167446

Location: UK

Years of Birth: ND

Mean GA (range), wk: 

Trial 1: 

Group A: 31.1

Group B: 31

Trial 2:

Group A: 31

Group B: 31.2

Mean BW (range), g:

Trial 1: 

Group A: 1397±297

Group B: 1387±278

Trial 2:

Group A: 1399±301

Group B: 1416±306

Male: 

Trial 1: 

Group A: 53%

Group B: 52%

Trial 2:

Group A: 47%

Group B: 46%

Race: ND

Enrolled: 833

Evaluated: 781

Number of sites: 5

Premature

BW< 1850 g

Survivors of participants in the two 

RCTs with 2 parallel arms each ( 

assessing effect of different 

neonatal diets of growth)

Age 7.5-8 yrs

Lost to follow-up Trial 1: 

Group A: Premature 

infants, breast-fed 

until weight 2000 

g or discharge 

(207)

Group B: Premature 

infants, preterm 

formula-fed (213)

Trial 2:

Group A: Premature 

infants, standard 

term formula-fed 

until weight 2000 

g or discharge 

(181)

Group B: Premature 

infants, premature 

formula-fed (213)

RCT: Trial 1 and 2, with 

2 parallel arms in each 

trial (at 9 months, 18 

months, 7.5-8 years)
Evidence Table 11. Randomized Controlled Trials in LBW Neonates for Growth Outcomes

Part II

346

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Wauben

1998

98387708

Other: 

 Feedings: Breast, Milk+ multinutrient fortifier or breast milk + 

Ca + P supplement only, or 

preterm formula

ND Growth: 

1) Weight, length, head 

circumference

2) Body mass + body composition

ND

Morley

2000

20167446

Trial 1:

Type of diet in early neonatal 

period: 

Banked donor breast milk vs 

Preterm formula (with or 

without supplementation with 

its mother’s milk)

Trial 2:

Preterm formula vs term formula 

(with or without 

supplementation with 

mother’s milk)

Not further specified Trial 1:

Growth: Assessment at 9 and 18 

months post-term: Weight (kg), 

Length (cm), HC, Subscapular 

skinfold thickness, Body mass 

index

Assessment at 7.5 –8 yrs: All of the 

above, Also weight to hip ratio

Trial 2: 

Growth at 18 mo

Growth at 7.5-8 yrs

Not further specified 
Evidence Table 11. Randomized Controlled Trials in LBW Neonates for Growth Outcomes

Part III

347

Author, Year Associations found Potential Biases Comments

Wauben, 1998 MM+MNF MM+CaCP PTF

Term: 

 Weight (kg): 3.3+0.3 3.2+0.4 3.5+0.4

 Length (cm): 49.6+1.3 48.4+1.8 49.4+2.3

12 months:

 Weight (kg): 9.0+0.9 9.0+0.9 9.6+1.4

Length (cm): 74.9+3.7 75.9+2.5 76.0+2.8

Head circumference (cm) 46.9+3.9 46.8+? 6.8+2.0 

Whole body BMC (g) 209.9+27.1 223.0+29.2 243.9+40.6

Lean mass (%): 74.0+5.0 73+4.7 73.8+5.6

Fat mass (%): 23.6+5.0 24.3+4.7 23.9+5.6

Used a “New multinutrient fortifier” design to 

their specifications. Generalizability?

No relation examined between feeding + 

neurodevelopment. Unclear that their findings 

have or had any potential for clinical 

significance.

Small study- unlikely to find anything other than 

major differences

Post-discharge crossover between breast 

fed‡formula fed, further dilutes effect or 

small #’s

No correction for multiple comparison, although 

it is desperately needed 

Study was privately 

funded

Morley, 2000 Trial 1: There was no association between the neonatal diet (banked donor 

milk vs preterm formula ) and the 6 anthropome trics at any follow up point 

(9 mo, 18 mo and 7.5-8 yrs)

Trial 2: There was no association between neonatal diet (term vs preterm 

formula) and the Weight, Height, HC and skinfold thickness at any follow up 

point (18 mo and 7.5 yrs). Except for a signifi cantly lower waist to hip ratio at 

7.5 yrs in infants fed preterm vs term formula solely (without 

supplementation with mother’s milk) (0.86 vs 0.89, p<0.001)

(None) ? Funding
Evidence Table 12. Studies evaluating association of LBW and Nutritional Outcomes

348

Part I

Author, Year

UI#

Demographics Inclusion Criteria Exclusion Criteria Disease/Condition 

Type (N)

Study Design

(Duration)

Kennedy

1999

20076945

Also in growth 

paper

Location: US

Years of Birth: Jan-Dec 1994

Mean GA (range), wk: 31±2.6 (26-

34)

Mean BW (range), g: 1534±371 

(810-2000)

Male: ND

Race: White 93%

Enrolled: 28

Evaluated: 28

Number of sites: 1

Single or twin birth BW less 2000g, 

follow-up at hospital clinic, 

completion of 3 screening visits. 

