Pregnancy and Perinatology Branch (PPB) 

Strategic Plan 

Fiscal Year 2005 through Fiscal Year 2010 

U.S. Department of Health and Human Services 

National Institutes of Health
 

National Institute of Child Health and Human Development 

For Administrative Use 

October 2003 

 

 

TABLE OF CONTENTS 

Background ................................................................................................................................... 1
 

Summary of the PPB Planning Workshop ................................................................................. 2
 

The PPB Strategic Plan ................................................................................................................ 3
 

Ongoing Areas of Emphasis..................................................................................................... 3
 

Evidence-based Medicine in Obstetrics and Neonatology ..................................................... 3
 

Sudden Infant Death Syndrome (SIDS)................................................................................... 4
 

Stillbirth .................................................................................................................................. 6
 

Obstetrical-Fetal Pharmacology ............................................................................................ 7
 

Neonatal Pharmacology ......................................................................................................... 8
 

Maternal-Fetal Surgery .......................................................................................................... 9
 

New Areas of Emphasis............................................................................................................ 9 

Prematurity ............................................................................................................................. 9
 

Fetal Development, Including Maturation of Individual Organ Systems and 

Fetal/Neonatal Brain Development and Damage (Including Prenatal, Perinatal, 

Define and Improve the Link Between Fetal, Obstetrical, and Neonatal Intervention 

 Impact of Interventions on Long-Term Function............................................................. 11
 

Maternal Morbidities............................................................................................................ 12 
 

Neonatology (Specifically Intensive Care, and Long-Term Outcome Issues) ...................... 13
 

Neonatal, and Infant Periods).......................................................................................... 14
 

Specifically, this discussion addressed the following topics: ............................................... 14
 

Training for the Future: Scientists and Physician-Scientists ............................................... 15
 

 and Infant/Child Outcomes.............................................................................................. 18
 

Appendix A: PPB Summation for the 2003 Planning Workshop ..................... Appendix A-1
 

History of RFAs Fiscal Year 1994 to Fiscal Year 2002 .................................. Appendix A-1
 

PPB-Related Workshops and Conferences, Fiscal Year 1991 to Present..... Appendix A-5
 

PPB Ongoing Activities ...................................................................................... Appendix A-7
 

PPB Planned Activities Fiscal Year 2003 to Fiscal year 2004...................... Appendix A-19
 

Appendix B: Areas of Opportunity Statements Compiled at the
 

PPB Workshop.........................................................................................................Appendix B-1
 

Area of Opportunity: Prematurity.....................................................................Appendix B-1
 

Area of Opportunity: Fetal and Embryonic Development—Maturation of Individual 

Organ Systems and Impact of Interventions on Long-Term Function ..........Appendix B-4
 

Area of Opportunity: Maternal Morbidities— Hypertension and
 

Thrombophilias....................................................................................................Appendix B-8
 

Area of Opportunity: Neonatology ..................................................................Appendix B-11
 
Area of Opportunity: Prenatal Screening, Diagnosis, and
 

Fetal Therapy .....................................................................................................Appendix B-13
 

Area of Opportunity: Fetal/Neonatal Brain Development and Damage 

(Including the Prenatal, Perinatal, Neonatal, and Infant Periods) ...............Appendix B-17
 

Area of Opportunity: Training.........................................................................Appendix B-19
 

Area of Opportunity: Obstetrical, Fetal and Neonatal Interventions and 

Infant/Child Outcomes ......................................................................................Appendix B-24
 

Appendix C: PPB Staff and PPB Planning Workshop Participants................ Appendix C-1
 

PPB Staff (In Alphabetical Order).................................................................... Appendix C-1
 

Participants in PPB Planning Workshop ......................................................... Appendix C-2
 
BACKGROUND 

The Pregnancy and Perinatology Branch (PPB) is one of three branches in the Center for 

Developmental Biology and Perinatal Medicine at the National Institute of Child Health and 

Human Development (NICHD). The mission of the Branch is to improve the health of mothers 

and children, with focuses on maternal health, pregnancy, fetal well-being, labor and delivery, 

and the developing child. 

The purpose of research supported by the Branch is to promote the acquisition of scientific 

information through basic, translational, and clinical investigation, that supports the Branch 

mission. Important research areas for PPB include: basic mechanisms underlying normal and 

disease processes; the identification of new treatments, methodologies and preventative 

strategies arising from translational and evidence-based research; and assessment of the 

dissemination and impact of therapeutic and preventative interventions. In addition, the Branch 

aims to increase scientific resources for these fields of study through recruitment and training of 

investigators. 

In March 2001, the Branch began a process of self-assessment, reviewing the goals and mission 

of the Branch, its initiatives, and its portfolio in preparation for a PPB Planning Workshop to be 

held in 2002. This extensive internal review included large projects, such as the PPB-supported 

Networks, the Maternal-Fetal Medicine Unit (MFMU) Network and the Neonatal Research 

Network (NRN), as well as various program projects (P01s). To familiarize Branch members 

with the PPB portfolio, each program project was assigned to three Branch members, who 

reviewed, discussed, and assessed the project’s progress since initiation, contributions to the 

field, and novelty. Seminars held by the NICHD Center for Research on Mothers and Children 

(CRMC) also gave Network program officers the opportunity to present updates on their projects 

to Branch members; other discussions were held on projects within the sudden infant death 

syndrome (SIDS) portfolio. Prior to the PPB Planning Workshop, the Branch members also 

reviewed the NICHD SIDS Strategic Plan, the Society for Maternal Fetal Medicine’s Research 

Priorities in Maternal Fetal Medicine, and the Committee Research Agenda from the American 

Academy of Pediatrics (AAP) Section on Perinatal Pediatrics. 

As a result of these inquires, Branch staff identified research priorities in three areas: 1) Areas 

already under investigation that remained important; 2) Areas that needed stimulation; and 3) 

Areas that needed new approaches or directions. Based on these general areas, Branch staff 

identified 10 target research areas for the PPB Planning Workshop. In addition, the Branch 

prepared background information for the Workshop, including the Branch’s history, the Request 

for Applications (RFAs), contracts, workshops and conferences, grant portfolios, ongoing 

activities, and planned activities for fiscal year 2003 and fiscal year 2004 (See Appendix A). 

1 
 

SUMMARY OF THE PPB PLANNING WORKSHOP 

In December 2002, the PPB convened its two-day Planning Workshop to develop a research 

agenda that would help guide Branch activities and priorities for the years 2005 through 2010. 

The Branch invited 14 eminent scientists to the Workshop to identify the needs of the scientific 

community served by the PPB and to prioritize Branch scientific areas and research issues. 

During the bulk of the Workshop, participants discussed the Areas of Opportunity, based on 

prepared statements that detailed important new directions for research, and on the 

recommendations of PPB staff. The final half-day focused on priority setting by the group. 

Additional follow-up activities included the development and finalization of the group’s 

recommendations. The findings from and recommendations of this PPB Planning Workshop 

formed the basis for this Strategic Plan document. 

The participants were assigned as champions for one of the Areas of Opportunity and developed 

summary sheets on each topic. These summations were revised after the workshop to include 

items from these discussions (see Appendix B). 

The Areas of Opportunity discussed during the Workshop included: 

• 	 Prematurity; 

• 	 Fetal development, including maturation of individual organ systems and impact of 

interventions on long-term functional outcomes; 

• 	 Maternal morbidities; 

• 	 Neonatology, specifically intensive care and long-term outcome issues; 

• 	 Fetal/neonatal brain development and damage (including prenatal, perinatal, neonatal, infant 

periods, and environmental effects on child development); 

• 	 Training for the future: scientists and physician-scientists; and 

• 	 Links between fetal, obstetrical and neonatal intervention and infant/child outcome. 

In addition, workshop participants discussed several cross-cutting themes that were relevant to 

all areas of opportunity, including: 

• 	 Infrastructure resources; 

• 	 Environmental and genetic influences; 

• 	 Health disparity issues; 

• 	 Technology development, including the application of new technologies (e.g., genomics, 

proteomics, fMRI, bioinformatics, etc.) in pregnancy and perinatology research; and 

• 	 Research risk and ethical aspects of research. 

2 
THE PPB STRATEGIC PLAN 

Based on workshop discussions and on input from the PPB research community, the Branch 

developed a Strategic Plan to guide its activities for fiscal year 2005 through fiscal year 2010. 

The Strategic Plan will help guide the Branch’s investments in areas of need that are important to 

the field, and in identifying new strategies for solving old problems. The Strategic Plan will also 

be a useful tool for the scientific community to use for stimulating research interests. The plan 

will help to refine the Branch’s goals, but not narrow its mission. 

Within the scope of the Center for Developmental Biology and Perinatal Medicine, the PPB will 

use the Strategic Plan to recommend workshops, conferences, and RFAs. Additionally, in 

accordance with the mission of the National Institutes of Health (NIH), the PPB will continue to 

welcome, assist, and support investigators who propose applications relevant to the PPB mission, 

regardless whether the applications relate specifically to the Strategic Plan. 

The Strategic Plan includes Ongoing Areas of Emphasis and New Areas of Emphasis, and, where 

possible, action steps and priorities for each area. Given the broad nature of the PPB mission, 

the Plan is not intended to be comprehensive. The Branch anticipates that research conducted 

within the grants and contracts portfolios will continue to address many issues not covered in this 

plan. With this in mind, the Strategic Plan was developed to be flexible, so that the PPB can 

address new and emerging areas relevant to the field as they use. Rather than being a restrictive 

entity, the PPB Strategic Plan will allow for the expansion of research, both within this 

framework, and outside of it. 

ONGOING AREAS OF EMPHASIS 

The ongoing areas of emphasis include critical topics of research that are currently underway and 

are crucial to the PPB mission. Some of these areas, such as the Networks, have a long history in 

the Branch and provide a mechanism for timely, cost-effective clinical investigations. Others, 

such as stillbirth and obstetrical-fetal pharmacology, are more recent efforts to fill gaps that were 

identified by the field, which now have initiatives planned for implementation. 

EVIDENCE-BASED MEDICINE IN OBSTETRICS AND NEONATOLOGY 

Modern medical management has, in some instances, adopted solid principles of care, while at 

other times it has employed pharmaceuticals and methodologies without rigorous use of the 

controlled observation necessary for objective evaluation. This disconnect sometimes results in 

the enthusiastic initial adoption of concepts and procedures, followed by their modification or 

replacement, sometimes decades later, after extensive experience has failed to support their 

usefulness or has shown unexpected consequences. To respond to the need for well-designed 

clinical trials in maternal-fetal medicine and neonatology, the NICHD established the MFMU 

Network and the NRN in 1986. Each Network is guided by its respective Steering Committee, 

which consists of representatives from each clinical center, the NICHD, and the data3 
coordinating center. Protocols are developed and approved by the Steering Committee. 

Typically each Network has two to three randomized controlled trials and two to three 

observational studies ongoing at any given time. These Networks allow for a timely response to 

urgent clinical questions in a cost effective manner. Currently, the MFMU Network has 14 sites, 

and the NRN has 16 sites. Sites are selected every five years following an open competition. 

ACTION STEPS: 

1. Continue to support the MFMU Network and the NRN. 

2. Facilitate the collaboration between the two Networks through improved communication 

among various groups, interaction beyond the Network meetings, and input on protocols 

from one group to the other. 

3. Encourage research through clinical trials that are not Network activities. Because the 

Networks are competed every five years and, thus, are not open to all institutions at all times, 

the Branch recognizes the need to support researcher-initiated investigations that evaluate 

evidence-based practice in maternal-fetal medicine and neonatology outside these Networks. 

Examples include the ongoing Vaginal Ultrasound Cerclage Trial (1 U01 HD039939-01A1; 

Principal Investigator: John Owen, MD), a multicenter, randomized clinical trial, designed to 

determine the efficacy of cerclage (a purse-string suture placed around the uterine cervix) for 

the prevention of spontaneous preterm birth prior to 35 weeks' gestation; and the Twin-Twin 

Transfusion Syndrome Trial (5 R01 HD041149-02 Principal Investigator: Tim 

Crombleholme, MD), a prospective, randomized multicenter trial of pregnancies complicated 

by twin-twin transfusion syndrome (TTTS) to compare serial amnioreduction with selective 

fetoscopic laser photocoagulation. The overall goal of the latter study is to improve the 

outcome of twins with TTTS by determining which treatment for TTTS improves survival as 

well as cardiac, neurologic, and developmental outcomes. 

SUDDEN INFANT DEATH SYNDROME (SIDS) 

In the United States alone, about 2,500 infants now die each year from SIDS; but SIDS occurs 

worldwide. The majority of SIDS deaths occur before babies reach six months of age. These 

deaths, although associated with a sleep period, are sudden and unpredictable. In most cases, 

infants appear healthy before succumbing to SIDS. No explanation for these deaths can be 

found, even when a complete postmortem is performed, including an autopsy, an examination of 

the death scene, and a review of the infant’s clinical and family history. In the absence of an 

identifiable cause of death, these infant deaths are, by standard definition, labeled SIDS. 

SIDS exacts a devastating emotional toll on affected families and caregivers. In 1974, landmark 

legislation—the Sudden Infant Death Syndrome Act (P.L. 93-270)—gave the NICHD the 

statutory responsibility to oversee SIDS research and to develop a public education and 

information program about SIDS. The Institute’s ultimate goal is to eliminate SIDS in all 

populations. To reach this aim, it is important to understand the underlying causes and 

mechanisms of the syndrome, develop strategies to identify infants at high risk for SIDS, and 

develop and implement preventive strategies that can effectively reduce the incidence of SIDS 

across diverse populations. 

4 
 

The research agenda of the NICHD’s SIDS program is outlined in Targeting Sudden Infant 

Death Syndrome (SIDS): A Strategic Plan, one of several NICHD strategic planning documents 

available on the NICHD Web Site, at http://www.nichd.nih.gov/strategicplan/cells/. 

Since 1994, as a way to address the second part of the SIDS Act, the NICHD, the Maternal and 

Child Heath Bureau, the AAP, the SIDS Alliance and the Association of SIDS, and Infant 

Mortality Programs have sponsored the Back to Sleep campaign; to educate caregivers that 

healthy infants be placed on their backs to sleep to reduce the risk of SIDS. The campaign also 

explains other ways to reduce the risk of SIDS, including placing an infant on a firm mattress. 

Information about the Back to Sleep campaign is available at the NICHD Web Site, at 

http://www.nichd.nih.gov/sids/sids.cfm. 

AREAS TO INVESTIGATE: 

The NICHD’s SIDS Strategic Plan is divided into four sections; each section recommends a 

number of research questions related to SIDS. These sections are explained below. 

Etiology and Pathogenesis 

The recommendations in this section are targeted toward understanding: 

• 	 How the neural abnormalities observable in SIDS infants develop; 

• 	 How these neural abnormalities affect infant health and development before and after birth; 

• 	 How environmental factors in the Neonatal Intensive Care Unit (NICU) and beyond affect 

the growing brain of preterm infants; 

• 	 Whether there are genetic factors that predispose infants to sudden death; and 

• 	 How specific characteristics of the fetal and postnatal environment either contribute to the 

pathological process or serve to protect infants. 

