Overview

The report from which this summary was

developed presents a comprehensive literature

review of the effect of bilirubin on

neurodevelopmental outcomes. It also examines

the role of various effect modifiers such as sepsis

and hemolysis on neurodevelopment, the efficacy

of phototherapy, the accuracy of transcutaneous

measurement of bilirubin, and the various

strategies in predicting hyperbilirubinemia. 

As background, in 1994, the American

Academy of Pediatrics (AAP) published guidelines

on the management of neonatal

hyperbilirubinemia developed by the Provisional

Committee for Quality Improvement and

Subcommittee on Hyperbilirubinemia. Although

there was no definitive evidence showing a specific

level of bilirubin and subsequent serious adverse

neurodevelopmental outcome, the task force,

relying on retrospective epidemiologic data

primarily derived from North American and

European research, offered recommendations for

the management of neonatal hyperbilirubinemia.

These were based on evidence when appropriate

data existed, and based on expert consensus when

data were lacking.

These recommendations were specifically

directed at evaluation and treatment of

hyperbilirubinemia in healthy term newborns; i.e.,

only infants without signs of illness or apparent

hemolytic disease. Highlights in the

recommendations included visual inspection of

the skin to determine jaundice, use of total serum

bilirubin (TSB) level as the relevant variable in

determining treatment, and recommendation for

exchange transfusion only if intensive

phototherapy fails to lower the TSB to less than

20 mg/dl. Criticisms regarding these

recommendations included the fact that:

• Visual inspection of jaundice may not be

reliable.

• Criteria based on age measured by number of

days rather than hours are too coarse for

precise interpretation of bilirubin level.

• Evidence about whether there is any adverse

effect of phototherapy treatment on healthy

term newborns is absent.

Furthermore, some term infants without

evidence of hemolysis may develop

hyperbilirubinemia and kernicterus, and there

have not been any randomized controlled trials to

assess the relation between bilirubin levels and

adverse neurodevelopmental effects. Through

review of evidence for five key questions, the

report aims to supply data for an update of these

recommendations.

Reporting the Evidence

The Evidence-based Practice Center (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

meetings and teleconferences with external

technical experts representing the AAP, the

American Academy of Family Physicians, the

National Association of Pediatric Nurse

Practitioners, the Center for Quality of Care

Research and Education, the Harvard School of

Public Health, and the Parents of Infants and

Children with Kernicterus organization. The EPC

and its panel of external technical experts refined

key questions proposed by the AAP and identified

issues central to this report. A comprehensive

search of the medical literature was conducted to

Evidence Report/Technology Assessment

Number 65

Management of Neonatal Hyperbilirubinemia

Summary

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

Agency for Healthcare Research and Quality
identify the evidence available to address the following

questions: 

Association of Neonatal Hyperbilirubinemia

With Neurodevelopmental Outcomes

1. What is the relationship between peak bilirubin levels and/or

duration of hyperbilirubinemia and neurodevelopmental

outcome?

2. What is the evidence for effect modification of the results in

Question 1, by gestational age, hemolysis, serum albumin,

and other factors?

Treatments for Neonatal Hyperbilirubinemia

3. What are the quantitative estimates of efficacy of treatment at

(1) reducing peak bilirubin levels (e.g., number needed to

treat at 20 mg/dl to keep TSB from rising); (2) reducing the

duration of hyperbilirubinemia (e.g., average number of

hours by which time TSB greater than 20 mg/dl may be

shortened by treatment); and (3) improving

neurodevelopmental outcomes?

Diagnosis of Neonatal Hyperbilirubinemia

4. What is the efficacy of various strategies for predicting

hyperbilrubinemia, including hour-specific bilirubin

percentiles?

5. What is the accuracy of transcutaneous bilirubin (TcB)

measurements?

Methodology

Patient Population and Settings

The target population included infants of at least 34 weeks

gestational age. Based on the findings of an earlier National

Institute of Child Health and Human Development (NICHD)

study, in which none of the 1,339 infants greater than or equal

to 2,500 grams was less than 34 weeks, the EPC grouped

infants weighing greater than or equal to 2,500 grams with

those greater than or equal to 34 weeks gestation.