ND Preterm LBW infants (28) Retrospective cohort 

(4, 9, 18 months)

Part II

Author, Year Predictors Predictor Measures Outcomes Outcome Measures

Kennedy

1999

20076945

General : BW

Other:

 1) Nutrition/Growth

 2) Discharge weight

ND Growth:

1) weight and length 

2) Head circumference

1)Denver II Developmental Test

2) “2”-Scroes

Part III

Author, Year Associations found Potential Biases Comments

Kennedy

1999

20076945

NICU discharge weight: mean “z” score was-2.97+/- 0.53 below mean BW of 

term infants

18 months: mean growth in wt, hc&l :WNL

Denver II: normal at 18 months

Only 2 infants weighed less than 1kg

Lowest GA 26 weeks

26/28 were white

No data on funding source

 
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part I

349

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Saarela

1999

99345620

Location: Finland

Years of Birth: 1990-1994

Mean GA:

Sample 1: 21.2±2.1

Sample 2: 29.3±2.4

Mean BW:

Sample 1: 993±242

Sample 2: 1174±238

Male:

Sample 1: 62%

Sample 2: 54%

Race: ND

Enrolled: 174

Evaluated: 129 

Number of sites: 1

BW<1500

GA<34

Death 

Multiple congenital 

anomalies

Severe toxoplasmosis

Lack of repeat renal n/s

Sample 1: Preterm

infants with 

nephrocalcinosis 26)

Sample 2: Preterm

infants without

Nephrocalcinosis

(103)

Prospective cohort 

(6 years)

Saarela

1999

20069000

Location: Finland

Years of Birth: 1990-1994

Mean GA:

 Sample 1: 26.7 ±2

 Sample 2: 27.2 ±2

Mean BW:

 Sample 1: 905 ±209

 Sample 2: 957 ±226

Male:

 Sample 1: 30%

 Sample 2: 50%

Race: ND

Enrolled : ND for total (enrolled 

cases: 29)

Evaluated : 40

Number of sites: 1

Cases with nephrocalcinosis:

VLBW treated in the

NICU of Oulu University Hospital

Born during 1990-1994

Control cases:

Matched to the cases

VLBW: nearest to the index cases 

in the hospital records

Difference from case’s BW less 

than 250 g

Negative renal U/S during 

neonatal period for 

nephrocalcinosis

Age difference during f/up renal 

examination less than 8 months 

from the index cases.

Urinary incontinence Sample 1:

Cases with Neonatal

Nephrocalcinosis(20)

Sample 2:

Controls, matched 

control cases without 

neonatal 

nephrocalcinosis (20)

Prospective

comparative

longitudinal study

[Follow up 

during early

childhood (not

specified but the

mean age during

f/up assessment

was 4.6 yrs)
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part I

350

Author, Year

UI# Demographics Inclusion Criteria Exclusion Criteria

Disease/Condition 

Type (N)

Study Design

(Duration)

Slonim

2000

20214515

Location: USA

Years of Birth: 1992-1994

Mean GA:

 Sample 1: 1704.3 ±52.7

 Sample 2: ND

Mean BW:

 Sample 1: 30.9 ±0.2

 Sample 2: ND

Male:

 Sample 1: 57%

 Sample 2: 58%

Race: ND

Enrolled: 5927

Evaluated: 5750 

Number of sites: 16

Patients with prematurity (<37 

wks) and either an anatomic defect 

(congenital heart disease, GI tract 

anatomic lesion, neurologic 

complications (e.g., spina bifida, 

pulmonary lesions e.g., pulmonary 

agenesis)) or a prematurity related 

complication (BPD, 

Hydrocephalus, IVH, Short gut 

syndrome, trecheostomy, birth 

asphyxia, cerebral palsy) 

Admitted in any of the 16 

participating in the study PICUs

During period 12/1992-12/1994

Patients admitted in PICU 

in continuous 

cardiopulmonary 

resuscitation.

Patients not reaching 

stable vital signs for > 2 

hrs

Sample 1

Formerly premature 

patients admitted in 

PICU (FPP) (431)

Sample 2

Their complement 

formerly nonpremature 

admitted in PICU (5.319 )

Cross sectional study

(FPP were

assessed at a

mean age of 35

mo and formerly

nonprematures

were assessed at

a mean age of 72

mo in the 2 groups

respectively)
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part II

351

Author, Year Predictors Predictor Measure Outcomes Outcome Measures

Saarela

1999

99345620

General :

1) BW

2) GA

Audiology: 

1) Furosemide

Cardiovascular or Pulmonary: 

1) Chronic Lung disease

Other:

1) Dexamethasone

2) Furosemide use

ND Other:

Nephrocalcinosis

Described natural resolution of 

nephrocalcinosis
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part II

352

Author, Year Predictors Predictor Measure Outcomes Outcome Measures

Saarela

1999

20069000

General:

1) Neonatal nephrocalcinosis 

in VLBW infants

Nephrocalcinosis defined by the 

presence of medullay echogenic 

densities in the renal tubular 

pyramids

General:

Renal function during early childhood 

(4-5 yrs)

1) Renal tubular function

2) Distal tubular acidification 

capacity

3) Renal glomerular function

ÿ Serum electrolytes

ÿ Venous blood pH, pCO2, Base 

excess, bicarbonates

ÿ Urine pH,

ÿ Urine??2-microglobulin

ÿ Ca/Cr

ÿ Ca/Na

ÿ Acetazolamide acidification test

ÿ Other variables:

ÿ Ccr (ml/min/1.73 m2)

ÿ FENa (%)

ÿ FEK (%)

ÿ Tubular reabsorption of 

Phosphate (TRP) (%)

ÿ Maximum tubular reabsorption 

of phosphate per glomerular 

filtration rate (TmP/GFR: mmol/l)

4) Kidney growth

5) Systolic blood pressure

Tubular reabsorption of phospate and 

maximal tubular reabsorption of 

phosphate per glomerular filtration rate 

were calculated from the baseline urine 

and blood sample data. Creatinine 

clearance were calculated by the 

method described by Schwartz
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part II

353

Author, Year Predictors Predictor Measure Outcomes Outcome Measures

Slonim

2000

20214515

General:

1) Prematurity with anatomic 

abnormalities and/or 

complications of 

prematurity (prematures vs 

nonprematures)

2) GA (<26 wks vs 26-32 wks 

vs >32 wks)

Anatomic abnormalities:

Congenital heart disease

Anatomical lesions of the GI tract

Neurologic abnormalities: such as 

spina bifida

Pulmonary lesions: such as 

pulmonary agenesis

Complications of prematurity:

BPD

Birth asphyxia

Cerebral palsy

General:

1) Characteristics of utilization of 

chronic care resources, PICU 

resources and characteristics of 

their PICU admissions:

2) Age of PICU admission

3) PICU readmissions during same 

hospitalization

4) Chronic care resources 

utilization

5) At least one chronic care 

resource used

6) Prior living conditions

7) Discharge location

8) PICU resource use

9) Length of stay in PICU (mean 

days)

10) PRISM-III score (mean)

Chronic care resources utilization:

Ventilator

Tracheostomy

Gastrostomy

Parental nutrition

Prior living conditions:

Home

Institutions

Never discharged

Chronic hospital

Discharge location

Home

Routine care

Intermediate care

Another PICU

Chronic care

PICU resource use:

Ventilator

Vasopressors

Arterial catheter

Central venous catheter

PRISM-II scores: at first 24 hrs of PICU 

admission
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part III

354

Author, Year Associations found Potential Biases Comments

Saarela

1999

99345620

Occurrence of nephrocalcinosis (NC) by birth weight.

BW group n % without NC % with peripheral NC % with extensive NC

< 750g 8 50% 25% 25%

751-999 36 65% 20% 15%

1000-1249 33 85% 5% 10%

1250-1499 52 90% 7% 3%

Association of BW with NC sigificant at P< 0.001.

NC was also significantly associated (p<0.001) with: Gestational age, 

Presence of RDS, Presence of BPD (O2 at 28 days), Presence of CLD (O2 

at 36 weeks), Furosemide use, Dexamethasone use

(None) Study was privately 

funded
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part III

355

Author, Year Associations found Potential Biases Comments

Saarela

1999

20069000

Predictors of renal outcome at age 4-5 yr

1) Neonatal nephrocalcinosis in VLBW children seems to lead to some signs 

of renal tubular dysfunction in early childhood. 

2) However, distal tubular acidification, as measured by the actazolamide 

test 

3) and glomerular function appears not to be specifically disturbed by 

nephrocalcinosis 

Renal function during early childhood (mean age: 4.6 yrs)

Renal tubular function: ÿ Urinary calcium /Cr and (p<0.004) ÿ ?2-microglobulin/Cr excretion were higher in the children with 

nephrocalcinosis (p<0.05)

ÿ There was no difference in the fractional excretion of Na, K, or tubular 

reabsorption of phospate

Distal Tubular Acidification capacity: • There was no difference in the distal tubular acidification capacity, as 

tested by the acetazolamide test 

: Abnormal response:

Renal glomerular function: ÿ Creatinine clearance was no different between the 2 groups

There was no difference between the 2 groups in the following : ÿ Serum electrolytes ÿ Venous blood pH, pCO2, Base excess, bicarbonates ÿ Urine pH,

Kidney growth: ÿ Kidney growth was impaired by more than 2 SD ÿ There was no difference in the systolic blood pressure above 97.5 

percentile

ÿ None of the children had hematuria
Evidence Table 13. Studies Evaluating Association of LBW and Other Outcomes

Part III

356

Author, Year Associations found Potential Biases Comments

Slonim

2000

20214515

Utilization of chronic care resources and PICU resources and characteristics of 

their PICU admissions of former prematures with a prematurity -related 

complication or an anatomical deformity [431] when compared to 

nonprema tures [5319] was:

• PICU survivors: 90% vs 94% (p=0.008)

• Age of PICU admission (mean): 35 mo vs 72 mo (p=0.01)

• Postoperative care (%): 44% vs 40% (p=0.15)

• Prior PICU admissions: 11% vs 5.5% (p=0.01)

Chronic care resources utilization:

• Ventilator: 7% vs 1% (p=0.001) Tracheostomy: 16% vs 2% (p=0.001)

• Gastrostomy: 23% vs 4% (p=0.001)

• Parental nutrition: 3% vs 0.6% (p=0.001)

At least one chronic care resource used: 30% vs 5.6% , p=0.001

Prior living conditions:

• Home: 90% vs 97% (p=0.001) Institutions: 3% vs 1% (p=0.001)

• Never discharged: 6.5% vs 2% (p=0.002)

• Chronic hospital: 3% vs 1% (p=0.001)

Discharge location

• Home: 11% vs 6% (p=0.001) Routine care: 63% vs 77% (p=0.001)

• Intermediate care: 15% vs 10% (p=0.03)

• Another PICU: 1% vs 1.6% (p=0.52)

• Chronic care: 1.6% vs 0.7% (p=0.02)

PICU resource use:

• Ventilator: 45% vs 35% (p=0.007)

• Vasopressors: 15% vs 16% (p=0.12)

• Arterial catheter: 28% vs 36% (p=0.006)

• Central venous catheter: 17% vs 21% (p=0.03)

Limits to care (%): 5.5% vs 4% (p=0.11)

Length of stay in PICU (mean days): 5.98 ds vs 3.56 ds (p=0.01)

PRISM-III score AT 24 HRS (mean): 4.90 vs 4.53 (p=0.80)

Those born < 26 wks had a higher utilization of chronic care resources 

(ventilator, trachesostomy, gastrostomy ) and chronic hospital care (p< 0.006) 

as compared to the other prematures.

There is a strong selection bias in this study 

as the inclusion criteria used for the 

selection of the FPPs were strongly 

correlated with the outcomes studied (the 

presence of an anatomic abnormality 

(150/431) or a complication of prematurity 

(281/483) in FPPs is strongly Correlated 

with the utilization of chronic care 

resources)

Funding: Not Reported
161

Appendix A: MEDLINE, ERIC, PsycInfo and 

 Healthstar Search Strategies

MEDLINE – CNS search

1. exp Infant, Low Birth Weight/

2. low birth weight.tw.