Prognostics and Diagnostics 

The recommendations in this section address: 

• 	 Assessment of neural maturity through infancy; and 

• 	 Development of tools to assess the neurological and developmental maturation of newborn 

infants through early infancy and the predictive value of screening tools used in the neonatal 

period. 

Preventive Strategies 

The recommendations in this section emphasize the need for: 

• 	 Strong community partnerships; 

• 	 Knowledge of cultural variations; 

• 	 Rigorous evaluations of interventions and feedback from the lay community; 

• 	 Comprehensive and consistent assessments of fetal and infant deaths; and 

• 	 Understanding of how multiple risk factors may interact. 

Health Disparities 

The recommendations in this section emphasize: 

• 	 Creation and maintenance of strong community resources for research and intervention; 

• 	 Investigation of both protective and adverse forces operating within and across populations; 

and 

5 
• 	 Investigation of both macro- (e.g., equity of care) and micro-level (e.g., genetic 

predisposition) forces that operate within and across populations. 

ACTION STEPS: 

1. Support the RFA: HD-03-004—Prenatal Alcohol Exposure Among High-Risk Populations: 

Relationship To Sudden Infant Death Syndrome. The NICHD and the National Institute on 

Alcohol Abuse and Alcoholism (NIAAA) invited cooperative agreement applications for the 

development of community-linked studies to investigate the role of prenatal alcohol exposure 

in the risk for SIDS and adverse pregnancy outcomes, such as stillbirth and fetal alcohol 

syndrome (FAS), and how they may be inter-related. The investigators will work 

collaboratively under cooperative agreements with NICHD and NIAAA over a three-year 

period to plan and pilot multidisciplinary investigations, using common protocols, within 

communities at high risk for prenatal maternal alcohol consumption. The long-term goals of 

this initiative are to decrease fetal and infant mortality and improve child health in these 

communities. Applications were due March 17, 2003; funding plans were reviewed at the 

September 2003 meeting of the National Advisory Child Health and Human Development 

(NACHHD) Council. 

2. Issue a Letter of Invitation: HD-02-104—Data Coordinating and Analysis Center, Event 

Recordings of High Risk Infants on Apnea Monitors: The Collaborative Home Infant 

Monitoring Study (CHIME). This grant, awarded in 2003, continued the National Infant 

Sleep Position Study (NISP), which evaluates trends in infant sleep practices, the 

dissemination of the Back to Sleep recommendations, and the factors that influence these 

trends. This invitation also facilitated the scientific community’s access to the databases 

collected by NISP and the CHIME efforts. 

3. Support the RFA: HD-02-08—Development of Community Child Health Research. The 

purpose of this solicitation was to support community/research institution partnerships that 

will span two-and-a-half years. These partners planned a multi-site, multi-level study to 

examine: how community, family, and individual-level influences interacted with biological 

influences; and how these interactions resulted in health disparities in pregnancy outcomes 

and in infant and early childhood mortality and morbidity. The funding plan was reviewed at 

the January 2003 meeting of the NACHHD Council. 

STILLBIRTH 

Stillbirths account for a large proportion of perinatal mortality. According to annual national 

vital statistics, the number of fetal deaths (defined as deaths at 20 weeks or more gestation) is 

similar in magnitude to the total number of infant deaths in the United States. While the infant 

mortality rate declined by about 32 percent to 7.2 deaths in 1000 live births between 1985 and 

1998, the stillbirth rate declined by only about 14 percent to 6.7 deaths in 1000 live births. 

Despite the significant and persistent burden of stillbirth, the phenomenon has remained largely 

unstudied. For at least half of all stillbirths, the cause remains undetermined. 

6 
AREAS TO INVESTIGATE: 

• 	 In-depth studies of the causes, reproductive and fetal risks in predicting stillbirth; 

• 	 The role of placentation in fetal demise, including the role of genetic mosaicism in the 

placenta; 

• 	 Unexplained stillbirths and the potential role of fetal autonomic dysfunction; 

• 	 The relationship of stillbirths to other adverse pregnancy outcomes, particularly those with a 

potential infectious etiology; and 

• 	 Quantitative evaluation of the role of thrombophilias to aid in screening and management 

decisions. 

ACTION STEPS: 

1. Convene a workshop. The NICHD held a workshop in March 2001, Setting a Research 

Agenda for Stillbirth, to explore the current knowledge in the field and identify research 

topics. The findings from this workshop were published in the February 2002 issue of 

Seminars in Perinatology. 

2. Support the RFA: HD-02-025—Research on the Scope And Causes of Stillbirth in the United 

States. This 2002 RFA created a network of clinical sites, with central data collection and 

analysis, to develop and implement common research protocols to study stillbirth (defined as 

fetal death at 20 weeks’ or greater gestation). The resulting network of multidisciplinary 

investigators will develop research diagnostic protocols, as well as a body of data on the 

scope and causes of stillbirths among varied populations within the United States, while 

encouraging community involvement to obtain an adequate sampling of rural and urban 

populations and a diverse ethnic/racial makeup. The information obtained from this effort 

will aid in future research in improving preventive and therapeutic interventions and in 

understanding the pathologic mechanisms that lead to fetal death. Applications were due on 

March 13, 2003; the funding plans were reviewed at the September 2003 meeting of the 

NACHHD Council. 

3. Encourage and create other research opportunities. Initiatives to address the Areas to 

Investigate for stillbirth not covered above will be considered by the Branch for its yearly 

initiatives. 

OBSTETRICAL-FETAL PHARMACOLOGY 

The study of drugs used during pregnancy is one of the most neglected areas in the fields of 

clinical pharmacology and drug research. The data available on drug biodisposition and effect 

are scarce, fragmentary, and frequently contradictory. The lack of Food and Drug 

Administration (FDA) obstetric labeling and the universal off-label use of drugs are a direct 

result of the lack of research and clinical trials in this special population. Epidemiological 

surveys have determined that nearly two-thirds of all pregnant women take at least four or five 

drugs during pregnancy and labor. These data demonstrate that drug use during pregnancy is of 

great public concern because it is mostly based on an empiric approach, rather than on a 

scientific basis; further, current use does not take into account the profound physiologic changes 

characteristic of the pregnant state. 

7 
 

 

ACTION STEPS: 

1. Convene the experts. The PPB, in collaboration with the NICHD’s Endocrine, Nutrition, and 

Growth Branch (ENGB), the NICHD Office of the Director, the CRMC, and the FDA, held a 

series of workshops in the fall and winter 2001-2002 to identify research topics and 

determine the status of the field. In addition, within NIH, presentations to Office of Research 

on Women’s Health’s liaisons were made in an attempt to develop inter-Institute initiatives. 

2. Support a new RFA. The NICHD issued a RFA (HD-03-017) on July 29,2003 for ObstetricFetal Pharmacology Research Units, to support integrated basic, translational, and clinical 

research centers that will: 

• 	 Conduct pharmacologic studies of drug disposition and effect during normal and 

abnormal pregnancies; 

• 	 Conduct single-site and multi-site cooperative clinical trials; 

• 	 Conduct pharmacogenetic studies on the effect of pregnancy on drug metabolizing 

enzymes, transporters, and effectors; 

• 	 Perform studies of placental transfer of drugs; 

• 	 Conduct studies of fetal and maternal pharmacology; 

• 	 Facilitate the utilization of clinical materials for basic research studies; and 

• 	 Enhance the exchange of information between basic scientists and obstetricians, and 

among various specialists involved in treating pregnant women. 

The receipt date is November 24, 2003, and the funding plan will be reviewed in June 2004 

at the NACHHD Council meeting. 

3. Identify future initiatives, based on the progress of the grants awarded in response to the new 

RFA, and on the status of researcher-initiated investigations. 

NEONATAL PHARMACOLOGY 

Similar to the paucity of research on drugs used during pregnancy, the field of neonatal 

pharmacology is also a highly neglected field. The mandates of the Best Pharmaceuticals for 

Children Act (BPCA) provide an excellent opportunity for addressing many of the unresolved 

issues related to research and clinical practice of drugs used in newborn infants. This work is in 

cooperation with the ENGB, which maintains primary responsibility for the Pediatric 

Pharmacology Research Units (PPRUs) and the BPCA. 

ACTION STEPS: 

1. Partner with the PPRU Network, and with the FDA’s Newborn Drug Development Initiative. 

Two program officers from the PPB are participating in a series of planning workshops that 

will lead to a multidisciplinary national workshop, planned for the winter/spring of 2003-

2004, on this topic. PPB staff anticipates that the executive summary issued from the 

workshop will prioritize research and regulatory issues related to neonatal pharmacology. 

This summary will provide a background for future studies including clinical trials to foster 

the development of safe and effective drug therapies for preterm and neonatal populations. 

8 
 

MATERNAL-FETAL SURGERY 

An increasing number of maternal-fetal surgeries for non-lethal conditions, such as 

meningomyelocele are being performed; yet, in utero surgery has not been validated to show 

improvement over postnatal repair. In addition, the risks to the fetus (i.e., death, preterm 

delivery) and to the mother (e.g., two classical uterine incisions within one pregnancy, all future 

pregnancies to be delivered by cesarean section, and complications such as placenta increta, 

uterine rupture) have not been evaluated. To address this research need, the NICHD established 

the Maternal-Fetal Surgery Network within the MFMU Network in 2001 to evaluate in utero 

fetal surgery versus standard postnatal repair as a treatment for antenatally diagnosed spina 

bifida in a randomized clinical trial. 

ACTION STEPS: 

1. Monitor the trial closely for adverse events and protocol compliance. The Branch, through 

an Inter Personnel Agency agreement, hired maternal-fetal medicine specialist and fetal 

surgeon, Dr. Nancy Chescheir, to act as the NICHD Program Scientist. 

2. Assemble the field. The Branch will plan a workshop on the ethics and role of maternal-fetal 

surgery, to clarify conditions that might benefit from in utero repair, and to identify future 

trials needed in this progressive area. 

NEW AREAS OF EMPHASIS 

PREMATURITY 

Preterm delivery accounts for 70 percent of perinatal mortality, and for nearly half of the longterm neurologic morbidity of newborns. Despite years of intense effort to reduce preterm 

delivery rates, approximately 10 percent of all births in the United States are still preterm, and 

the incidence of very preterm births has been rising in recent years. The understanding of the 

underlying mechanisms of preterm birth is limited; less than half of all preterm births have an 

identifiable risk factor. 

The PPB staff and the Workshop participants recognized that significant research has been 

devoted to this condition; but noted that much remains to be understood. The Branch selected 

this topic as one that needed novel approaches for the future. Participants added that into the 

etiology of preterm birth should take into consideration its multi-factorial nature, including 

utero-placental insufficiency, fetal growth abnormalities, and fetal stress. 

AREAS TO INVESTIGATE: 

• 	 New tools are needed for: 

o Fetal growth assessment; and 

o Non-invasive methods to assess cervical, myometrial, and placental changes 

longitudinally. 

9 
 

 

• 	 Research should focus on the: 

o Pre-pregnancy and early pregnancy periods; 

o Role of the cervix; 

o Variability in host response; and 

o Role of the placenta; including: 

♦ 	 Functional mechanisms related to pregnancy outcomes and fetal well-being, such as 

fetal growth and preterm delivery; and 

♦ 	 Innovative technologies to study function in utero. 

• 	 Strategies for predicting preterm birth should include multivariate analysis, such as that used 

in neural network analysis, and should focus on identifying the potentially reversible changes 

that take place in pre- and early pregnancy stages. 

• 	 Research should focus on the cases with highest mortality and morbidity and should not be 

diluted by inclusion of less relevant cases of preterm birth that are close to term. 

• 	 The field needs to develop clinically applicable methods to identify pregnancies for which 

delaying delivery is futile or detrimental, and the effects of intervention on outcome. 

ACTION STEPS: 

1. Support the RFA: HD-01-005—Health Disparity In Preterm Birth: The Role Of Infectious 

And Inflammatory Processes. The PPB funded six grants under this RFA from fiscal year 

2001 and will follow closely the findings from these grants. The disparity in the rate of 

preterm births between African American and all other ethnic minorities remains one of the 

most striking of U.S. health disparities. Preterm births are twice as high among African 

American women as among any other group of women in the United States; with an even 

greater discrepancy exists in the rate of very early preterm birth. The findings from these 

studies may provide groundwork for new initiatives. 

2. Issue a new Program Announcement (PA). In conjunction with the National Institute of 

Environmental Health Sciences (NIEHS) and the National Institute of Nursing Research 

(NINR), the PPB issued PA-02-102: The Role of Gene-Environmental Interactions 

Underlying the Health Disparity of Premature Birth, to address the need to better understand 

how adverse societal, behavioral, and environmental conditions alter gene expression, and 

how these factors interact with diverse genetic backgrounds to increase a woman’s 

susceptibility for premature birth in high-risk racial and ethnic groups. The solicitation 

encourages multidisciplinary approaches to clarify the potential role of genetics in the 

increased risk of premature birth among certain populations. This PA will close on January 

1, 2005. The Branch will closely follow the number and caliber of applications submitted in 

response to this PA. If the research community does not adequately respond to the PA, the 

PPB will consider issuing an RFA. 

3. Issue a new RFA. In 2004, the Branch plans to issue the RFA Research into Mechanisms of 

Fetal Growth Restriction. The aim of this initiative is to stimulate research into the 

mechanisms of fetal growth restriction, and to gain a better understanding of the factors that 

regulate fetal growth during pregnancy. 

10 
4. Increase participation in the National Children’s Study (NCS). The Branch has begun these 

activities: 

• 	 The PPB, in conjunction with the NCS, held a workshop on the assessment of fetal 

growth and integrity on December 15-16, 2002, in Baltimore, Maryland. This workshop 

reviewed the current models of fetal growth assessment. 

• 	 The PPB is working with NCS staff to develop the requirements for a pilot study of the 

feasibility of three-dimensional ultrasound data acquisition, storage and retrieval for the 

measurement of fetal growth. 

• 	 The Pregnancy and the Infant Working Group is encouraging collection of data that will 

allow for novel assessments of fetal growth and integrity. 

5. Create other research opportunities. Initiatives to address the Areas to Investigate for 

Prematurity, which is not covered above, will be considered by the Branch for its yearly 

initiatives. Given the importance of this topic to the Branch, an initiative on prematurity will 

be proposed each year once the findings from ongoing grants and trials are reviewed. 

FETAL DEVELOPMENT, INCLUDING MATURATION OF INDIVIDUAL ORGAN SYSTEMS 

AND IMPACT OF INTERVENTIONS ON LONG-TERM FUNCTION 

Within this area, participants noted the following: 

• 	 New tools for defining fetal growth are needed. 

• 	 The gender-specific effects of “stressors” on prenatal organ maturation at critical windows of 

development are not well understood. 