Literature Search and Review Parameters

Search Strategies. MEDLINE® and PreMEDLINE®

databases were searched for the evidence report. In September

2001, the MEDLINE® database was searched for publications

from 1966 to the present using relevant MeSH terms

(“hyperbilirubinemia,” “hyperbilirubinemia, hereditary,”

“bilirubin,” “jaundice, neonatal,” “kernicterus”) and text words

(“bilirubin,” “hyperbilirubin$,” “jaundice,” “kernicterus,”

“neonat$”). The abstracts were limited to human and English

studies focusing on newborns between birth and 1 month of

age. In addition, the same text words used for the

MEDLINE® search were used to search the PreMEDLINE®

database. The strategy yielded 4,280 MEDLINE® and 45

PreMEDLINE® abstracts. The EPC consulted domain experts

and examined relevant review articles for additional studies.

Study Selection. Preliminary screening of abstracts for each

question identified over 600 potentially relevant articles for

Questions 1, 2, and 3. For Questions 1 and 2, only studies

that reported neurodevelopmental outcomes were included.

Except for part of Question 3, studies concerning effects of

different variables on bilirubin without neurodevelopmental

outcome were not included in this review. For the specific

question of quantitative estimates of treatment efficacy, all

studies concerning therapies for bilirubin ≥20 mg/dl were

included in the review. The inclusion and exclusion criteria for

the systematic review were discussed in several teleconferences

of the EPC evidence review team and technical experts. The

criteria underwent several revisions before final acceptance by

the panel members. The final screening criteria for inclusion

and exclusion of articles are described below.

Association of Neonatal Hyperbilirubinemia With

Neurodevelopmental Outcomes 

For the two questions on the association of neonatal

hyperbilirubinemia with neurodevelopment outcomes, the

inclusion criteria were: Infants ≥34 weeks of gestation or

≥2,500 grams and a sample size of more than five subjects per

arm (except for case reports of kernicterus). The predictors

were jaundice or hyperbilirubinemia and at least one of the

neurodevelopmental outcomes was reported in the article. The

study designs included prospective cohorts (more than two

arms), prospective cross-sectional study, prospective

longitudinal study, prospective single-arm study, or

retrospective cohorts (more than two arms). 

Treatments for Neonatal Hyperbilirubinemia 

For Question 3 on the treatments for neonatal

hyperbilirubinemia, studies which focused on the number

needed to treat had the following inclusion criteria: Infants ≥34

weeks of gestation or ≥2,500 grams and a study size of more

than 10 subjects per arm. Treatments included any treatment

for neonatal hyperbilirubinemia. Outcomes included serum

bilirubin level ≥20 mg/dl or frequency of exchange transfusion

specifically for bilirubin level ≥20 mg/dl. The study design was

randomized or non-randomized controlled trials.

For all other studies reviewed for Question 3, the selection

criteria were: Infants ≥ 34 weeks of gestation or ≥ 2,500 grams

and sample size of more than 10 subjects per arm for

phototherapy; any sample size for other treatments. Any

treatment for neonatal hyperbilirubinemia was included and at

least one neurodevelopmental outcome was reported in the

article.

Diagnosis of Neonatal Hyperbilirubinemia 

For Questions 4 or 5 on the diagnosis of hyperbilirubinemia,

the inclusion criteria were: Infants ≥34 weeks of gestation or

birthweight ≥2,500 grams and a sample size of more than 10

2
subjects. The reference standard was laboratory-based serum

bilirubin.

Results of Abstract and Article Screening

Six hundred and sixty-three of a total 4,560 abstracts were

identified as potentially relevant articles after preliminary

screening. There were 158, 174, 99, 153, and 79 abstracts for

Questions 1, 2, 3, 4, and 5, respectively. 