3. exp Infant, Premature/

4. 1 or 2 or 3

5. exp infant, low birth weight/ or exp infant, premature/

6. (small for gestational age or SGA).tw.

7. (preterm infant$ or infant or prematur$ or newborn).tw.

8. disab$.af.

9. limitation$.af.

10. handicap$.af.

11. impair$.af.

12. follow-up studies/

13. follow-up.tw.

14. exp Case-Control Studies/

15. case-control.tw.

16. exp Longitudinal Studies/

17. longitudinal.tw.

18. exp Cohort Studies/

19. cohort.tw.

20. (random$ or rct).tw.

21. exp Randomized Controlled Trials/

22. exp random allocation/

23. exp Double-Blind Method/

24. exp Single-Blind Method/

25. randomized controlled trial.pt.

26. clinical trial.pt.

27. (clin$ adj trial$).tw.

28. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.

29. exp PLACEBOS/

30. placebo$.tw.

31. exp Research Design/

32. Comparative Study/

33. exp Evaluation Studies/

34. exp Prospective Studies/

35. 5 or 6 or 7

36. 35 and (8 or 9 or 10 or 11)

37. limit 36 to (clinical trial or clinical trial, phase ii or clinical trial, phase iii or clinical trial, 

phase iv or controlled clinical trial or guideline or meta analysis or practice guideline or 

randomized controlled trial or review or review literature or review, academic or review, 

multicase or review, tutorial)
162

38. 36 and (12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 

or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34)

39. 37 or 38

40. limit 39 to human

41. limit 40 to english language

42. neuro$.tw.

43. white matter damage.tw.

44. exp intracranial hemorrhages/ or exp leukomalacia, periventricular/

45. exp Retinopathy of Prematurity/

46. ROP.tw.

47. 43 or 44

48. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 

28 or 29 or 30 or 31 or 32 or 33 or 34

49. 2 or 5 or 6 or 7

50. 48 and 49 and 47

51. 42 or 43 or 44

52. 48 and 49 and 51

53. limit 50 to (addresses or bibliography or biography or comment or dictionary or directory or 

editorial or festschrift or guideline or lectures or legal cases or letter or meta analysis or news 

or periodical index or practice guideline or review or review literature or review of reported 

cases or review, academic or review, multicase or review, tutorial)

54. 52 not 53

55. limit 54 to human

56. limit 55 to english language

Eric search

1. follow-up studies/

2. follow-up.tw.

3. exp Case-Control Studies/

4. case-control.tw.

5. exp Longitudinal Studies/

6. longitudinal.tw.

7. exp Cohort Studies/

8. cohort.tw.

9. (random$ or rct).tw.

10. exp Randomized Controlled Trials/

11. exp random allocation/

12. exp Double-Blind Method/

13. exp Single-Blind Method/

14. randomized controlled trial.pt.

15. clinical trial.pt.

16. (clin$ adj trial$).tw.

17. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.

18. exp PLACEBOS/

19. placebo$.tw.

20. exp Research Design/
163

21. Comparative Study/

22. exp Evaluation Studies/

23. disab$.af.

24. exp disabilities/

25. limitation$.af.

26. handicap$.af.

27. impair$.af.

28. exp PHYSICAL DISABILITIES/ or exp SEVERE DISABILITIES/ or exp 

DEVELOPMENTAL DISABILITIES/ or exp LEARNING DISABILITIES/ or exp MILD 

DISABILITIES/ or exp MULTIPLE DISABILITIES/

29. (small for gestational age or SGA).tw.

30. exp birth weight/

31. exp premature infants/

32. (preterm infant$ or infant or prematur$ or newborn).tw.

33. 23 or 24 or 25 or 26 or 27 or 28

34. 33 and (29 or 30 or 31 or 32)

35. 34 and (1 or 2 or 4 or 6 or 8 or 9 or 16 or 17 or 19 or 20 or 21)

GI search

174. exp enterocolitis/

175. exp cholestasis/

176. exp short bowel syndrome/

177. enterocolitis$.tw.

178. NEC.tw.

179. necrot$.tw.

180. (Total parenteral nutrition or TPN).tw.

181. cirrhosis.tw.

182. (gastrostomies or GERD or Fundoplication).tw.

183. short bowel syndrome.tw.

184. cholestasis.tw.

185. short gut.tw.

186. necrotizing.tw.

187. exp cirrhosis/

Health Care

174. rehospitalization.af.

175. costs.af.

176. costs.tw.

177. physical therapy.af.

178. exp *Occupational Therapy/

179. exp *Physical Therapy/

180. orthopedic.tw.

181. occupational therapy.af.

189. Health care resource.mp. or utilization.af. [mp=title, abstract, registry number word, mesh 

subject heading]

190. arthopedic.af.
164

191. orthopedic.af.

Healthstar

1. exp infant, low birth weight/ or exp infant, premature/

2. (small for gestational age or SGA).tw.

3. (preterm infant$ or infant or prematur$ or newborn).tw.

4. disab$.af.

5. limitation$.af.

6. handicap$.af.

7. impair$.af.

8. follow-up studies/

9. follow-up.tw.

10. exp Case-Control Studies/

11. case-control.tw.

12. exp Longitudinal Studies/

13. longitudinal.tw.

14. exp Cohort Studies/

15. cohort.tw.

16. (random$ or rct).tw.

17. exp Randomized Controlled Trials/

18. exp random allocation/

19. exp Double-Blind Method/

20. exp Single-Blind Method/

21. randomized controlled trial.pt.

22. clinical trial.pt.