• 	 The epidemiological associations of specific intrauterine stressors and later outcomes are ripe 

for further study. 

• 	 The integration of the complex effects intrauterine stress has been little studied. 

• 	 New treatment offerings need to be developed for use once undergrowth and/or fetal stress 

are detected. 

• 	 The phenomenon of intergenerational programming is not well understood. 

• 	 The mechanisms that determine embryonic and fetal growth trajectory during the postfertilization period are not known. 

• 	 The role of maternal stress during pre- and post-natal life requires further investigation 

• 	 There is a great need to determine the role of the placenta in programming. 

• 	 The field of human and animal development needs a structured repository of developmental 

information that allows computerized retrieval methods. 

• 	 The role of maternal nutrition on fetal growth and growth restriction requires further 

investigation. 

• 	 Assessment of outcome should focus on the long-term (into adulthood) functional outcome 

of high-risk infants. Developing a nation-wide database to prospectively record high-risk 

infant outcomes should be given a priority so that researchers can evaluate the effectiveness 

of therapeutic interventions in perinatal and neonatal periods on the health and well-being 

during adult life. 

11 
 

ACTION STEPS 

1. Convene the experts. In collaboration with the Pregnancy and the Infant Working Group of 

the NCS, members of the PPB held a workshop December 15 and 16, 2002, on the 

Evaluation of Fetal Growth and Integrity. In addition, the PPB and the Pregnancy and the 

Infant Working Group of the NCS plan to hold workshop to evaluate the measurement and 

identification of stress in pregnancy, in late 2003. 

2. Issue the RFA: HD-03-018—Research into Mechanisms of Fetal Growth Restriction. The 

aim of this initiative is to stimulate research into the mechanisms of fetal growth restriction, 

and to gain a better understanding of the factors that regulate fetal growth during pregnancy. 

The target receipt date was July 23, 2003, and the funding plan will be reviewed at the 

January 2004 meeting of the NACHHD Council. 

3. Create other research opportunities. In addition to the above, Branch staff will consider the 

avenues for investigating fetal development, maturation of individual organ systems, and 

impact on long-term function in the yearly Branch initiatives. 

MATERNAL MORBIDITIES 

Hypertension 

Workshop participants identified the following needs for hypertension research: 

• 	 Understand pathophysiologic abnormalities that lead to adverse pregnancy outcome in 

hypertensive women; 

• 	 Identify the risk factors for adverse outcome (i.e., preeclampsia, abruption, preterm birth) in 

hypertensive women and design prevention strategies based on these risk factors. 

• 	 Understand the genetic diversity that underlies hypertension in pregnancy and that could: 1) 

Lead to a role for pharmacogenetic therapy; and 2) Identify a subset of women at risk for 

preeclampsia or cardiovascular complications in the future. 

• 	 Generate a program of long-term follow-up of hypertensive women, from preconception to 

ten years postpartum, similar to studies in non-pregnant hypertensive individuals. Identify 

risk factors for cardiovascular complications from these data. 

• 	 Initiate career development programs to enhance the research capabilities of scientists 

interested in hypertension during pregnancy. 

Thrombophilias 

Workshop participants cited a need to understand the fundamental pathologic processes in 

patients with thrombophilic conditions, in order to: 

• 	 Enable accurate counseling regarding personal, fetal, and neonatal risk assessment 

surrounding pregnancy. 

• 	 Stratify the at-risk patient population to assess risk for thromboembolic events and adverse 

pregnancy outcomes. 

• 	 Build base prevention and treatment strategies on risk assessment. 

• 	 Focus on specific prevention and treatment strategies, once the natural history of the 

individual thrombophilic mutations and pathologic mechanisms have been elucidated. 

12 
• 	 Develop a comprehensive database, with epidemiologic information, tissue, biologic fluids, 

and biophysical components, and make it available for future investigations. 

• 	 Establish regional Centers of Excellence comprising of scientists, researchers, and clinicians, 

with special interest in thrombophilias. Such Centers would optimize resources and patient 

care, and, most importantly, would strengthen research. 

Maternal Obesity 

The patients explained the need to understand the fundamental pathologic processes in patients 

with obesity, in order to: 

• 	 Evaluate the impact of the obesity epidemic on pregnancy outcome, and, specifically, 

determine the impact on fetal growth and assessment. 

• 	 Evaluate the role of obesity on stillbirth, given the known association between obesity and 

stillbirth. 

• 	 Evaluate the association between the maternal metabolic syndrome and pregnancy outcome. 

ACTION STEPS: 

1. Continue to participate in the U.S. Department of Health and Humane Services (DHHS) Safe 

Motherhood Group. This Group, which includes the NIH, the DHHS, the Centers for 

Disease Control and Prevention (CDC), the Health Resources and Services Administration 

(HRSA), and the Substance Abuse and Mental Health Services Administration (SAMSA); 

aims to facilitate collaboration across agencies and Institutes on issues including maternal 

morbidity. 

2. Encourage applications in these areas. A large application (more than $500,00) that 

incorporated some of the aims under thrombophilias was accepted for review by the NICHD, 

as a result of a Branch-initiated request. The Branch will seek co-funding from other 

Institutes and agencies to support this and future projects. 

3. Consider the other needs regarding maternal morbidities for yearly Branch initiatives. 

NEONATOLOGY (SPECIFICALLY INTENSIVE CARE, AND LONG-TERM OUTCOME ISSUES) 

In spite of major advances in the management of high-risk newborn infants, substantial progress 

is still needed in reducing both acute and long-term morbidity. Particular concern remains in 

regard to acute issues, such as bacterial and fungal infection, optimizing nutrition of the growing 

preterm infant, medical decision making at the border of viability, and optimizing the intensive 

care environment to foster optimal developmental care. Additional concerns include: the high 

rates of chronic lung disease in survivors of neonatal assisted ventilatory support; concerns about 

high rates of long-term morbidities and deficits in cognitive functions in very low birth weight 

infants; and the unresolved issues concerning the effect of perinatal/neonatal and family 

environment on outcomes during childhood, adolescent and adult lives. 

One major obstacle to understanding the toll of long-term morbidity on the survivors of neonatal 

intensive care is the lack of nation-wide data on outcome. While some investigators have carried 

out excellent studies on outcomes, all such studies have been limited to the researcher’s 

institution, and no national trends on morbidity can be discerned from these studies alone. There 

13 
is a great need for developing a National Registry of Outcomes for the survivors of neonatal 

intensive care. 

AREAS TO INVESTIGATE 

• 	 Research regarding the cause, prevention, and treatment of prematurity could lead to 

improvement in the neurological outcomes for the infant. Basic research in neuroscience and 

translational research should be a priority. The early identification of infants at high risk for 

long-term neurodevelopmental impairment is needed. 

• 	 Basic and translational research on organ development, and on the effects of intensive care 

interventions and prenatal and postnatal influences on development and long-term potential 

for function should be a priority. 

• 	 Basic and translational research in fetal nutrition and gastrointestinal development are key to 

preventing extrauterine growth retardation and malnutrition, and to addressing developmental 

issues in organ development during critical windows of development. 

• 	 Information regarding factors that impact on medical decision making at the limit of 

viability, including factors that relate to maternal health, parental involvement, 

physician/nursing/staff involvement, societal norms, and cost-effective use of therapies, is 

necessary to provide optimum medical care and to improve outcomes. 

• 	 A collaborative effort is needed to developing a comprehensive registry for long-term 

outcomes. The collaboration may include several federal agencies (i.e., the NICHD, CDC, 

the Agency for Healthcare and Research Quality, etc.) and may utilize network databases and 

state health department information. 

ACTION STEPS: 

1. Develop and coordinate a workshop, in collaboration with the AAP, to identify the research 

priorities specific to neonatology. This workshop will occur in late 2003 or 2004. 

2. Consider other areas for investigation under neonatology for yearly Branch initiatives. 

FETAL/NEONATAL BRAIN DEVELOPMENT AND DAMAGE (INCLUDING PRENATAL, PERINATAL, 

NEONATAL, AND INFANT PERIODS) 

Specifically, this discussion addressed the following topics: 

• 	 Neonatal/infant nutrition and the long-term impact on growth and maturation; and 

• 	 Prevention of brain injury in the newborn period, such as from hyperbilirubinemia, 

hypoglycemia, and other metabolic abnormalities in the preterm and term infants. 

AREAS TO INVESTIGATE 

• 	 Interaction of the environment and the genome in developing brain, including molecular, 

cellular, and animal models of injury and repair: 

o Identification of common pathways of injury to developing brain, including metabolic, 

infectious, and xenobiotic agents; 

14 
 

o Genomic factors that render the developing brain resistant and/or susceptible to injury; 

specific complications, including intraventricular hemorrhage, periventricular 

leukomalacia, cerebral palsy, retinopathy, and speech and language disorders are 

potential areas of research to target genomic influences on diseases; 

o Environmental factors which promote plasticity or enhance defect; and 

o Development of strategies to prevent injury and promote neural repair. 

• 	 Translation of the basic science data to the newborn unit and beyond; for example: 

o Collaborative use of the MFMU Network to validate animal models of injury and repair; 

and 

o Development of intervention and prevention trials. 

• 	 Improved methodologies for assessment of normal neurobehavioral development, for 

diagnosis of injury, and for documentation of efficacy of therapies and repair of 

developmental injury applicable in the clinical situation; this effort may entail: 

o Implementation of comprehensive infant follow-up studies as projected for the NCS; 

o Development of behavioral methodologies and probes to evaluate continuities 

and trajectories relevant to long-term outcome; 

o Development of improved fetal imaging strategies (e.g., fetal MRI, fMRI, volumetric 

studies); 

o Development of improved neonatal imaging strategies (MRI, MRS, DTI); and 

o Development of standardized strategies to assess early language abilities. 

• 	 Research involving brain development in the preterm infant for improvement of outcomes, 

including the assessment of optimal developmental care in the NICU. 

ACTION STEP: 

1. Consider the areas above for investigation as yearly Branch initiatives. 

TRAINING FOR THE FUTURE: SCIENTISTS AND PHYSICIAN-SCIENTISTS 

Areas for future emphasis include the following: 

• 	 Increase research exposure, involvement, and interest among medical students, 

undergraduate, and graduate students through support of perinatal research programs. 

• 	 Provide funding to reduce clinical service demands, in exchange for greater research training 

time; ensure liability costs do not necessitate a volume of clinical practice that precludes 

substantive research time; increase levels of funding for research training to compete with 

clinical compensation. 

• 	 Develop programs that will facilitate continuing research by MD, PhD, and other trainees 

who have already been involved in, and wish to continue, the perinatal research track. This 

item is particularly important at the junior faculty stage of career development. 

• 	 Incorporate and fund PhD and Masters of Public Health (MPH) tracks in training. 

• 	 Assure consistent and capable mentoring and rigorous oversight and quality control of 

training programs. 

• 	 Encourage interdisciplinary programs, including reproductive biology, and development of 

graduate studies programs in reproductive biology. 

• 	 Simplify methods for obtaining funding for pre-doctoral and postdoctoral positions. 

15 
• 	 Allow a principal investigator to apply for a pre-doctoral or postdoctoral award without 

having a named candidate. 

• 	 Remove U.S. citizen/permanent resident requirement from training eligibilities. 

• 	 Allow a supplement to R01 grants that allow addition of a training position. 

• 	 Provide postdoctoral grants for salary, supplies, and technical support for which trainees can 

apply during the postdoctoral training period; or consider extension funds to secure faculty 

position. 

• 	 Fund a bridge grant to include salary, supplies, and technical support for which a 

postdoctoral student can apply. 

• 	 Re-establish a starter grant mechanism similar to the R29 to foster development of new 

and/or junior faculty. 

• 	 Increase flexibility of programs such as Women’s Reproductive Health Research (WRHR), 

and establish WRHR-type programs for non-physician scientists in reproductive biology. 

• 	 Expand loan forgiveness programs for physicians and establish loan forgiveness program for 

non-physician scientists. 

Recruitment, training, and retention activities would involve the following items: 

• 	 Recruitment efforts should be emphasized to draw potential candidates into the research 

arena. 

• 	 To influence younger generations of potential scientists, efforts should focus on the depth of 

training and enhancement of candidate pool. 

• 	 The current support provided by the NICHD is valued, but the consensus is that fellows are 

not getting support early or often enough. Can NICHD direct support to medical students, 

residents, and early post-docs by speaking to these audiences? How about to 

undergraduates? 

• 	 More unified training efforts in both fields of maternal-fetal medicine and neonatology are 

crucial. 

• 	 Training needs to enhance the capacity of instructing teachers how to teach. 

• 	 Flexibility in the awards is important. 

• 	 International collaborations could be useful in training. 

• 	 Consider adding a PhD component to the WRHR program, or starting a similar program at 

WRHR sites, to facilitate interaction between PhD and MDs in reproductive sciences. 

• 	 Add flexibility of training to awarded R01 grants. 

• 	 With regard to neonatal training for fellows, increasing the funding mechanisms after the first 

year is critical. It was also suggested that the NIH extend the current program from three to 

four, or perhaps five years. 

ACTION STEPS: 

1. Propose an initiative(s) to increase the availability, scope, flexibility, and length of training in 

perinatology and neonatology. Conceivably a K12 mechanism that specifically focused on 

enhancing training could be used to incorporate many of the recommendations made by the 

workshop participants such as: 

• 	 Increasing research exposure, involvement, and interest among medical students, 

undergraduate, and graduate students; 

16 
 

 

• 	 Developing programs that will facilitate continuing research by MD, PhD, and other 

trainees who have already been involved in, and wish to continue, the perinatal research 

track; 

• 	 Incorporating and funding PhD, MPH, MSCE tracks in training; 

• 	 Encouraging interdisciplinary programs, including reproductive biology, and developing 

graduate studies programs in reproductive biology; 

• 	 Recruiting potential candidates into the research arena; 

• 	 Influencing younger generations of potential scientists, with efforts focusing on the depth 

of training and enhancement of candidate pool; 

• 	 Providing unified training efforts in both fields of maternal-fetal medicine and 

neonatology; 

• 	 Providing training needs to enhance the capacity of instructing the teachers how to teach. 

• 	 Expanding international training collaborations; 

• 	 Facilitating interactions between PhDs and MDs in reproductive sciences; and 

• 	 Increasing the trainee support from three to four, or perhaps five years. 

2. Encourage existing T32 programs to promote their programs to medical students, 

undergraduates, and graduate students. 

3. Promulgate this grant mechanism at society meetings and interaction with investigators. The 

K25 mechanism may not be readily known to the scientific community as a means for 

protecting research and mentoring time. 

4. Encourage institutions and individuals involved in perinatal research to apply for National 

Research Service Awards such as fellowship, training, and career awards. 

5. Continue to be vigilant in monitoring the quality of PPB training grants in terms of 

mentoring and training. 

6. Encourage existing research programs to promote interdisciplinary training, such as the 

Mentored Specialized Clinical Investigation Development Award grants through the NRN 

and MFMU Networks. 