After full-text screening (according to the inclusion and

exclusion criteria described above), 138 of 253 retrieved

articles were included in this report. Twenty-eight articles

reported on cases of kernicterus, 35 articles reported

correlations, 21 articles reported on treatments, and 54 articles

were included in the review of diagnosis. There was some

inevitable overlap because treatment effects and

neurodevelopmental outcomes were inherent in the study

designs.

Methodological Quality

Methodological quality or internal validity addresses the

design, conduct, and reporting of the study. Some of the items

belonging to this domain are widely used in various “quality”

scales and for randomized controlled trials, and usually include

items such as concealment of random allocation, treatment

blinding, and handling of dropouts. Because different types of

study designs are used to address different questions and for

consistency in the interpretation across different designs, a

three-category scale was defined to report the methodological

quality of the studies in the evidence report: A (least bias), B

(susceptible to some bias), or C (likely to have large bias).

Studies of Association (Questions 1 and 2). The criteria

for evaluating methodological quality of studies that assess

association are: 

• A–Prospective. Complete methods and results (including

inclusion/exclusion criteria). Proper control/comparison

group, correct analyses performed.

• 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.

Studies of Treatments (Question 3). The criteria for

evaluating methodological quality of studies that assess effects

of treatments are: 

• A–Randomized controlled trial. Complete methods and

results (including inclusion/exclusion criteria) described.

Proper randomization and/or blinding, and correct

analyses performed.

• B–Non-randomized controlled trial or other prospective

design (prospective cohort or case-control study). Proper

selection of control group. Not all criteria of A. Some

deficiencies; however, unlikely to cause major bias.

• C–Retrospective or no control group. Significant design or

reporting errors, large amount of missing information or

bias.

Studies of Diagnosis (Questions 4 and 5). The criteria for

evaluating methodological quality of studies that assess

diagnostic test performance are:

• A–Prospective. Complete methods and results (including

inclusion/exclusion criteria) described. Proper reference

standard used and correct analyses performed.

• 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.

Statistical Analysis

The number needed to treat (NNT), expressing the benefit

of an active treatment over a control, was calculated to quantify

the efficacy of treatment for neonatal hyperbilirubinemia. For

Question 3 in this report, NNT can be interpreted as the

number of newborns needed to be treated at 20 mg/dl to keep

the TSB in one newborn from rising. 

A meta-analysis of Question 4 was conducted using the

summary receiver operating characteristic (ROC) method to

combine studies which evaluated diagnostic test performance.

A meta-analysis of correlation coefficients was conducted to

correlate performance of transcutaneous bilirubin

measurements with serum bilirubin.

Results

Question 1

What is the relationship between peak bilirubin levels and/or

duration of hyperbilirubinemia and neurodevelopmental outcome?

• A summary of 28 reports that spanned over 30 years of

123 cases of kernicterus in term/near-term infants affirms

the role of elevated bilirubin level in kernicterus. The

disease, although infrequent, has significant mortality (at

least 10 percent) and long-term morbidity (at least 70

percent). It is important to note that a significant amount

of demographic information was missing in these case

reports. Thirty-five term/near-term (≥34 weeks gestation)

infants with idiopathic hyperbilirubinemia developed

kernicterus with a TSB level ranging from 22.5 mg/dl to

54 mg/dl. Eighty-eight infants with hyperbilirubinemia

and other comorbid factors (like sepsis and hemolysis)

developed kernicterus with TSB ranging from 4 mg/dl to

51 mg/dl.

3
• Excluding the Collaborative Perinatal Project (CPP) and

the studies looking at IQ, of the nine studies primarily

looking at behavioral and neurodevelopmental outcomes

in patients, only three studies were of high methodological

quality. One showed a correlation between bilirubin level

and decreased scores on newborn behavioral

measurements. One found no difference in prevalence of

central nervous system abnormalities at age 4 years when

bilirubin was below 20 mg/dl, but infants with bilirubin

above 20 mg/dl had a higher prevalence of central nervous

system abnormalities. Another that followed infants with

bilirubin greater than 16 mg/dl found no relationship

between bilirubin and neuro-visual-motor testing at 61 to

82 months of age.