23. (clin$ adj trial$).tw.

24. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.

25. exp PLACEBOS/

26. placebo$.tw.

27. exp Research Design/

28. Comparative Study/

29. exp Evaluation Studies/

30. exp Prospective Studies/

31. 1 or 2 or 3

32. 31 and (4 or 5 or 6 or 7)

33. limit 32 to (clinical trial or clinical trial, phase ii or clinical trial, phase iii or clinical trial, 

phase iv or controlled clinical trial or guideline or meta analysis or practice guideline or 

randomized controlled trial or review or review literature or review, academic or review, 

multicase or review, tutorial)

34. 32 and (8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 

23 or 24 or 25 or 26 or 27 or 28 or 29 or 30)

35. 33 or 34

36. limit 35 to human

37. limit 36 to english language

38. limit 37 to nonmedline
165

Immune

174. exp *Immunologic Diseases/ or exp *Autoimmune Diseases/ or exp *Collagen Diseases/ or 

exp *Immunologic Deficiency Syndromes/

Perinatal

174. antenatal steroid.tw.

175. Chorioamnioni$.tw.

176. chorionic villous sampling.tw.

177. diabet$.tw.

178. pre-eclamp$.tw.

179. 174 or 175 or 176 or 177 or 178

PsycInfo

1. follow-up studies/

2. follow-up.tw.

3. exp Case-Control Studies/

4. case-control.tw.

5. exp Longitudinal Studies/

6. longitudinal.tw.

7. exp Cohort Studies/

8. cohort.tw.

9. (random$ or rct).tw.

10. exp Randomized Controlled Trials/

11. exp random allocation/

12. exp Double-Blind Method/

13. exp Single-Blind Method/

14. randomized controlled trial.pt.

15. clinical trial.pt.

16. (clin$ adj trial$).tw.

17. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.

18. exp PLACEBOS/

19. placebo$.tw.

20. exp Research Design/

21. Comparative Study/

22. exp Evaluation Studies/

23. exp Prospective Studies/

24. exp Premature Birth/

25. exp birth weight/

26. (small for gestational age or SGA).tw.

27. (preterm infant$ or infant or prematur$ or newborn).tw.

28. exp DISABILITY EVALUATION/

29. exp disabled/

30. disab$.af.

31. limitation$.af.

32. exp Mentally Retarded/

33. exp Behavior Problems/
166

34. exp communication skills/

35. handicap$.af.

36. impair$.af.

37. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 

19 or 20 or 21 or 22 or 23

38. 24 or 25 or 26 or 27

39. 37 and 38

40. 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36

41. 39 and 40

42. 38 and 40

43. limit 42 to ("0840 follow up study" or "0850 longitudinal study" or "0860 treatment outcome 

study" or "0900 errata/retractions" or 1300 literature review/research review or 1400 metaanalysis)

44. 41 or 43

45. limit 44 to human

46. limit 45 to english language

ROP

174. (retinopathy of prematur$ or POP).tw.

175. exp retinopathy of prematur$/ or POP/

176. (visu$ impair$ or blindness).tw.

177. Hypoxic-Ischemic encephalopathy.tw.

Acuity

174. SNAP.tw.

175. CRIB.tw.

176. 174 or 175

Audiology

174. Lasix.tw.

175. exp lasix/

176. hearing disorder$.tw.

177. aminoglycosides.tw.

Infection

174. RSV.tw.

175. exp meningitis/

176. meningitis.tw.

177. exp sepsis/

178. (sepsis or septic).tw.

179. congenit$.tw.

180. acquired.tw.

Lung dz

174. chronic lung disease$.tw.

175. Bronchopulmonary dysplasia$.tw.
167

176. asthma$.tw.

177. exp asthma/

178. pulmonary function$.tw.

179. tracheostomy.tw.

180. upper airway.tw.

181. reactive airway.tw.

182. exercise tolerance.tw.

183. exp upper airway/

184. exp tracheostomy/

191. exp *Lung Diseases/ or exp *Hypertension, Pulmonary/ or exp *Lung Diseases, 

Obstructive/ or exp *Bronchopulmonary Dysplasia/

192. upper airway.af.

193. asthma.af.

194. pulmonary function$.af.

Medication

174. dexamethasone.tw.

175. 50-02-2.rn.

176. dexamethasone.af.

Nutrition

174. exp nutrition/

175. nutrition.tw.

176. growth disorder$.tw.

177. exp growth disorder$/

184. exp Child Nutrition Disorders/

185. exp PARENTERAL NUTRITION, TOTAL/ or exp INFANT NUTRITION DISORDERS/
169

Appendix B: Data Abstraction Form

Low Birth Weight and Prematurity Association with Disability 

Version 11b (10/14/02)

Instructions: Circle or fill-in where appropriate Only one answer except where indicated by an *

Reviewer: __ __________________ Review date: ____/_____/____

First author:________________ Year:________ UI:____________________

STUDY CHARACTERISTICS

*Country: US UK Canada Other ___________ N.D. 

Number of Sites: _______ N.D.