7. Forward several of the recommendations that involve changes to the current NIH policy to 

the director of the Office of Extramural Programs for consideration, including: 

• 	 Increasing the monetary compensation of the K25 grant to compete with clinical
 

compensation;
 

• 	 Allowing a principal investigator to apply for a predoctoral or postdoctoral award without 

having a named candidate; 

• 	 Removing U.S. citizen/permanent resident requirement from training eligibility; 

• 	 Allowing a supplement to R01 grants to allow addition of a training position; 

• 	 Providing postdoctoral grants for salary, supplies, and technical support for which 

trainees can apply during the postdoctoral training period; 

17 
• 	 Funding a bridge grant to include salary, supplies; and technical support for which a 

postdoctoral applicant can apply; 

• 	 Reestablishing a starter grant mechanism similar to the R29 to foster development of new 

and/or junior faculty; and 

• 	 Expanding the loan forgiveness programs for physicians and establishing loan 

forgiveness program for non-physician scientists. 

DEFINE AND IMPROVE THE LINK BETWEEN FETAL, OBSTETRICAL, AND NEONATAL 

INTERVENTION AND INFANT/CHILD OUTCOMES 

• 	 The mechanism/s that underlie fetal growth retardation (FGR) and the development of 

chronic adult disease are not known. 

• 	 Although short-term impact of nutritional and other interventions in the neonate are well 

known, their impact on health during adolescence and adulthood is not known. 

• 	 Prospective studies in humans, using state-of-the-art methods in a carefully identified 

contemporary cohort are required to distinguish the genetic, nutritional, metabolic, and 

hormonal influences during pregnancy that impact fetal growth, and to examine the 

relationship between size-at-birth and adolescent and adult health. 

• 	 Development of sophisticated techniques for animal models, including physiological 

phenotypes and non-invasive methods for physiological data are needed. 

• 	 The physiological mechanisms of early life experiences within socioeconomic disadvantaged 

individuals and their health during childhood, reproductive life, and adulthood need further 

study. 

• 	 The community needs to examine the biological basis of nutritional and pharmaceutical 

interventions, to determine the impact of timing of the intervention (i.e., early or late in 

pregnancy, intrapartum or the neonatal period). 

• 	 The field should support the development of new algorithms to examine outcomes, including 

sensitive techniques to address functions, including functional imaging methods (MRI), 

anthropometric studies (body composition measurements), and other methods to assess 

neurodevelopment early in life. 

• 	 Evaluation of intrauterine genetic environment, including fetal polymorphism and its relation 

to IUGR, preeclampsia, hypertension, and stroke is also needed. 

• 	 More data are needed on infections not related to prematurity that continue to result in 

significant fetal and neonatal morbidity such as hepatitis C, HIV, cytomegalovins, etc. 

• 	 Studies that focus on morbidity due to prematurity, particularly from high bilirubin, 

abnormalities of glucose and calcium metabolism, and from nutritional deficiencies are 

required. 

• 	 Studies to optimize nutritional support for a preterm infant receiving intensive care are 

necessary. 

ACTION STEPS: 

1. Support the Newborn Drug Development Initiative. The goal of this NICHD/FDA project is 

to foster the development of safe and effective drug therapies for pre-term and neonatal 

18 
 

populations. This five-year initiative will initially focus on defining the state-of-the-art and 

determining research priorities for cardiac, neurological, pulmonary diseases, and pain 

control. 

2. Support the RFA: HD-00-010—Cooperative Multicenter NRN. The PPB funded 16 clinical 

centers through this RFA to create multimember clinical programs that investigate the safety 

and efficacy of treatment and management strategies to care for newborn infants, particularly 

programs related to management of low-birth-weight infants. The NRN has the unique 

capability of conducting multicenter clinical trials research in the neonatal population and 

developing high-impact modalities of treatment for newborn infants. Follow up of high-risk 

infants is an integral part of the program for determining long-term outcomes. A Genomics 

Subcommittee was recently created to institute projects related to the impact of genetics on 

health and disease in the NRN. 

3. Support the PAR-02-105: The Fetal Basis of Adult Disease: Role of the Environment. This 

effort is an ongoing PA that may add to improving the link between fetal, obstetric, and 

neonatal outcomes. 

4. Issue the RFA: HD-03-018—Research into Mechanisms of Fetal Growth Restriction. The 

aim of this initiative is to stimulate research into the mechanisms of fetal growth restriction, 

and to gain a better understanding of the factors that regulate fetal growth during pregnancy. 

The target receipt date was July 23, 2003, and the funding plan will be reviewed at the 

January 2004 meeting of the NACHHD Council. 

5. Facilitate interaction between the NRN and the MFMU Network. Having a steering 

committee member from the MFMU present at the NRN meetings, and vice versa, was one 

recommended way to improve interaction. Program officials and program coordinators 

would also be present at both Network meetings to facilitate possible areas of overlap in 

projects. Joint projects could also be developed to maximize assessment of outcome 

variables (e.g., maternal, fetal, neonatal). 

19 
APPENDIX A: PPB SUMMATION FOR 

THE 2003 PLANNING WORKSHOP 

HISTORY OF RFAS 

FISCAL YEAR 1994 TO FISCAL YEAR 2002 

FISCAL YEAR 2002 

RFA-HD-02-025: Research on the Scope and Causes of Stillbirth in the United States 

The purpose of this solicitation was to create a network of clinical research sites with central data 

collection and analysis, which would develop and implement common research protocols to 

study stillbirth (defined as fetal death 20 weeks or greater gestation). According to annual 

national vital statistics, the number of fetal deaths at 20 weeks or greater gestation is similar in 

magnitude to the total number of infant deaths in the United States. Despite this significant and 

persistent burden, stillbirths remain largely unstudied. For at least half of all stillbirths, the cause 

remains undetermined. This RFA sought to create a network of multidisciplinary investigators to 

develop research diagnostic protocols, as well as to build a body of data on the scope and causes 

of stillbirths among varied populations within the United States, while encouraging community 

involvement to obtain an adequate sampling of rural and urban populations and a diverse 

ethnic/racial makeup. The information obtained will aid in future research to improve preventive 

and therapeutic interventions, and to understand the pathologic mechanisms leading to fetal 

death. 

RFA-HD-02-008: Development of Community Child Health Research 

The NICHD invited cooperative agreement applications for the development of a communitylinked collaboration to investigate disparities in maternal and child health. The purpose of the 

solicitation was to support community/research institution partnerships that would work together 

over a two and one-half year span. The partners planned a multi-site, multi-level study to 

examine how community, family, and individual level influences interact with biological 

influences, to result in health disparities in pregnancy outcome and infant and early childhood 

mortality and morbidity. The long-term goals were to decrease fetal and infant mortality and 

improve child health in minority urban and rural communities. 

FISCAL YEAR 2001 

RFA-HD-01-005: Health Disparity in Preterm Birth: The Role of Infectious and 

Inflammatory Processes 

This RFA aimed to determine the role of infectious and inflammatory processes in preterm birth 

and adverse neonatal outcomes in different ethnic populations. The research proposed in 

response to this solicitation involved multidisciplinary investigations to clarify the potential role 

of infectious diseases and the associated immune response as a cause of early preterm birth and 

fetal and neonatal morbidity. 

Appendix A-1 
FISCAL YEAR 2000 

RFA-HD-00-010: Cooperative Multicenter NRN 

The NICHD invited applications from investigators willing to participate, under a cooperative 

agreement (U10), in an ongoing multicenter clinical program designed to investigate the safety 

and efficacy of treatment and management strategies to care for newborn infants, particularly 

those related to management of low birth weight infants. The program sought to facilitate 

evaluation of these strategies by establishing a network of academic centers that, by rigorous 

patient evaluation using common protocols, studied the required numbers of patients and 

provided answers more rapidly than individual centers acting alone. The NICHD program staff 

assisted the principal investigators of the NRN and its Advisory Board in identifying research 

topics of high priority, and in designing and implementing protocols appropriate to the 

evaluation of optimal management in these areas. 

RFA-HD-00-009: Cooperative Multicenter MFMU Network 

The NICHD invited applications from investigators willing to participate, under a cooperative 

agreement (U10), in an ongoing multicenter clinical program designed to investigate problems in 

clinical obstetrics, particularly those related to prevention of low birth weight, prematurity, and 

medical problems of pregnancy. This program sought to facilitate resolution of these problems 

by establishing a network of academic centers that, by rigorous patient evaluation using common 

protocols, studied the required numbers of patients and provided answers more rapidly than 

individual centers acting alone. The NICHD program staff assisted the principal investigators of 

the MFMUs and the Advisory Board in identifying research topics of high priority, and in 

designing and implementing protocols appropriate to the evaluation of optimum management in 

these areas. 

FISCAL YEAR 1997 

RFA-HD-97-010: Data Coordinating Center (DCC) for the Cooperative Multicenter NRN 

The NICHD supported clinical research in neonatal medicine through its ongoing 14-center NRN 

to do clinical research investigating the safety and efficacy of treatment and management 

strategies to care for newborn infants, particularly those of low birth weight. The Network, 

funded by cooperative agreements, included a DCC that provided statistical expertise, data 

management, and analysis for Network trials and studies. The DCC had served the NRN since 

the Network’s inception; support for this DCC continued through March 31, 1998. NICHD 

invited all potential applicants to apply for the cooperative agreement to participate as the DCC 

for the NICHD NRN. The successful applicant is now responsible for completing ongoing trials 

and studies and initiating new research in neonatology and perinatology. 

RFA-HD-97-009: DCC for the Maternal-Fetal Research Network 

The NICHD fostered its strong and ongoing interest in clinical research in maternal-fetal 

medicine by establishing the MFMU Network in 1986. Support of the Network has continued 

until the present time, with recompetition of the clinical centers in 1991, and again in 1996. At 

the time of this RFA, the Network consisted of 13 clinical centers, a single data coordinating 

center independent of any of the clinical centers, and NICHD program staff. The Network DCC 

Appendix A-2 
 

was supported with a cooperative agreement. The incumbent grantee at this time had served the 

Network since the Network’s inception, providing statistical consultation, data management, and 

data analysis, in addition to various logistical services required in the multicenter research 

program of the Network. The competitive segment for the initial DCC ended March 31, 1998. 

The NICHD continued support of the DCC for five years to permit completion of ongoing 

studies and initiation of several new randomized clinical trials and other studies in obstetrics. 

The NICHD did not limit the competition to the incumbent grant for the DCC, but invited other 

applications as well. 

FISCAL YEAR 1995 

RFA-HD-95-009: Perinatal Emphasis Research Centers (PERC) 

The NICHD invited applications from investigators to develop multidisciplinary research efforts 

that would advance knowledge about diseases and disorders of pregnancy and infancy, with the 

aim of reducing infant morbidity and mortality in rural populations. The resulting grant was part 

of the PERC program. These centers were intended to support hypothesis-testing research 

efforts, not service or demonstration projects. PERCs were organized around problem/need 

themes and were established where research could be coordinated within existing programs of 

health care to ensure the rapid assimilation of new scientific knowledge into health care delivery. 

PERCs active when this RFA was issued addressed issues in high-risk pregnancies (e.g., 

diabetes, hypertension), prevention of prematurity, fetal hypoxia, IUGR, and infant sleep 

physiology. The PERC was to work closely with the NICHD in participating in the PERC 

network, and in carrying out its objectives in a manner consistent with NICHD goals and 

missions. 

RFA-HD-95-007: Cooperative Multicenter MFMU Network 

The NICHD invited applications from investigators willing to participate, under a cooperative 

agreement (U10), in an ongoing multicenter clinical program designed to investigate problems in 

clinical obstetrics, particularly those related to prevention of low birth weight. The program 

aimed to facilitate resolution of these problems by establishing a network of academic centers 

that, by rigorous patient evaluation using common protocols, studied the required numbers of 

patients and provided answers more rapidly than individual centers acting alone. The NICHD 

program staff assisted the principal investigators of the MFMUs and the Advisory Board in 

identifying research topics of high priority, and in designing and implementing protocols 

appropriate to the evaluation of optimum management in these areas. 

RFA-HD-95-006: Cooperative Multicenter NRN 

The NICHD invited applications from investigators willing to participate, under a cooperative 

agreement (U10), in an ongoing multicenter clinical program designed to investigate the safety 

and efficacy of treatment and management strategies to care for newborn infants, particularly 

those related to management of low birth weight infants. The program sought to facilitate 

evaluation of these strategies by establishing a network of academic centers that, by rigorous 

patient evaluation using common protocols, studied the required numbers of patients and 

provided answers more rapidly than individual centers acting alone. The NICHD program staff 

assisted the principal investigators of the NRN and its Advisory Board in identifying research 

Appendix A-3 
 

topics of high priority, and in designing and implementing protocols appropriate to the 

evaluation of optimal management in these areas. 

FISCAL YEAR 1994 

RFA-HD-94-013: PERC Program 

The NICHD invited applications from existing members of the PERC program (competitive 

continuation applications), and from prospective members (new applications) with the objective 

of encouraging investigators to develop multidisciplinary research efforts that would advance 

knowledge about diseases and disorders of pregnancy and infancy, and about special issues 

relevant to rural populations. These grants supported hypothesis-testing research efforts, not 

service or demonstration projects. PERCs were organized around problem/need themes and 

were established where research could be coordinated within existing programs of health care to 

ensure the rapid assimilation of new scientific knowledge into health care delivery. PERCs 

active at the time this RFA was issued addressed issues in high-risk pregnancies (e.g., diabetes, 

hypertension), prevention of prematurity, fetal hypoxia, IUGR, and infant sleep physiology. 

PERC centers worked closely with the NICHD in participating in the PERC network, and in 

carrying out its objectives in a manner consistent with NICHD goals and missions. 

RFA-HD-94-011: Diagnostic Methods to Assess Neurologic Integrity in Fetus/Neonate 

This RFA sought to stimulate research on the development of effective technologies to assess the 

integrity and function of the developing brain in human fetuses and newborns. The long-term 

goal of this research was to identify newborns with brain dysfunction due to early, repetitive, or 

chronic intrauterine central nervous system influences/insults, which may result in SIDS and 

developmental disabilities including cerebral palsy. Postnatally acquired and acute perinatal 

deficits were not within the scope of this RFA. The NICHD and the National Institute of 

Neurological Disorders and Stroke (NINDS) invited applications for studies in animals and/or 

humans that: (1) Elucidated the physiological parameters that would serve as reliable markers of 

central nervous system integrity/pathology; and (2) Explored the development of 

technologies/clinical tools that would identify infants who had, or were at risk for, abnormal 

neurologic development or sudden death from prenatal insults. 