• Six high quality studies (not counting the CPP) showed

significant relationship between abnormalities in

brainstem auditory evoked potentials and high bilirubin

levels. The majority reported resolution with treatment.

Three studies reported hearing impairment associated with

elevated bilirubin (>16 mg/dl to >20 mg/dl).

• Again excluding CPP, of the eight studies reporting

intelligence outcomes in subjects with hyperbilirubinemia,

four were considered high quality. These four studies

reported no association between IQ and bilirubin level

with followup ranging from 6.5 years to 17 years.

• The Collaborative Perinatal Project—with 54,795 live

births between 1959 and 1966 from 12 centers in the

United States—has, by far, the largest database for the

study of hyperbilirubinemia. The study focused only on

black and white infants with birthweight ≥2,500 grams,

and a comprehensive analysis of the 7-year outcomes of

33,272 subjects was performed. All causes of jaundice

were included in the analysis. No consistent association

between peak bilirubin level and IQ was found. Rate of

sensorineural hearing loss was not related to bilirubin

level. Only the frequency of abnormal or suspicious

neurologic examination result was associated with

bilirubin.

• Short-term studies tend to be of high methodological

quality compared to long-term studies but they use tools

that have unknown predictive abilities. Long-term studies

suffer from high attrition rates of study population and a

non-uniform approach to defining “normal

neurodevelopmental outcomes.”

• Given the overall diverse conclusions, except in cases of

kernicterus with sequelae, the EPC team concluded that

the use of a single total serum bilirubin level (within the

range described in the studies) to predict long-term

behavioral or neurodevelopmental outcomes is inadequate

and will lead to conflicting results.

Question 2

What is the evidence for effect modification of the results in

Question 1, by gestational age, hemolysis, serum albumin, and

other factors?

• The only study that directly addressed the above question

used the CPP population and reported that at age 4 years,

the frequency of low IQ with increasing bilirubin levels

increased more rapidly in infants with infected amniotic

fluid. At age 7 years, neurologic abnormalities were also

more prevalent in that subgroup of infants.

• In case reports of kernicterus, all four infants with

multiple comorbid factors had sequelae.

• Reserve albumin concentration and duration of

hyperbilirubinemia will need further studies to understand

the nature of neurodevelopment in relation to bilirubin

physiology.

Question 3

What are the quantitative estimates of efficacy of treatment at

reducing peak bilirubin levels (e.g., number needed to treat at 20

mg/dl to keep TSB from rising)?

• Regardless of different protocols of phototherapy, the

NNT for prevention of serum bilirubin level exceeding 20

mg/dl ranged from 6 to 10 in healthy term or near-term

infants. This implies that one needs to treat 6 to 10

otherwise healthy jaundiced neonates with TSB ≥15

mg/dl by phototherapy in order to prevent the TSB in 1

infant from rising above 20 mg/dl. Phototherapy

combined with cessation of breastfeeding and substitution

with formula was found to be the most efficient treatment

protocol for healthy term or near-term infants with

jaundice.

Question 4

What is the efficacy of various strategies for predicting

hyperbilrubinemia, including hour-specific bilirubin percentiles?

• For accuracy of various strategies for prediction of

neonatal hyperbilirubinemia, 153 articles were included

after title and abstract screening. However, only 17

articles were included after full text screening and 10

articles remained after data abstraction—7 percent of the

original number. This was the lowest yield of articles

among the five questions addressed, suggesting that

relatively few prospective or retrospective studies addressed

this question without significant design or reporting

errors, missing data, or apparent bias.

• A conclusion is difficult to make from these studies. The

first challenge is the lack of consistency in defining

clinically significant neonatal hyperbilirubinemia. Not

only did multiple studies use different levels of total serum

4
bilirubin to define neonatal hyperbilirubinemia, but the

levels of TSB defined as significant also varied by age; age

at TSB determination varied by study as well. 