METHODOLOGY

Study Design (CHOOSE ONE):

Randomized Controlled Trial 

 

Non-randomized Comparison Trial 

 

‚ Prospective (Single arm) Cohort 

Retrospective Cohort 

‚ Case Series (Retrospective) 

‚ Case –control (Retrospective)

STUDY POPULATION

Year of birth of population

From_____________ to _____________

Inclusion criteria: ____________________________________

_______ ____________________________________________

_______ ____________________________________________

___________________________________________________

Exclusion criteria: ____________________________________

___________________________________________________

___________________________________________________

*

Applicability of study sample to population of interest:

I. Sample representative of whole population with very

 low birth weight or premature infants

II. Sample is a relevant sub-group of whole population

III. Narrow sample, with limited applicability to study population.

If II or III, Why not I: 

DEMOGRAPHICS OF INITIAL POPULATION (A)

Sample 1 Sample 2

Description of 

group

N

Mean Age at entry

(range)

 Mean GA 

(range)

Mean BW

(range)

Male (%):

Race (%):

Other:

Other:

Comments:
170

DEMOGRAPHICS OF DIFFERENT FOLLOW-UP OR SUBGROUP POPULATION : 

B: Time of Evaluation:

Sample 1 Sample 2

Description of 

group

N 

Mean Age at eval

(range)

Mean GA

(range)

Mean BW

(range)

Male (%):

Race (%):

Other:

Other:

D: Time of Evaluation:

Sample 1 Sample 2

Description of 

group

N 

Mean Age at eval

(range)

Mean GA

(range)

Mean BW

(range)

Male (%):

Race (%):

Other:

Other:
171

C: Time of Evaluation:

Sample 1 Sample 2

Description of 

group

N 

Mean Age at eval

(range)

Mean GA

(range)

Mean BW

(range)

Male (%):

Race (%):

Other:

Other:

E: Time of Evaluation:

Sample 1 Sample 2

Description of 

group

N 

Mean Age at eval

(range)

Mean GA

(range)

Mean BW

(range)

Male (%):

Race (%):

Other:

Other:

PREDICTORS OF DISBILITY EXAMINED I *General Predictors of Disability Examined: 
172

A) Birth weight

B) GA 

C) SGA/IUGR

D) Maternal disease

E) Antenatal steroids 

F) Chronic illness

G) Cord pH

H) Apgar score

I) Illness severity 

J) Intrauterine substance abuse (Opiates, Cocaine, 

Ethanol. Other___________________________) 

K) Other:

II *CNS Predictors of Disability Examined:

A) Intracranial/Intraventricular hemorrhage

B) White Matter Disorder 

C) Periventricular leukomalacia

D) Ventriculomegaly/ Ventricular Dilation

E) Neurological feeding disorder /Swallowing

F) Seizures

G) Hypoxic-Ischemic Encephalopathy (HIE)

H) Indomethacin

I) Other:

III *Ophthalmology Predictors of Disability 

Examined:

A) Retinopathy of Prematurity (ROP)

B) Other:

IV *Audiology Predictors of Disability 

Examined:

A) Aminoglycosides

B) Furosemide

C) Hearing screen failure

D) Other:

V *Cardiovascular or Pulmonary Predictors 

of Disability Examined:

A) Chronic Lung Diseases

B) Bronchopulmonary dysplasia

C) Other:

VI *Gastrointestinal Predictors of Disability 

Examined:

A) Short gut

B) Necrotizing “enterocolitis”

C) Total Patenteral Nutrition

D) Cholestasis

E) Other:

VII *Other Predictors of Disability Examined:

A) Nutrition / Growth

B) Infectious disease

C) Immune Disorders

D) Hospital / Health care resource utilization

E) Illness Acuity

F) Dexamethasone

G) Perinatal Factors

H) Osteomalacia

I) Other:

J) Other:

K) Other:

How predictors defined/measured: 

ND

Are the definitions correct/ appropriate? Y N If No, 

Why not?
173

OUTCOMES EXAMINED

I *CNS Outcomes Examined: 

A) Motor delay

B) Cerebral palsy

C) Cognitive delay

D) Mental retardation

E) Behavioral disorders

F) School problems

G) Learning disabilities

H) Seizure disorder

I) Post Hemorrhagic Hydrocephalus (PHH)

J) Other: 

II *Ophthalmology Outcomes Examined:

A) Visual impairment

B) Blindness

C) Other: 

III *Audiology Outcomes Examined

A) Hearing disorders

B) Deafness

C) Speech

D) Language

E) Communication disorder

F) Other: 

IV *Pulmonary Outcomes Examined

A) ____________________________________

___

B) ____________________________________

___

V *Growth Outcomes Examined

A) ____________________________________

___

B) ____________________________________

___

VI *GI Outcomes Examined

A) ____________________________________

___

B) ____________________________________

___

VII *Other Outcomes Examined

A) ____________________________________

___

B) ____________________________________

___
174

Definition of Outcomes Used by Author (methods 

of measure ): 

N.D.

Are the definitions correct/ appropriate? 

‚ Unable to evaluate ‚ Yes 

‚ No

If no, why ?
175

RESULTS: Group Predictor Category

Predictors/Conditions N

Outcome 

Category

Outcome of Interest/ Instruments 

used

% (or n/N) with 

Outcome

Methods of 

Correlation
176

RESULTS (cont’d): Group Predictor Category

Predictors/Conditions N

Outcome 

Category

Outcome of Interest/ Instruments 

used

% (or n/N) with 

Outcome

Methods of 

Correlation
177

 
178

Bias Limitation:: 

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

__________________________________________________________________________________________

Internal Validity (Quality of Methods)

A Prospective (Not Retrospective). Complete reporting of methods and results (incl. inclusion/exclusion 

criteria, “Table 1 data,”) proper reference (“gold”) standard, correct analyses performed (No data 

inconsistency and discrepancy).

B Prospective or Retrospective. Not all criteria of A. Some deficiencies, however, unlikely to cause major 

bias

C Prospective or Retrospective. Significant design or reporting errors, large amount of missing information 

or bias. No reference standard provided or use of inappropriate reference standard.

If B or C: Deficiency:

______________________________________________________________________________

___
179

General instructions for LBW data extraction:

The form has been designed to collect all the relevant information from each article. The data on the form will 

allow us to fully evaluate each study’s population, basic methods, relevant results (relevant for the SSA project), 

applicability to other children with the condition of interest, and overall quality.