Appendix A-4 
PPB-RELATED WORKSHOPS AND CONFERENCES, 

FISCAL YEAR 1991 TO PRESENT
 

• 	 The NIH Workshop on Defining the Content of Follow-Up Care, June 19-20, 2002, Bethesda, 

Maryland 

• 	 SIDS Pathogenesis in the New Millennium, November 29-30, 2000, Rockville, Maryland 

• 	 Prenatal Alcohol Exposure and Risk for Adverse Pregnancy Outcomes and SIDS, August 6-

7, 2001, Bethesda, Maryland 

• 	 The Role of Genetics in the Health Disparity of Premature Birth and Low Birth Weight 

Infants, May 4, 2001, Rockville, Maryland 

• 	 Setting a Research Agenda for Stillbirth, March 26, 2001, Rockville, Maryland 

• 	 Nausea and Vomiting during Pregnancy, September 20-21, 2000, Bethesda, Maryland 

• 	 Maternal-Fetal Surgery Conference, July 16-18, 2000, Bethesda, Maryland 

• 	 From Bronchopulmonary Dysplasia (BPD) to Chronic Lung Disease (CLD): The Evolution 

of a New Disease, Chronic Lung Disease Workshop, May 31-June 2, 2000, Rockville, 

Maryland 

• 	 Fetal Origins of Adult Disease, September 2-3, 1999, Bethesda, Maryland 

• 	 Workshop of Sleep Needs, Patterns, and Difficulties of Adolescents, Forum on Adolescence, 

Board on Children, Youth, and Families, National Academy of Sciences, September 22, 

1999, Washington, DC 

• 	 Endothelial-Derived Vasoactive Substances and Free Radicals in Perinatal Biology, May 6-

8, 1999, Alexandria, Virginia 

• 	 Epidural Conference, February 19-20, 1999, Bethesda, Maryland 

• 	 Bed Coverings for Infants: What is Safe? December 8, 1998, Bethesda, Maryland 

• 	 Colloquium on Perinatal Endocrinology, September 20-22, 1998, Nancy, France 

• 	 SIDS Pathogenesis: Approaches to Identifying High-Risk Infants, September 13, 1998, Lake 

Arrowhead, California 

• 	 Postpartum Hemorrhage and Placenta Accreta Conference, February 11-12, 1998, Detroit, 

Michigan 

• 	 Mi in a kin towani ewaktonji kte ni: “I will never forget my child,” September 17-19, 1997, 

Rapid City, South Dakota 

• 	 Placenta and Child’s Brain, July 18-19, 1996, Bethesda, Maryland 

• 	 Infant Sleep Environment and SIDS Risk, January 9-10, 1997, Bethesda, Maryland 

• 	 4th SIDS International Conference, June 23-26, 1996, Bethesda, Maryland 

• 	 Pregnant Women in the Workplace: Sound and Vibration Exposure, February 22-23, 1996, 

Gainesville, Florida 

• 	 Electronic Fetal Heart Rate Monitoring: Research Guidelines for Interpretation, May 15-

16, 1995, Bethesda, Maryland 

• 	 Fetal Growth: Its Regulation and Disorders, April 18-19, 1995, Providence, Rhode Island 

• 	 Early Discharge and Neonatal Hyperbilirubinemia, March 28, 1995, Rockville, Maryland 

• 	 Nitric Oxide (NO) in the Perinatal Period, December 7, 1994, Rockville, Maryland 

• 	 Placental Growth and Function, July 7-8, 1994, Bethesda Maryland 

• 	 Neonatal Pain: Physiology and Management, June 3-4, 1994, Philadelphia, Pennsylvania 

Appendix A-5 
• 	 Animal Models of SIDS, June 2-3, 1994, Bethesda, Maryland 

• 	 Infant Sleep Position and SIDS Risk, January 13-14, 1994, Bethesda, Maryland 

• 	 NIH Consensus Development Conference on Antenatal Steroid Treatment, February 28-

March 2, 1994, Bethesda, Maryland 

• 	 Routine Antenatal Diagnostic Imaging with Ultrasound (RADIUS), September 23, 1993, 

National Press Club, Washington, DC 

• 	 Acute Perinatal Asphyxia, August 30-31, 1993 

• 	 Research Definition of Birth Asphyxia, April 2-3, 1992, Chevy Chase, Maryland 

• 	 Sleep Position and SIDS Risk, March 30, 1992, Bethesda, Maryland 

• 	 The Global Strategy Meeting on SIDS, February 17-18, 1992, Sydney, Australia 

• 	 Fetal Therapy: Current Status and Future Prospects, October 31-November 1, 1991, 

Bethesda, Maryland 

• 	 Roles of Endothelial-Derived Vasoactive Factors in Perinatal Biology, August 17-19, 1991, 

San Diego, California 

Appendix A-6 
PPB ONGOING ACTIVITIES 

GRANTS PORTFOLIO 

In the last five years (fiscal years 1997-2001) a total of 11,450 competitive grant applications 

were received by the NICHD. 1,075 or 9.4 percent were assigned to the PPB. The largest 

majority of the applications were R01s, which represented 45.4 percent of all assigned 

applications. A total of 304 assigned applications were awarded, representing a success rate of 

28.8 percent; this rate is similar to the overall NICHD success rate of 29.3 percent. Overall 

competitive renewals had a much higher success rate than new applications (48.4 percent vs. 

23.2 percent). The number of awards broken down by general or specific mechanism type and 

their relative percentage are listed below. 

MECHANISM TYPE NUMBER RELATIVE 

PERCENTAGE (%) 

Fellowship Awards (F series) 12 3.9 

Career Awards (K series) 20 6.6 

Program Projects (P01) 10 3.3 

Research Projects (R01) 138 45.4 

Small Research Projects (R03) 40 13.1 

Conferences Grants (R13) 4 1.3 

Academic Enhancement Grants (R15) 2 0.6 

Exploratory/development Grants (R21) 2 0.6 

FIRST Awards (R29) 6 2.0 

MERIT Awards (R37) 2 0.6 

STTR/SBIR Grants (R41, R43, R44) 21 6.9 

Institutional Training Grants (T32) 9 2.9 

Cooperative Agreements (U series) 38 12.5 

The success rates varied significantly based on a particular mechanism type. For example, R01s 

had the lowest success rate (23.9 percent), while P01 applications had the highest success rate 

(55.5 percent). 

Appendix A-7 
 

The success rates for selected mechanisms are tabulated below. 

MECHANISM TOTAL AWARDED SUCCESS RATE (%) 

F31 & F32 35 12 34.3 

K08 14 6 42.9 

K23 8 4 50.0 

K24 9 5 55.6 

P01 18 10 55.5 

R01 576 138 23.9 

R03 156 40 25.6 

T32 18 8 44.4 

PROGRAM PROJECT (P01) DESCRIPTIONS 

Initiation of Human Labor: Prevention of Prematurity 

PI: MENDELSON, CAROLE; 5 P01 HD011149-25 

The long-range goals of this program-project are to: 1) Define the functional phenotypes of the 

uterus and the cellular changes that account for the differences in these phenotypes during 

pregnancy/parturition; 2) Evaluate the mechanisms by which the transitions in the uterine 

phenotypes are effected at the cellular/gene level; 3) Define the ontogeny/regulation of 

interstitial collagen formation in amnion and the impact of selected risk factors for pre-term, 

premature rupture of the fetal membranes (PT-PROM) on pro-collagen synthesis/processing; and 

4) Define the cellular interactions in the fetal membranes that contribute to the tensile strength of 

this tissue and to liability for PT-PROM. 

Hypoxia in Development: Injury and Adaptation Mechanisms 

PI: HADDAD, GABRIEL G; 5 P01 HD032573-05 

One main consequence of numerous cardiovascular and respiratory disorders, whether in the 

neonate, older infant or at a later more mature age, is tissue O2 deprivation. Our overall program 

hypothesis is that O2 deprivation leads to alterations in cytosolic, membrane and nuclear events 

that form the underlying basis for cellular adaptation, sublethal injury, or cell death. The extent 

of these alterations depends on many factors including age, type of cell, its endowments in 

excitable cells (e.g., neurons) and non-excitable cells (e.g., glia, renal tubular epithelium), 

interactions between cells, and severity and chronicity of hypoxia. The central aims of this 

program will therefore be to: 1) Define the nature of the response to hypoxia in neurons, glia, 

and renal tubular epithelium in mature and immature cells; and 2) Delineate the underlying 

mechanisms at the cellular and molecular levels. 

Metabolic Regulation of Fetal Growth 

PI: HAY, WILLIAM W; 5 P01 HD020761-14 

The focus of this program grant is metabolic regulation of fetal growth, emphasizing experiments 

in comparative reproductive and developmental physiology to determine pathogenesis and 

Appendix A-8 
metabolic consequences of fetal growth restriction (FGR). FGR affects a large number of human 

pregnancies and is responsible for increased fetal, neonatal, and adult morbidity and mortality. 

Three projects will address the following experimental aims and hypotheses: 1) In pregnant 

sheep, deprivation of glucose and amino acid supply to the fetus produces fetal insulin deficiency 

and insulin resistance, resulting in FGR and a limitation to nutrient therapy; 2) In pregnant sheep, 

placental insufficiency from abnormal growth and function produces severe FGR and limitation 

to nutrient therapy; 3) Clinical studies in normal and FGR pregnancies are directed at fetal 

surveillance and fetal and placental amino acid metabolism using techniques comparable to those 

in the animal models; these studies also provide measures of placental and fetal responses to 

nutrient therapy. 

Perinatal Studies of Disorders of Fetal Metabolism 

PI: KALHAN, SATISH C; 5 P01 HD011089-25 

The long-range objective of the PERC is to explore the influence of maternal metabolic 

environment and its perturbations on maternal, fetal, and newborn metabolism and growth. 

Because fetal and neonatal growth, differentiation, and organization can be affected by both 

environmental and genetic programming, additional goals of these studies are to identify the 

influences of these factors, metabolic or genetic, on key regulatory events in the newborn and to 

explore the mechanism(s) involved. 

Ventral Medulla and the Sudden Infant Death Syndrome 

PI: KINNEY, HANNAH C; 5 P01 HD036379-05 

The overall hypothesis is that SIDS, or a subset of SIDS, is due to developmental abnormalities 

of the ventral medulla, which interferes with normal protective cardiorespiratory responses to 

potentially life-threatening, but often-occurring events during sleep, such as hypoxia, 

hypercapnia, and apnea. We recently reported neurotransmitter receptor binding deficiencies in 

the arcuate nucleus of SIDS victims; this region contains ventral medullary surface neurons that 

are considered homologous to neurons located in similar areas in cats’ brains, which are 

necessary for the protective responses to hypercapnia and asphyxia. We propose a triple-risk 

model of SIDS, in which an infant dies of SIDS only if he/she possesses: 1) An underlying 

vulnerability (e.g., an abnormality in the ventral medulla); 2) A critical period in the 

development of homeostatic control (i.e., early infancy); and 3) An exogenous stressor (e.g., 

positional asphyxia). 

Fetal and Adult Adaptations to Long-Term Hypoxemia 

PI: LONGO, LAWRENCE D; 5 P01 HD031226-08 

The overall theme of this proposal is to explore the fundamental mechanisms whereby the fetus 

and adult adapt to long-term, high-altitude hypoxemia. In addition, we will examine several of 

these mechanisms in association with development of the fetus into an adult. This proposal is a 

broadly based, multidisciplinary program that uses physiologic, pharmacologic, biochemical, and 

molecular approaches to explore adaptations of the cardiovascular system, the cerebral blood 

vessels, uterine vessels, the fetal hypothalamic-pituitary-adrenal axis, and the myometrium in 

response to long-term hypoxemia. 

Appendix A-9 
Placental Angiogenic Factors and Uterine Artery Endothelial Cells (UAEC) and Placental 

Artery Endothelial Cells (PAEC) Nitric Oxide Production 

PI: MAGNESS, RONALD R; 5 P01 HD038843-02 

The body of a pregnant woman faces the unique physiological challenge of reorganizing the 

maternal uterine vascular network to accommodate the metabolic demands of the feto-placental 

and uteroplacental blood flow by angiogenic growth factors (with particular focus on bFGF and 

VEGF), and by the vascular regulator, nitric oxide. This grant has two overall specific aims: 1) 

To establish molecular and cellular models of the regulation of the vascular endothelium at the 

maternal-fetal interface; and 2) To investigate these basic mechanisms in clinical settings where 

changes in placental regulator factors are hypothesized to control vascular adaptation to 

pregnancy. Data from these studies will further our understanding of the basic control of 

placental and uterine angiogenesis and mechanisms contributing to fetal pathophysiology in 

diabetes, in ethanol exposure, as well as in preeclampsia and IUGR. 

Fetal Neuroendocrinology, Parturition, and the Myometrium 

PI: NATHANIELSZ, PETER W; 5 P01 HD021350-14 

The focus is on fetal neuroendocrine maturation and parturition. The hypotheses are related to 

fetal endocrinology, placental and fetal membranes, and decidual and myometrial regulation. In 

parallel experiments the present proposal will continue to utilize chronically instrumented 

pregnant sheep and non-human primates. The work is unique in several aspects, particularly in 

focused efforts to correlate and compare work in ovine and non-human primate pregnancy. 

Biological Basis for Perinatal Transition 

PI: PADBURY, JAMES F; 5 P01 HD011343-22 

This program project will focus on the development of the mammalian fetus and its transition to 

postnatal life to define how these events impact fetal and newborn development. We will study 

the following as model systems: 1) The factors that regulate proliferation and differentiation of 

developing the trophoblast factors, which regulate the growth and proliferation of fetal and 

neonatal hepatocytes; 2) Unique mechanisms for hormonal regulation of gene transcription 

between fetal and adult life; and 3) The role of glucocorticoids in the regulation of critical 

aspects of brain maturation. 

Preeclampsia: Mechanisms and Post-Pregnancy Implications 

PI: ROBERTS, JAMES M; 2 P01 HD030367-09 

In the past five years, we have characterized and identified mechanisms of abnormal trophoblast 

invasion in preeclampsia, which supports the involvement of oxidative stress in the linkage of 

abnormal implantation to the systemic syndrome. This program extends the studies to include 

detailed mechanistic examination and tests the long-range significance to mother and baby. 

Abnormal implantation and reduced placental perfusion are insufficient to explain the syndrome. 

Apparently, similar changes are present in pregnancies complicated by IUGR, and in one-third of 

preterm pregnancies. 

Biology at the Maternal-Fetal Interface 

PI: SOARES, MICHAEL J; 1 P01 HD039878-01A1 

The overall goal of the program project is to understand regulatory processes that lead to the 

development of therapeutic strategies for the purpose of improving the quality and success of 

Appendix A-10 
 

pregnancy. The program project grant studies uterine decidual cell-signaling mechanisms 

involved in the regulation of maternal uterine inflammatory cells, multi-drug resistant efflux 

systems used by the placenta to protect the fetus, and the impact of soluble placental major 

histocompatibility complex proteins on maternal inflammatory and immune cell responses. 