The second challenge is the lack of consistency in study

populations. These studies were conducted among

multiple racial groups in multiple countries, including

China, Denmark, India, Israel, Japan, Spain, and the

United States. Although infants were defined as healthy

term and near-term newborns, these studies included

neonates with potential for hemolysis from ABOincompatible pregnancies, as well as breast-fed and bottlefed infants. This information was often not specified.

Question 5 

What is the accuracy of transcutaneous bilirubin measurements?

• Based on the evidence from the systematic review,

transcutaneous measurements of bilirubin by each of the

three devices described in the literature—the Minolta

Airshields Jaundice MeterTM, the Ingram Icterometer, and

the SpectRx BiliCheckTM—have a linear correlation to

total serum bilirubin and may be useful as screening

devices to detect clinically significant jaundice and

decrease the need of serum bilirubin determinations.

• The Minolta Airshields Jaundice MeterTM appears to

perform less well in black infants as compared to white

infants, performs best when measurements are made at the

sternum, and performs less well when infants have been

exposed to phototherapy. This instrument requires daily

calibrations and each institution must develop its own

correlation curves of TcB to TSB. As a screening test it

does not perform consistently across studies as evidenced

by the summary ROC curves. The Ingram Icterometer has

the added limitation of lacking objectivity of the other

methods as it depends on observer visualization of depth

of yellow color of the skin. 

• The recently introduced BiliCheckTM and Colormate III

devices (that utilize reflectance data from multiple

wavelengths) appear to be a significant improvement over

the older devices, the Ingram Icterometer and the Minolta

AirShields bilirubinometer, because of the ability to

determine correction factors for the effect of melanin and

hemoglobin. In one study, the BiliCheckTM was shown to

be as accurate as standard laboratory methods in

predicting TSB determined by the reference standard of

high performance liquid chromatography (HPLC).

Future Research

• Future research in kernicterus would benefit from a

uniform definition of the disease. Making kernicterus a

reportable condition coupled with multi-center

cooperation will help to elucidate its epidemiology and

other factors in the development of the disease.

• Duration of hyperbilirubinemia, bilirubin binding, and

the role of hour-specific bilirubin measurement all merit

further investigation. 

• Validation of an age-specific (by hour) nomogram for TSB

in healthy full-term infants—with evaluation of potential

differences by gender, race, and ethnicity, as well as

prenatal, natal, and postnatal factors—would be

beneficial. Once established, use of the 95th percentile to

define clinically significant jaundice would provide

uniformity across studies. This would be analogous to the

use of age-specific systolic and diastolic blood pressure to

define hypertension and age-specific body mass index to

define overweight and obesity in children. Validation of a

standardized TSB nomogram would either incorporate

these potential differences or result in the development of

population-specific nomograms if differences were

significant. This would be analogous to the use of

population-specific growth charts for weight and height

percentiles in children.

• Given the interlaboratory variability of measurements of

serum bilirubin, future studies should use HPLC as the

reference standard along with the routine laboratory

methods of TSB in use when evaluating noninvasive

measures of bilirubin.

• Validation is needed of new technological advances in the

transcutaneous measurement of bilirubin, such as the

BilicheckTM and Colormate III (that have the ability to

correct for skin color effects and hemoglobin) in diverse

clinical populations. This would address issues that might

affect performance such as race, gestational age, age at

measurement, phototherapy, sunlight exposure, feeding,

and accuracy as screening instruments and for ongoing

monitoring of jaundice. Additionally, studies should

address cost effectiveness and reproducibility in actual

clinical practice.

Ordering Information

The full evidence report from which this summary was taken

was prepared for AHRQ by the Tufts New England Medical

Center Evidence-based Practice Center, Boston, MA, under

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

early 2003. When available, printed copies may be obtained

free of charge from the AHRQ Publications Clearinghouse by

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

Report/Technology Assessment No. 65, Management of

Neonatal Hyperbilirubinemia. Internet users will be able to

access the report online through AHRQ’s Web site at

www.ahrq.gov.

5
www.ahrq.gov

AHRQ Pub. No. 03-E005

November 2002 

ISSN 1530-440X