For each line (or section), please circle the appropriate answer to the question (in bold) or fill in the data on the 

lines provided. Questions proceeded by an * can have multiple answers (such as study performed in UK and France). 

Please circle “N.D (no data).” if the answer to the question is not provided (eg, if information on the age of the subjects 

is not provided). 

Study Characteristics: Self-explanatory for Country and number of sites. 

Length of Following up time: Enter corrected age and average duration.

Corrected age mean: age from the obstetric due date to follow-up evaluation date. 

Demographics: Enter all relevant demographic information when provided (eg, 

mean, standard error and range).

If median is provided, cross out mean and write in median.

For weight, please fill in the relevant data as reported in 

the article.

For gender and race, fill in the percentages (or the fraction).

Study population: Enter inclusion and exclusion criteria (may need to check abstract,

results, and discussion sections for completeness).

Enter total number of subjects with low birth weight enrolled 

(including those eventually excluded or who withdrew, etc.). If 

 only the number of subjects evaluated is reported, circle N.D.

Enter final sample size (the total number of subjects with low birth 

 weight evaluated)

Enter total number of control subjects (presumably of normal 

Birth weight) enrolled and evaluated.

If reported, list reasons for withdrawal, etc. (Consider this in the 

assessment of possible bias later on.)

Assess Applicability of study to population of interest:

Consider all the data that has just been entered (study characteristics, demographics, inclusion/exclusion criteria, 

sample size, number and reasons for withdrawal) to determine how applicable the study is to the population of interest 

to us. Note that this may be a different population than the population of interest to the study authors. 

First circle the question that the study is most relevant for.
180

Then choose one of the categories:

Category I. If sample is representative of the whole population of babies with prematurity and low birth weight 

condition relevant to the topic question (eg, whole population of preterm babies and infants with BW 1200-2000g). 

This implies a reasonable sample size, a diverse group of infants with the condition, and inclusion/exclusion criteria that 

will capture the whole group. Consider both who the study aimed to recruit and also who they actually included.

Category II. A relevant sub-group or subgroups of very low birth weight and prematurity, (only those with a 

specific, though common, condition eg: BW 1200-1500g). 

Category III. A very narrow group of subjects who are a limited sample of very low birth weight and prematurity 

(only those with a relatively rare condition, or a non-representative demographic group e.g. crack babies)).

If Category II or III chosen, please indicate reason not in Category I (i.e., why not 

fully generalizable)

Methodology:

Study design: Provide one answer per line:

What is study design? (For RCT, ensure that authors state “randomized”). Prospective or retrospective cohort studies, 

retrospective case-control and case series may have one or more arms (i.e. treatment vs placebo).

Predictors of Disability Examined

Please circle or write in the predictors of disability that were examined in the study. These can include the 

factors or combination of factors predict future disability in the low birth weight and prematurity babies.

Note that the study might not clearly list the predictors evaluated. You may need to check the methods, results 

and discussion section to figure this out.

If provided, give the definitions the authors used for the various predictors. This may be as simple as Birth 

weight 1200 gms, or it may be a detailed description of their definition of HIE. This can be kept succinct.

Are the definitions used appropriate? 

Outcomes Examined

Similar to predictors, circle or write in the outcomes examined.

Not all examined outcomes are necessary. Include only those that are relevant to the Topic question).

Define outcomes and determine appropriateness.

Results

The tables provided should be able to accommodate most (hopefully all) studies. Even if no statistical analysis 

was done by the authors, the table should be completed.

 Each row will represent specific condition/predictor combination.

 In a study with these four groups of subjects, each group would be put on a separate row in the first column of 

the table.
181

For each condition/predictor put the number of subjects evaluated in the second column.

In each row, write in the specific outcome evaluated. Each different outcome of interest should have its own 

row, or group of rows, write the instruments that being used. (How to measure outcome). 

In the fourth column, give the results. What percentage of subjects in each group had the outcome of interest. 

You can also enter the fraction (or number of subjects), if that is easier. If other results are reported (such as odds ratio 

(OR)) write that in. However, please clarify what the outcome being reported is, if it’s not percentage.

If there were results that are of interest, that do not conform to the table, write them in below.

Biases/Limitations:

Write down biases or limitations 

 

Quality of Methods:

Grade quality of study (methods and reporting, not results) in 3 categories, A, B, or C. 

Consider methods, definitions used, statistical analyses done, biases, etc. 

A: Prospective study that is clearly reported, uses explicit and 

 appropriate eligibility criteria, uses appropriate definitions of predictors and 

 outcomes that are properly measured or estimated, uses appropriate statistical and 

 analytical methods, and is free of obvious bias. Retrospective studies, irrespective 

 of other aspects of quality, cannot be in category A. Study size should not be a 

 factor for quality.

B: Prospective or retrospective study that does not meet qualifications of category A 

but deficiencies are unlikely to cause major bias.

C: Major deficiencies that cannot exclude possibility of significant bias. 

 Insufficiently reported information.

If B or C, indicate briefly what the deficiency or deficiencies are in the paper.