Response to Hypoxia and Nutrition during Development 

PI: STARK, RAYMOND I; 5 P01 HD013063-23 

The central theme of this program is based on the axiom that, during early stages of 

development, organisms are uniquely vulnerable to environmental challenges, which constrain 

the physiological and behavioral phenotypes that are manifest throughout the rest of the lifespan 

of the organism. Understanding the mechanisms that confer risk or resistance to these challenges 

is the fundamental goal of these projects. 

Maternofetal Signaling and Life-Long Consequences 

PI: THORNBURG, KENT L; 2 P01 HD034430-06 

The program is designed to test the umbrella hypothesis that stressors of the fetal cardiovascular 

and renal systems irreversibly alter early gene expression patterns and, thereby, predispose the 

offspring for disease in later life. 

INSTITUTIONAL TRAINING GRANT (T32) DESCRIPTIONS 

Physiology of Reproduction 

PI: CARR, BRUCE; 5 T32 HD007190-24 

This program has been in place for several decades at the Cecil H. and Ida Green Center for 

Reproductive Biology Sciences. Investigators from the departments of obstetrics and 

gynecology, pediatrics, biochemistry, cell biology-neuroscience, microbiology, and physiology 

participate in this training program. Basic scientists (e.g., biochemists-molecular biologists, 

physiologists, immunologists, microbiologists, cell biologists, and pharmacologists) and clinical 

scientists (e.g., obstetricians and gynecologists specializing in endocrinology, oncology, and 

maternal-fetal medicine, and pediatricians specializing in perinatal medicine) work side-by-side 

in contiguous, well-equipped, modern laboratory spaces. Over the years, this program has 

maintained a similar number of MD and PhD postdoctoral trainees, who also work side-by-side. 

Each of the research faculty spends more than 85 percent of their time in the conduct of research, 

research-related endeavors (i.e., preparations of grant applications, manuscript and abstract 

preparation), and other research training activities. Each of the trainees is supervised by one or 

more of the senior faculty; the primary or secondary mentor of the MD trainees is a senior basic 

scientist in all cases. 

Mechanisms of Disease in the Newborn Human Infant 

PI: COLE, F. S; 1 T32 HD041925-01 

This project is a recent institutional research training grant within the department of pediatrics at 

the Washington University School of Medicine. The long-term objective is to foster the growth 

and development of physician-scientists in newborn medicine and developmental biology. The 

aim of this program is to utilize the unique resources of the institution, including the 

developmental biology group in the department of pediatrics and the developmental biology 

Appendix A-11 
program in the division of biology and biomedical sciences, for a training program with a 

participating faculty of pediatricians and basic scientists, who share common interests and 

frequent investigative and scholarly interactions. The program provides funding for an initial 

two years of laboratory investigation and emphasizes the application of cell and molecular 

biologic approaches to address fundamental issues in the most important problems of newborn 

infants. The substantive collaboration of established pediatric physician-scientists and basic 

investigators pursuing questions in developmental biology provides a unique opportunity for the 

training of selected individuals in the application of fundamental experimental methods to the 

treatment and prevention of diseases of the newborn infant. As such, the program provides new 

pediatric scholars to lead the way for future advances in this important area of child health. 

Training in Neonatal and Developmental Diseases 

PI: DEVASKAR, SHERIN U; 5 T32 HD007549-02 

This project is a new training program in neonatal and developmental diseases, which was 

established within University of California, San Francisco, School of Medicine’s existing 

neonatology program. This five-year program is geared toward training post resident 

neonatology fellows (MD and MD/PhD) with the idea of developing independent and productive 

physician-scientists, and of training of postdoctoral PhD fellows in the areas of neonatal and 

developmental diseases. This program strives to attract individuals with a commitment to 

academic medicine, and to provide a scientifically rich environment where MD and PhD postresident and postdoctoral trainees are afforded the opportunity of training side-by-side in 

established laboratories with expertise in developmental biology, genetics, molecular biology, 

and cell biology. The program is structured to include clinical neonatology training (as per the 

requirements spelled out by the American Board of Pediatrics), the bulk of which occurs during 

the first year, the second and third years are devoted to training in laboratory-based research for 

the post-residency fellows. Following the initial training period, and after rigorous evaluation, 

the post-residency fellows progress into the postdoctoral portion of their fellowship, which 

consists of two additional years (four and five). After this time, they are expected to obtain 

independent funding for their research programs. 

Research in Perinatal Medicine 

PI: GROSS, IAN; 5 T32 HD007094-26 

This program offers an intensive laboratory experience in experimental biology and structured 

training in clinical research and epidemiology. The goal of this postdoctoral program, since its 

inception in 1977, has been to provide pediatricians and PhD graduates who are interested in 

developmental medicine with an environment that will permit them to gain the skills necessary 

for a successful academic career. Both clinical and basic science departments at Yale University 

are involved with this program including pediatrics, genetics, molecular biophysics and 

biochemistry, cell biology, pathology, and epidemiology. Trainees who elect to do clinical 

research are required to take courses in designing clinical trials, in statistics, and in 

epidemiology. They may also become candidates for the MPH degree at the Yale School of 

Public Health. Trainees are appointed for three years and must be committed to pursuing a 

career in academic medicine. MD trainees complete their residency prior to entering the 

program. PhD graduates will have a demonstrated interest in developmental biology. This 

program has been functioning successfully for more than 23 years. Graduates hold academic 

positions throughout the United States, and many have become leaders in perinatal medicine. 

Appendix A-12 
Training in Developmental and Perinatal Endocrinology 

PI: HANDWERGER, STUART; 5 T32 HD007463-09 

This program provides training in developmental and perinatal endocrinology at the University 

of Cincinnati College of Medicine and the Children’s Hospital Medical Center in Cincinnati. 

The faculty advisors consist of 20 established investigators with major interests in developmental 

and perinatal endocrinology from three clinical and three basic science departments. The 

research themes include: the regulation of trophoblast differentiation and function in the 

regulation of decidualization; the role of growth factors in mammalian development; the 

molecular biology of the growth hormone, prolactin, and placental lactogen gene family; and 

mechanisms of hormone action. Pre-doctoral trainees obtain their PhD degrees in the department 

of cell biology, neurobiology, and anatomy, in the department of molecular and cellular 

physiology, in the department of molecular genetics, biochemistry, and microbiology, and in the 

program in developmental biology of the University of Cincinnati College of Medicine. 

Postdoctoral trainees must have the MD or PhD degree, or both. 

Training in Perinatal Medicine 

PI: WILLIAM HAY; T32-HD007186-23 

The purpose of this training program is to provide basic and clinical postdoctoral research 

training for pediatric (neonatology) and obstetric (maternal-fetal medicine) physicians and basic 

scientists who have completed residency training or hold a PhD degree. The research training, in 

perinatal/developmental physiology and biology, lasts for three years in preparation for academic 

careers in reproductive medicine within departments of pediatrics and obstetrics and gynecology. 

During the first year, which is largely clinical and is not funded by this grant, trainees work with 

faculty advisors to select basic research projects and mentors. Three areas of research excellence 

are offered: 1) Fetal nutritional metabolism and growth; 2) Placental development and function; 

and 3) Vascular development and regulation of blood flow. During all three years of training, 

trainees attend seminars that review: intrauterine development and fetal, maternal, and neonatal 

physiology courses in the graduate school, as well as those dealing with cell culture, cell and 

molecular biology, isotope applications, biostatistics, microcomputer applications to data 

processing, statistics, graphics, bioethics, and ethical conduct of research. The second and third 

years are devoted to the completion of the basic research projects begun in the first year and to 

expansion into new areas of research that includes new research techniques. Trainees plan and 

conduct their research projects independently, but with full faculty guidance. 

Neonatal Training Grant 

PI: JOBE, ALAN H; 5 T32 HD007541-02 

This program provides training for third and fourth year MD neonatology fellows to develop 

sufficient research experience to initiate careers in academic neonatology. This training program 

supplements the clinical neonatology fellowship at Children’s Hospital Medical Center. The 

program supports only those select fellows who demonstrate real research potential and 

motivation after the first two years of fellowship. The research training is structured to provide a 

mentored experience, with the fellow-in-training working with a senior mentor and often with an 

associate mentor. All mentors are researchers who work as a large collaborative group and focus 

on the common research themes of lung development and lung injury. The group uses state-ofthe-art technology to explore questions in lung biology that range from molecular genetics and 

transgenic models to lung physiology. The lung research is supplemented by clinical research 

Appendix A-13 
 

supported by the NICHD’s NRN. The goal for this training grant is to support only research 

training for neonatologists who have the potential and motivation to become successful researchoriented academic neonatologists. 

Graduate Research Training in Perinatal Biology 

PI: KITTERMAN, JOSEPH; T32-HD007162-23 

This program is designed to train physicians to conduct fundamental research in perinatal 

biology, and to integrate advances in basic and clinical research with clinical care for improving 

treatment of pregnant women, their fetuses, and newborn infants. The faculty (e.g., basic 

scientists, clinical researchers, and health policy researchers) conducts research in cardiovascular 

biology, lung biology, neurobiology, perinatal epidemiology, and reproductive biology. 

Disciplines employed include cellular and molecular biology, integrative physiology, clinical 

investigation, and health policy research. Trainees enter the program after completing a 

residency in obstetrics and gynecology or in pediatrics and are appointed for three to four years, 

of which, at least two are devoted to research. Trainees also complete clinical training in an 

accredited fellowship program in maternal-fetal medicine or neonatal-perinatal medicine. 

Perinatal Biology Training Grant 

PI: PADBURY, JAMES F; 5 T32 HD007511-04 

The grant at Women & Infants’ Hospital is an interdisciplinary program to prepare neonatal, 

maternal-fetal medicine, and post-doctoral fellows who are recognized early in training to have 

great potential for an academic career. The faculty are in the Brown University School of 

Medicine and Biology. The emphasis includes understanding cell-to-cell signaling and signal 

transduction pathways, mechanisms of morphogenesis and differentiation, and the role of 

transcription factors and transcription regulation in development and the control of cell division 

and cell death during organ formation. The clinical relevance of these areas of investigation is 

borne out by their likelihood to identify important mechanisms for: the regulation of fetal 

growth and of the growth and differentiation of major organ systems and the developing oocyte; 

the role of transcription factors in development; and the mechanisms for brain development and 

the prevention of brain injury during the transition from fetal to newborn life. 

Developmental and Neonatal Biology Training Program 

PI: STEVENSON, DAVID K; 5 T32 HD007249-19 

The aim of this training program is to provide educational opportunities for young people to 

achieve excellence in clinical newborn medicine, scholarly basic science and clinical research, 

and medical education. The program is designed to encourage the cross-fertilization of ideas that 

will enrich the ideas of both the basic- and the clinically oriented scientist. For those trainees 

interested in clinical training, the program offers intensive clinical experiences with newborns, 

including the opportunity for clinical investigation, as well as the opportunity for advanced study 

in developmental biology, especially at the cellular and molecular levels. 

Appendix A-14 
MULTICENTER TRIAL DESCRIPTIONS 

The NICHD Maternal Fetal Medicine Units Network 

The NICHD created the MFMU Network in 1986 to focus on clinical questions in maternal fetal 

medicine and obstetrics, particularly with respect to the continuing problem of preterm birth. 

Operating under cooperative agreements, the current Network comprises 14 university-based 

clinical centers and a DCC. More than 24 randomized clinical trials, cohort studies, and 

registries have been completed or are in progress through the MFMU Network. MFMU Web 

site is http://www.bsc.gwu.edu/mfmu/. 

The Neonatal Research Network 

The NICHD’s NRN was established in 1986 to improve the care and outcome of neonates, 

especially VLBW infants. Operating under competitive cooperative agreements, the NRN 

includes investigators from 16 university-based clinical centers, a Network DCC, and NICHD 

program staff. The Network has addressed the major problem areas in neonatology with 

randomized controlled trials, studies, and outcomes research in the prevention and treatment of 

sepsis, intraventricular hemorrhage, CLD, pulmonary hypertension, anemia, acute perinatal 

asphyxia, and nutrition. For more information about the NRN, please go to 

http://neonatal.rti.org. 

Fetal Surgery Network 

The NICHD created the Fetal Surgery Network in 2001 to evaluate in utero fetal surgery as a 

treatment for antenatally diagnosed spina bifida in a randomized clinical trial. The objective of 

this program is to establish a network of three academic centers as Fetal Surgery Units, as well as 

a Data and Study Coordinating Center that, by rigorous patient evaluation using a common 

protocol, can study the required numbers of patients and can provide a valid answer more rapidly 

than individual centers acting alone. 

Vaginal Ultrasound Cerclage Trial 

PI: OWEN, JOHN MD; 1 U01 HD039939-01A1 

This trial is a multicenter, randomized clinical trial designed to determine the efficacy of 

cerclage (a purse-string suture placed around the uterine cervix) for the prevention of 

spontaneous preterm birth prior to 35 weeks’ gestation. Women at significant risk for recurrent 

spontaneous preterm birth (i.e., those with a prior spontaneous birth at 17-32 weeks’ gestation), 

and those who have an increased risk based on mid-trimester ultrasonographic findings of a 

cervical length <25mm will be studied at seven centers. This topic is one of the most 

controversial issues in obstetrics/maternal-fetal medicine at present. Prior studies have 

demonstrated that the presence of a short cervix significantly increases the risk of preterm 

delivery; however, there is no consensus or scientific evidence on the proper clinical 

management. This trial will provide significant evidence for the specialty, for women, and for 

their pregnancies. 

Twin-Twin Transfusion Syndrome (TTTS) Trial 

PI: CROMBLEHOLME, TIM MD; 5 R01 HD041149-02 

This is a prospective randomized multicenter trial of pregnancies complicated by TTTS to 

compare serial amnioreduction with selective fetoscopic laser photocoagulation. There are 16 

Appendix A-15 
 

participating centers; two centers perform selective fetoscopic laser surgery. Long-term 

neurodevelopmental outcome will be evaluated by the NICHD NRN at 18 to 22 months of age. 

The overall goal of the study is to improve the outcomes of twins with TTTS by determining 

which treatment for TTTS has a better survival outcome, as well as better cardiac, neurologic, 

and developmental outcomes. 

Prophylaxis of Adrenal Insufficiency to Prevent CLD 

PI: WATTERBERG, KRISTI MD; 5 R01 HD038540-02 

This project is a multicenter, randomized trial of 712 extremely low birth weight (ELBW) births, 

to further define the benefits and assess the risks of hydrocortisone prophylaxis against adrenal 

insufficiency in these infants. Primary outcome measures will be: (1) Benefit: increased 

survival without CLD at 36 weeks postmenstrual age; (2) Risk: no increase in cerebral palsy at 

18 to 22 months adjusted age. Other measures of neurodevelopmental outcome will also be 

assessed. The sample size will detect a change of 10 percentage points in successful outcome, 

and in the incidence of specific adverse effects, with a power of 80 percent. Baseline data on 

mother and infant, daily clinical data for the first 28 days of life, outcome data at 36 weeks 

postmenstrual age, and outcome data at 18 to 22 months adjusted age will be collected. If this 

study confirms the benefits seen in the pilot study, the results will mean a significant 

improvement in health care for premature infants, both by introducing a beneficial new therapy, 

and by avoiding higher dose dexamethasone. 

Maternal Lifestyles Study 

NICHD and National Institute on Drug Abuse (NIDA)—LOI-HD-02-103 

This cooperative agreement (U10) is for a clinical research program designed to evaluate the 

effects of in utero drug exposure to cocaine and/or opiates on child and family outcomes. The 

objective of this program is to continue the research of four academic centers that are currently 

participating as centers in the Maternal Lifestyle Study (MLS) protocol. These centers, the 

Maternal Lifestyle Study Centers, are the only four academic institutions currently participating 

in the study, and represent a subgroup of the existing NICHD NRN performing the MLS 

Phase 4. Data coordination is performed by the two participating data and study coordinating 

centers at the Research Triangle Institute and the Brown University Neurodevelopmental Data 

Center. 

SUDDEN INFANT DEATH SYNDROME (SIDS) 

The NICHD’s research agenda on SIDS is outlined in Targeting Sudden Infant Death Syndrome 

(SIDS): A Strategic Plan, which is one of several NICHD strategic planning documents available 

on the NICHD Web site, at http://www.nichd.nih.gov/strategicplan/cells/. 

Since 1994, the NICHD, the Maternal and Child Heath Bureau, the AAP, the SIDS Alliance, and 

the Association of SIDS and Infant Mortality Programs have sponsored the Back to Sleep 

campaign, to educate caregivers that healthy infants be placed on their backs to sleep to reduce 

the risk of SIDS. The campaign also explains other ways to reduce the risk of SIDS, including 

placing an infant on a firm mattress. Information about the Back to Sleep campaign is available 

at: http://www.nichd.nih.gov/sids/sids.cfm. 

Appendix A-16 
NATIONAL CHILDREN’S STUDY (NCS) 

The NCS is a large, long-term study of environmental influences on children’s health and 

development. This Study will explore a broad range of environmental factors, both helpful and 

harmful, that influence the health and well-being of children. For this Study, environment is 

broadly defined to include chemical, physical, social, and behavioral influences on children, 

which will allow better understanding of the role of these factors on health and disease. 

The Study grew out of the President’s Task Force on Environmental Health Risks and Safety 

Risks to Children and was authorized in the Children’s Health Act of 2000. The Act directed the 

NICHD to conduct the study along with a consortium of federal agencies, including the 

Environmental Protection Agency, the CDC, and the NIEHS. 

The study will examine about 100,000 children across the United States and will follow them 

during prenatal development, through birth, childhood, and into adulthood. The Study will allow 

the evaluation of exposure and outcome links in the context of life stages of development. 

Planning and organization of the Study are underway, including the formation of Working 

Groups to consider issues such as hypotheses and study design, ethics, development and 

behavior, chemical and physical exposures, injuries, emerging technologies to measure 

exposures and outcomes, and community outreach/participation. 

The PPB is participating in the planning process of this large effort. Drs. Marian Willinger and 

Cathy Spong are the federal co-chairs of the Pregnancy and the Infant Working Group. Dr. Gary 

Hankins (UTMB-Galveston) is the non-federal co-chair of the Working Group. 

PA-02-102: THE ROLE OF GENE-ENVIRONMENTAL INTERACTIONS UNDERLYING THE 

HEALTH DISPARITY OF PREMATURE BIRTH 

Expiration Date: January 1, 2005, unless reissued. 

The NICHD, the NIEHS, and the NINR are seeking research grant applications on the role of 

gene-environmental interactions that underlie the health disparity of premature birth in the 

United States. This solicitation specifically addresses the need to better understand how adverse 

societal, behavioral, and environmental conditions alter gene expression, and how these factors 

interact with diverse genetic backgrounds to increase a woman’s susceptibility for premature 

birth in high-risk racial and ethnic groups. The solicitation encourages multidisciplinary 

approaches to clarify the potential role of genetics in the increased risk of premature birth in 

these disadvantaged populations. 

Appendix A-17 
LETTER OF INVITATION: HD-02-104 DATA COORDINATING AND ANALYSIS CENTER, EVENT 

RECORDINGS OF HIGH-RISK INFANTS ON APNEA MONITORS: THE COLLABORATIVE HOME 

INFANT MONITORING STUDY (CHIME) 

This cooperative agreement (U10) aims to continue specific analyses of the CHIME Study (U10 

HD 29067-08), to continue to conduct the NISP study, and to serve as a resource for public-use 

datasets from CHIME and NISP, which were developed during the previous grant award period. 

CONTRACT: COCHRANE COLLABORATION 

The Cochrane Collaboration is an international effort whose mission is the preparation, 

maintenance, and dissemination of frequently updated systematic reviews of health care 

interventions in all fields of medical practice. The reviews are prepared using systematic 

methods that are designed to produce unbiased and precise estimates of the effect of a treatment 

on each of the major outcomes of clinical importance. The Neonatal Cochrane Collaboration is 

one of 40 such groups. The NICHD funds the infrastructure of the Neonatal Collaborative 

Review Group to prepare up-to-date systematic reviews of the effectiveness of interventions in 

the field of neonatology to help neonatologists, researchers designing clinical trials, funding 

agencies, and individuals making decisions about the allocation of resources for neonatal care 

make more informed decisions. The Neonatal Cochrane Review Group’s systematic reviews are 

available on the NICHD Web site, at http://www.nichd.nih.gov/cochrane. 

Appendix A-18 
PPB PLANNED ACTIVITIES 

FISCAL YEAR 2003 TO FISCAL YEAR 2004 

RFAS, FISCAL YEAR 2003 

RFA HD-03-004: Prenatal Alcohol Exposure Among High-Risk Populations: 

Relationship to SIDS 

The NICHD and the NIAAA invite cooperative agreement applications for the development of 

community-linked studies to investigate the role of prenatal alcohol exposure in the risk for SIDS 

and adverse pregnancy outcomes, such as stillbirth and FAS, and how they may be inter-related. 

The investigators will work collaboratively under cooperative agreements with the NICHD and 

NIAAA over a three-year period to plan and pilot multidisciplinary investigations using common 

protocols within communities at high risk for prenatal maternal alcohol consumption. The longterm goals of this initiative are to decrease fetal and infant mortality and to improve child health 

in these communities. 

RFAS PLANNED FOR FISCAL YEAR 2004 

Research into Mechanisms of Fetal Growth Restriction 

The aim of this initiative is to stimulate research into the mechanisms of FGR, and to gain a 

better understanding of the factors that regulate fetal growth during pregnancy. FGR is the 

second-leading cause of perinatal morbidity and mortality, after only prematurity. The incidence 

of FGR is estimated to be approximately 5 percent in the general obstetric population. Further 

research into the mechanisms that control normal fetal growth will increase understanding of and 

prevention of situations of abnormal fetal growth. Providing the best possible environment for 

the fetus would not only ensure adequate fetal growth and health in the newborn period, but also 

protect against the development of diseases in adult life. 

Obstetrical-Fetal Pharmacology Research Units 

The purpose of this initiative for cooperative research is to support integrated basic, translational, 

and clinical research centers for conducting: pharmacologic studies of drug disposition and 

effect during normal and abnormal pregnancies; single-site and multi-site cooperative clinical 

trials; pharmacogenetic studies of the effect of pregnancy on drug metabolizing enzymes, 

transporters, and effectors; studies of placental transfer of drugs; and studies of fetal and 

maternal pharmacology. The units will also facilitate the utilization of clinical materials for 

basic research studies and enhance the exchange of information between basic scientists and 

obstetricians, and among various specialists involved in the treating pregnant women. 

WORKSHOPS/CONFERENCES 

PPB Planning Workshop 

The PPB supports basic and clinical research directed toward improving the outcome of 

pregnancy, reducing infant mortality, and minimizing maternal and infant morbidities. Activities 

Appendix A-19 
in the Branch have been focused around six emphasis areas: maternal, fetal, placental, labor and 

delivery, neonatal, and SIDS. The major emphasis areas within the Branch were internally 

evaluated to determine areas of opportunity and to develop plans to implement changes. The 

objective of this workshop was to obtain outside evaluation of the PPB vision statement and 

long-term plan, developed by careful review within the Branch, and by experts in the fields of 

maternal-fetal medicine, neonatology, obstetrics, pediatrics, SIDS, and in related targeted fields. 

These experts evaluated, refined, and adapted the Branch’s plan. Evaluation by outside experts 

helped to solidify the goals of PPB and to improve its relationship with the participating fields in 

attaining the goals. 

Investigation of Fetal Origins of Adult Health in Twin Cohorts 

The purpose of the meeting was to evaluate research to date, and to identify new approaches of 

using twin cohorts to elucidate mechanisms of fetal origins of health throughout the lifespan. 

Twin cohorts enable investigators to separate environmental and genetic effects through 

comparison of monozygotic and dizygotic pairs, and to investigate the contribution of maternal 

factors using within pair analysis. Studies in the literature, which explore fetal origins 

hypotheses, vary in their capacity to fully exploit the opportunities that twin cohorts provide. 

While twins represent valuable experiments in nature, it is also necessary to address whether 

information from twin pregnancies can be generalized to singletons. In addition, the outcome of 

twin pregnancies, which are increasing due to assisted reproductive technologies, are important 

in their own right because these twins are at higher risk for SIDS, cerebral palsy, and other 

morbidities in infancy and childhood. By exploring how to utilize information gained from the 

study of twin pregnancies, it is hoped that effective public health interventions can be developed 

to improve health throughout the lifespan and across generations. 

Poorly Explored Genetic Factors Affecting Pregnancy Outcome 

The purpose of the workshop was to discuss the current scientific knowledge, and to stimulate 

research interest in and collaboration with the scientific community in this poorly developed 

research area. This topic involves certain genetic factors that affect pregnancy outcome. The 

topics covered include genomic imprinting, uniparental disomy, and confined placental 

mosaicism. The basic science and clinical aspects underlying these topics were presented and 

potential future directions in research were discussed. 

Bilirubin-Induced Brain Injury (BIBI) 

This conference focused on BIBI and kernicterus. The workshop was designed around three 

themes: 1) Evaluating the neurobiology of BIBI, including exploration of the molecular and 

cellular basis for breakdown of blood brain barrier function for bilirubin, factors modulating 

regional susceptibility or resistance of neurons to damage from bilirubin, etc.; 2) Evaluating 

various system-related causes that have led to a mini epidemic of BIBI and kernicterus, so that 

appropriate strategies and practice guidelines can be developed; and 3) Evaluating the value and 

limitations of the existing and evolving methods for rapid diagnosis of hyperbilirubinemia and its 

effective treatment. The final topic also focused on the photobiology as it relates to 

phototherapy. 

Appendix A-20 
APPENDIX B: AREAS OF OPPORTUNITY 

STATEMENTS COMPILED AT THE PPB WORKSHOP 

AREA OF OPPORTUNITY: PREMATURITY 

Prematurity remains the most prevalent cause of perinatal mortality and morbidity, as well as a 

significant contributor to high health-care costs. Other than improvement in neonatal care, one 

that comes at a considerable cost and morbidity, research into prematurity and preterm labor has 

not lead to significant tangible benefits. 

Research into preterm delivery can be divided into investigations related to its etiology, 

prediction, prevention, diagnosis, and management. These categories do overlap, which means 

advances in one are could significantly impact the course of action in the others. 

RESEARCH GAPS AND OPPORTUNITIES 

Significant research effort and resources have been invested into discovering the etiology of 

preterm birth, but have resulted in limited success. Much of the previous work has been invested 

in studying single mechanisms. Recent advances have focused on the role of 

infection/inflammation; however, the infectious source and the cascade of events linking this 

process to preterm delivery are still not well understood. Moreover, infection alone may not be 

the only determinant; the process leading to preterm delivery appears to be multifactorial and 

includes a dependency on host response. 

Other areas that have received little attention but may have potential impact on the etiology of 

prematurity include utero-placental insufficiency, fetal growth abnormalities, and fetal stress. 

Investigation into the etiology of premature birth has traditionally focused on the period 

immediately preceding the onset of contractions or preceding Premature Rupture of Membranes 

(pPROM). The period in early pregnancy, and even pre-pregnancy, has received little attention. 

Additional areas needing attention include infection/inflammation predating pregnancy or 

implantation, deficient placentation, and utero-placental insufficiency. While there is a plethora 

of data regarding myometrial function in labor, there is also a dearth of information regarding the 

role of the cervix, fetus, and placenta in labor. In addition, most of the in vitro data related to 

myometrial function are gathered from studies involving tissues obtained from the lower 

segment at the time of delivery. This limitation is mostly due to the difficulties in conducting 

longitudinal non-invasive molecular and biochemical studies involving the myometrium and 

cervix in pregnancy. 

Identifying women at risk of preterm birth will also allow targeted use of modalities to improve 

neonatal outcome, such as maternal administration of corticosteroids. More optimistically, 

identification of these women will allow the use of strategies to prevent preterm delivery. Until 

recently; however, these strategies have been largely ineffective. One reason is that available 

Appendix B-1 
methods to identify women at risk of preterm delivery had positive and negative likelihood ratios 

that were not in the clinically useful range and, therefore, did not significantly modify a priori 

risks. More importantly, however, the methods currently available identify at-risk women at an 

advanced stage in the process that leads to preterm delivery, making them unamenable to 

prevention. Structural and biochemical changes in the cervix and amniotic fluid are underway 

weeks before the onset of labor. As the process gets closer to delivery of the fetus, these changes 

become irreversible. Unless women are identified at an early stage in this process, sometimes as 

early as the first half of gestation, prevention of preterm delivery may prove to be futile. 

Identification of such preventive strategies may also impact pPROM, a condition that accounts 

for a large proportion of preterm births. Moreover, prediction strategies have been mostly 

limited to univariate analysis and have not taken into consideration the multifactorial nature of 

the problem. 

Every year, millions of women are admitted to hospitals and treated for preterm contractions. 

Only a minority of these women can be considered in true preterm labor and, if left untreated, go 

on to have preterm deliveries. Admitting and treating only women who are at risk of preterm 

delivery, rather than all those with preterm contractions, would result in substantial cost savings, 

as well as in a decrease in maternal morbidity from unnecessary admissions, bed rest, and 

therapy. T he available methods for diagnosing labor have very low specificities. Even the 

presence of cervical change, once thought to be the hallmark of labor, is associated with falsepositive diagnosis prior to term. 

The management of preterm labor has mostly focused on tocolysis and bed rest despite the lack 

of strong evidence to support such practices. Moreover, there is no consensus as to the type of 

tocolytic or regimen (including maintenance) to use. Despite the reasonable assumption that, in 

some cases, treatment of preterm labor may be futile and even detrimental (resulting in infection, 

utero-placental insufficiency), there are no clinically applicable tests to guide management. 