Please check data information:

Check abstract numbers, tables, results and discussion for discrepancy (e.g. add them all
179

Appendix C: Acronyms and Abbreviations

AA Arachidonic acid

AGA Appropriate for gestational age

ADIT Auditory discriminating test

BPD Bronchopulmonary dysplasia

BSCP Bilateral spastic cerebra palsy

BWVK Bourdon-Wiersma-Vos concentration test for infants

BW Birth weight

CBCL Child Behavior Check List

CLD Chronic lung disease

CNS Central Nervous System

CP Cerebral Palsy

CRIB Clinical Risk Index for Babies

CRYO ROP Multicenter Trial of Cryotherapy for ROP

dBHL Decibels

DHA Docosahexaenoic acid

DDST Development Screening test

DQ Developmental quotient

DR-CPR Delivery room resuscitation

EHM-T Exclusively human milk-fed until term CA

ELBW Extremely Low Birth Weight

GA Gestational age

GM Isolated germinal matrix hemorrhage

IBR Infant behavior record

ICH Intracranial hemorrhage

IQ Intelligence quotient

IUGR Intrauterine growth retardation

IVH Intraventricular hemorrhage

LBW Low Birth Weight

MDI Mental Development Index

MR Mental Retardation

NBRS Neurobiologic Risk Score

NBW Normal Birth Weight

NCHS National Center for Health Statistics

ND No data 

NEC Necrotizing enterocolitis

NICHD National Institute of Child Health and Development

NICU Neonatal Intensive Care Unit

NS Not significant

PDA Patent ductus arteriosus

PDI Psychomotor Developmental Indexes

PEV Periventricular echodensities

PL Parenchymal lesions

PMA Postmenstrual age
180

PPVT Peabody Picture Vocabulary Test

PROM Premature rupture of membranes

PVL Periventricular leukomalacia

RCP Revised Class Play

RDS Respiratory distress syndrome

ROP Retinopathy of Prematurity

SGA Small for gestational age

SNHL Sensorineural hearing loss

TRF Teacher Report Form

US Ultrasound

VE Ventricular enlargement

VLBW Very Low Birth Weight

VMI Visual-motor integration test

VM Ventriculomegaly

WISC-R Wechsler Intelligence Scale for Children-Revised

WMD White Matter Damage

WPPSI Wechsler Preschool and Primary Scale of 

Intelligence
181

Appendix D. Acknowledgments

The Evidence-based Practice Center staff acknowledges the collaboration of the clinical experts 

who served on the EPC Technical Expert Panel. The EPC also acknowledges the contributions 

by those who acted as peer reviewers for the evidence report.

New England Medical Center EPC Project Staff

Joseph Lau, MD; EPC/Project Director

Ethan Balk, MD, MPH, Assistant Project Director and Project Leader, Short Stature

Cynthia Cole, MD, MPH, Coordinating Team Leader

Deirdre DeVine, M Litt, Project Manager

Priscilla Chew, MPH, Project Leader, Failure to Thrive

Kimberly Miller, BA, Research Assistant

Chenchen Wang, MD, MSc, Project Leader, Low Birth Weight

Technical Expert Panel

Evidence Review Teams, Tufts New England Medical Center

Very Low Birth Weight: 

Dr. Cynthia Cole, Project Coordinator and Team Leader

Drs. Geoffrey Binney, John Fiascone, James Hagadorn, and Chiwan Kim

 Patricia Casey, NNP

Short Stature: Dr. Patricia Wheeler, Team Leader

Drs. Barbara Shephard and Karen Bresnahan

Failure To Thrive: Dr. Ellen Perrin, Team Leader

Drs. Stephan Glicken, Nicholas Guerina, Kevin Petit, Robert Sege, MaryAnn Volpe, and 

Deborah Frank 

 James Perrin, MD, Pediatric Consultant to the EPC 

Social Security Administration (SSA):

Science Partner: Dr. Paul Burgan, MD, PhD; Regina Connell, MS 

Agency for Healthcare Research and Quality (AHRQ)

Marian James, PhD, Task Order Officer 
182

American Academy of Pediatrics 

Marilee Allen, MD (Very Low Birth Weight)

Professor

Neonatology, Department of Pediatrics

Johns Hopkins University 

Baltimore, Maryland

Joseph Hersh, MD (Short Stature)

Louisville, Kentucky

Michael Farrell, MD (Failure to Thrive)

Chief of Staff

Children’s Hospital Medical Center

Cincinnati, Ohio

Carla Herrerias, BS, MPH

Senior Health Policy Analyst

Department of Practice and Research

American Academy of Pediatrics

Elk Grove Village, Illinois

Disability Law Center, Inc.

Linda Landry, Esq.

Peer Reviewers

American Academy of Pediatrics

Very Low Birth Weight

Deborah Campbell, MD

Hartsdale, New York 

Warren N. Rosenfeld, MD

Department of Pediatrics

Winthrop University Hospital

Mineola, New York

Short Stature

Susan Rose, MD

Department of Endocrinology

Children's Hospital Medical Center of Cincinnati

Cincinnati, Ohio
183

Failure to Thrive

William Cochran, MD

Department of Pediatric GI/Nutrition

Geisinger Health System

Danville, Pennsylvania

American Association of Clinical Endocrinologists

A. Jay Cohen, MD

The Endocrine Clinic, PC

Memphis, Tennessee

Lawson Wilkins Pediatric Endocrine Society

David M. Brown, MD

Professor of Pediatrics

University of Minnesota

Minneapolis, Minnesota

National Institute of Child Health and Human Development

Gilman Grave, MD (for Short Stature)

Chief, Endocrinology, Nutrition and Growth Branch

Center for Research for Mothers and Children 

Bethesda, Maryland

Catherine Y. Spong, MD (for VLBW and Failure to Thrive)

Chief, Pregnancy and Perinatology Branch

Center for Research for Mothers and Children

Bethesda, Maryland

Tonse Raju, MD (for VLBW and Failure to Thrive)

Pregnancy and Perinatology Branch

Center for Research for Mothers and Children

Bethesda, Maryland

Society for Developmental and Behavioral Pediatrics

Denis Drotar, MD

Professor and Chief

Division of Behavioral Pediatrics and Psychology

Rainbow Babies and Children’s Hospital

Cleveland, Ohio

Daniel Kessler, MD

Phoenix, Arizona