NEW DIRECTIONS AND APPROACHES TO ADDRESS GAPS 

Investigations into the etiology of preterm birth should take into consideration the multifactorial 

nature of the problem, including utero-placental insufficiency, fetal growth abnormalities, and 

fetal stress. With regard to fetal growth, a better approach than currently available is needed; 

individualized growth assessment appears to hold the most promise. Research should also focus 

on early pregnancy and pre-pregnancy periods and should include into the role of the cervix and 

variability in host responses. Similarly, strategies for the prediction of preterm birth should 

include multivariate analysis, such as neural networks, and should focus on identifying the 

preparatory and potentially reversible changes in early pregnancy or pre-pregnancy. Noninvasive methods to assess cervical, myometrial, and placental changes, both longitudinally and 

in early pregnancy, should be pursued. In order to tailor management, methods of differentiating 

between women who are and are not in true labor are needed. As for the prevention of preterm 

delivery, treatments geared toward the early changes, rather than tocolysis, should be pursued; 

however, studies to determine the role of tocolytics are still needed. Many of the proposed 

studies discussed require access to a large and diverse patient population, as well as to 

representative tissue samples. 

Appendix B-2 
In order to achieve the aims proposed above, a consortium of centers involved in preterm labor 

research is recommended; tissue and data banks should also be included in the design. 

Consolidation, coordination, and collaboration between the various groups involved in this area 

of research, including neonatology, would be more efficient than the present system. 

Categorization of preterm birth should be improved. In addition, studies should focus on the 

cases with highest mortality and morbidity, and not be diluted by inclusion of preterm birth close 

to term, which is clinically less relevant. Finally, clinically applicable methods for identifying 

pregnancies in which delaying delivery is futile or detrimental may be useful. 

PRIORITY OF AREA OF OPPORTUNITY WITHIN THE PPB 

Prematurity is obviously a priority for the PPB as evidenced by prior funding in this area. Some 

existing resources, as well as additional ones, may have to be reassigned. Funding should be 

made available for both clinical and laboratory investigation. 

INFRASTRUCTURE RESOURCES NEEDED 

RFAs, research funding, data analysis resources, and established consortiums and tissue/data 

banks are important resources necessary to adequately address the research gaps in prematurity 

research. 

Environmental and Genetic Influences 

Prematurity is the model area to investigate environmental and genetic influences. These studies 

would obviously require large sample sizes and extensive databases. 

Health Disparity 

It is well known that a health disparity exists in the rate of premature birth, as well as in perinatal 

outcomes, among different racial and socioeconomic groups. 

Technology Development 

Proteomics, genomics, as well as high-throughput screening for polymorphisms will be essential 

for investigating the multifactorial nature of preterm birth. In addition, nuclear magnetic 

resonance and other fetal and placental imaging techniques will allow non-invasive assessment 

of the early changes leading up to preterm birth. Bioinformatics will be needed to manage and 

analyze the required large databases, and to provide a clinically applicable model for prediction 

and diagnosis. 

Research Risk and Ethical Aspects of Research 

Pregnancy is always a challenging area with regard to risks and ethical considerations. In fact, 

this issue may be one of the major factors that has affected advances in this area. Safe, noninvasive methods of investigation are a priority. 

Appendix B-3 
AREA OF OPPORTUNITY: FETAL AND EMBRYONIC DEVELOPMENT— 

MATURATION OF INDIVIDUAL ORGAN SYSTEMS AND 

IMPACT OF INTERVENTIONS ON LONG-TERM FUNCTION
 

There is growing evidence that adult coronary disease, hypertension, obesity, insulin resistance 

(Syndrome X), cerebral palsy, osteoporosis, and a host of other adult diseases have their roots in 

prenatal and early postnatal life. Numerous studies from around the world show an increased 

risk for ischemic heart disease with decreased birth weight. Fetal overgrowth may carry similar 

risks. There appear to be critical windows during early post-fertilization, organogenesis, and 

later maturation stages where stressors (defined broadly) are potent in stimulating defensive 

biological adaptations that may have survival value. However, fetal adaptations to stress may 

also “inadvertently” bring postnatal harm by “programming” an individual for increased risk of 

adult-onset disease. Programming is the initiation of adaptive gene-expression patterns that alter 

the normal growth and development trajectories, and that become disadvantageous during 

postnatal life. There is evidence that interruption of the fetal nutritional supply line, maternal 

stresses that increase circulating cortisol levels, and intrauterine hypoxia all lead to programming 

of offspring. 

The programming hypothesis brings a new perspective to public health. Diseases that were once 

thought to arise near the time of their manifestation in adult life are now known to have roots in 

pre- and early post-natal life and, in some cases, in previous generations. For example, coronary 

disease, the number one cause of death among adult men and women, is more closely related to 

low birth weight than to known behavioral risk factors. Thus, a significant portion of the disease 

burden borne by adults may have roots in antenatal nutrition and a poor transgenerational 

maternal health history. The mechanisms that cause fetal undergrowth are complex, 

multifactorial, and mysterious, but several facts about growth are known. For example, it is 

known that the early fetal growth trajectory is strongly influenced by maternal weight, 

physiological status, and body composition at the time of conception. A significant 

improvement in maternal-fetal health has the potential to yield more benefit to population health 

than strategies that depend upon unraveling the pathophysiological underpinnings of diseases 

one at a time after they appear in adult life. However, there are enormous gaps in our 

understanding of programming that will impede the recognition and reversal of programmed 

disease. 

RESEARCH GAPS AND OPPORTUNITIES 

The information gaps that need attention over the next decade include: 

1. Tools for Defining Fetal Growth 

In past decades, growth has been primarily defined by weight at a given gestational age. 

However, it is becoming increasingly clear that fetuses of the same weight and gestational age 

may have internal organs of different sizes and levels of maturity. While the continuous 

improvement of imaging technologies over the past three decades to monitor growth of 

individual fetal structures has become increasingly accurate, imaging remains a rather crude tool 

for fetal assessment. Ultrasound technology has the limitations placed upon it by dispersion of 

Appendix B-4 
 

sound by tissues of varying density; other new technologies should be sought. In addition, 

growth norms for fetal organs, which could be used as sensitive growth standards, have not yet 

been developed. 

2. Gender-Specific Effects of “ Stressors” on Prenatal Organ Maturation at Critical 

Windows of Development 

Organs such as the kidney and pancreas have critical windows of vulnerability during phases of 

rapid growth and differentiation. For example, the kidney is particularly vulnerable to 

permanent damage during nephrogenesis; the pancreas is vulnerable during at least two waves of 

differentiation of islet beta cells. A single form of stress may lead to changes unique to each 

fetal/newborn organ, depending upon the age of gestation, the sex of the offspring, and the 

postnatal age at which it is studied. Thus, the further development of animal models (including 

genetic models) that determine how stressors lead to altered growth of specific organs during 

embryonic and fetal life are greatly needed. The judicious use of gene and protein expression 

technology (profiling) along with organ-specific outcomes (i.e., size and shape, physiology, 

histology, biochemistry, in vitro cell behavior, etc.) would be required to characterize the insult. 

Advantage should be taken of new technologies already in existence, and of those that will 

emerge in the next few years. These include MRI, PET scans, genomics, proteomics, gene 

therapy, as well as 3-D gene localization (spatial genomics). 

Examples of stressors include: 

• 	 Hypoxia, hyperoxia (reactive oxygen species) 

• 	 Receptor-mediated growth/maturation (hormones, growth factors, cytokines etc) 

• 	 Mechanoreceptor (heart, blood vessels, lung, kidney) 

• 	 Maternal emotional/disease stressors 

• 	 Fetal nutrient supply-line disruption 

• 	 Exogenous toxicants (drugs, etc.) 

• 	 Iatrogenic factors 

3. Epidemiological Associations of Specific Intrauterine Stressors and Later Outcomes 

Organ-specific studies are necessary to study fetal under- and over-growth in human populations. 

There is an urgent need for epidemiological studies to determine relationships between prenatal 

environmental insults (including gene expression patterns) and adult disease, as well as 

intermediate markers for adult outcomes. To take advantage of mechanistic animal studies, the 

development of clinical studies driven by parallel animal studies that will foster translational 

discoveries is vital. At present, the role of fetal undergrowth in adult-essential hypertension is 

highly controversial, even though several studies show that a low-protein diet during pregnancy 

programs for a form of adult high blood pressure that is evident in offspring early in life. 

Parallel studies between animals and humans would bring new information to the 

pathophysiology of hypertension in the human population. 

Examples of needed studies include: 

• 	 Human nutrition (diets and outcomes in subsets of pregnant women) 

• 	 Postnatal heart, pancreas, kidney, hypothalamic-pituitary-adrenal (HPA) function in 

individuals born undergrown at term 

• 	 Premature birth: short and long term outcomes 

Appendix B-5 
 

 

• Specific intrauterine complications (Rh disease, fetal infections, etc.) 

4. Biological Integration of Effects during Intrauterine Stress 

There are very few studies that analyze programming as a multi-organ disease. Yet, it is clear 

that humans who suffer from pre- and postnatal undergrowth are at risk for diseases in multiple 

organs. For example, there is a heightened risk for obesity, insulin resistance, and hypertension 

all within a single individual who is undergrown at birth. Thus, there is a need for animal studies 

to determine the interactive responses of organ growth/maturation via signaling (systems 

integration). 

Examples include: 

• Heart, kidney, placenta 

• HPA, pancreas, leptin, etc. 

• Immune system 

5. Treatment Offerings for when Undergrowth and/or Fetal Stress is Detected 

As evidence for associations between early developmental patterns and adult onset disease 

increases, there is increasing pressure from the medical community and the lay public to make 

diet recommendations to women for preventing fetal undergrowth. Some physicians have 

succumbed to the pressure and have recommended unproven dietary regimens. However, either 

low- or high-protein diets depress fetal growth by unknown mechanisms. Furthermore, there are 

many organ-specific growth deficits that could theoretically be corrected if the pathophysiology 

was understood. Thus, it might be possible to develop rescue strategies, ranging from dietary to 

gene therapies, for abnormal developmental patterns based upon the underlying pathophysiology, 

once it is known. This course of action would require the establishment of research programs 

designed to change biological patterns and reverse deleterious effects in utero in animal models. 

6. Intergenerational Programming 

There is evidence from epidemiological studies and from animal studies that growth effects are 

passed on from one generation to the next, over and above ethnic and genetic backgrounds. The 

mechanisms that cause this multigenerational underdevelopment are not understood. 

7. Post-Fertilization Biology 

Several lines of evidence point to the large effects of environmental temperature and chemical 

composition in determining the growth trajectory of an embryo from the moment of conception. 

For example, the protein or amino acid composition of the surrounding medium in which an 

early post-fertilization embryo grows may determine the allocation of cells between the 

trophectoderm and the inner cell mass, which may ultimately affect the birth weight of that 

individual. Because the relative importance of the early growth trajectory of an embryo versus 

the later nutritional provision of the placenta is not known, research strategies to study this issue 

are needed. 

8. Maternal Stress during Pre- and Postnatal Life 

The biology of maternal stress is complex, but it its importance in reproductive success and fetal 

growth and development is virtually unknown. There is evidence that severe emotional stress 

during pregnancy leads to impaired fetal growth, and that maternal stress-related baby neglect 

Appendix B-6 
alters growth of the newborn. Animal evidence points to postnatal care as important for 

neurological and psychological health of offspring. The investigation of this problem will 

require a multidisciplinary team approach, including psychologists, sociologists, obstetricians, 

fetal physiologists, placental physiologists, and endocrinologists. 

9. The Role of the Placenta in Programming 

All nutrient exchange between mother and fetus takes place at the placental interface. While 

placental nutrient transporters are known to be down regulated in cases of growth restriction, 

little is known about the regulation of placental growth, the establishment of the maternal/fetal 

circulations, or the regulatory systems that sense and regulate fetal growth. The profiles of gene 

expression that reflect normal and abnormal placenta function have not been determined. Thus, 

fetal growth regulation will not be understood without further investigation of placental 

physiology and its association with gene expression. 

10. Structured Repository of Developmental Information 

Rapid progress in understanding fetal/neonatal development depends upon ready access to 

information across a wide variety of disciplines. For example, searching for current information 

on fetal/neonatal organ development and programming would require labor-intensive searches in 

obstetrics, fetal physiology, pediatric and adult cardiology, endocrinology, epidemiology, 

medicine, and adult sports physiology because there is no long standing discipline where the 

subject is often reviewed. While computerized word searches are very helpful, every scientist 

knows that perhaps the majority of articles sought by a single search are not identified because of 

inadequate retrieval algorithms. In addition, much of the background information in the area of 

fetal growth was published before search engines were developed, so they are no longer easy to 

find. Information retrieval science has made it possible to get broad-based links between digital 

databases and intelligent links that find related words and concepts in a search session. Thus, it 

is possible to categorize, using informatics, methodologies from the key studies of prenatal (and 

early postnatal) development of organs that are most important in causing adult human disease, 

and to create database links with genetic information from the late 1980s to the present. There is 

a need, in this field particularly, to develop new retrieval systems that would allow scientists to 

more easily identify knowledge gaps in organ development. 

Appendix B-7 
AREA OF OPPORTUNITY: MATERNAL MORBIDITIES— 

HYPERTENSION AND THROMBOPHILIAS
 

HYPERTENSION 

Hypertensive disorders are the most common medical disorders during pregnancy, with a 

reported rate of 7 percent (Samali et al 1996). The estimated rate is projected to increase to 

approximately 10 percent by 2005 because of the epidemic of obesity in women, and because of 

the trend of delaying pregnancy to an older age. These disorders are a major cause of adverse 

maternal and perinatal outcomes, both acute and long-term (i.e., renal failure, stroke, 

cardiovascular complications). The direct and indirect costs attributable to the above 

complications are extremely high considering acute and/or IUGR, and the long-term care of 

women with these complications. 

Research Gaps 

• 	 What is the role of aggressive blood pressure management before conception? 

• 	 Should anti-hypertensive therapy be used in women with mild hypertension in pregnancy? If 

so, what drug should be used? 

• 	 If a woman with hypertension, who is already well controlled with a particular agent, 

becomes pregnant, should another agent be used? 

• 	 African-American women with hypertension before and during pregnancy have higher 

maternal and fetal complications than white women with hypertension. Racial disparities in 

management approaches and pregnancy outcome need to be studied. 

• 	 There is little information about the pharmacokinetics, pharmacodynamics, and fetal effects 

of anti-hypertensive drugs in pregnancy. 

Research Goals and Opportunities 

• 	 Understand pathophysiologic abnormalities leading to adverse pregnancy outcome in these 

women. 

• 	 Identify risk factors for adverse outcomes (e.g., preeclampsia, abruption, preterm birth) in 

these women and design preventive strategies based on these risk factors. 

• 	 Understand the genetic diversity that could lead to a role for pharmacogenetic research; and 

identify a subset of women at risk for preeclampsia or cardiovascular complications in the 

future. 

• 	 Develop long-term follow-up of these women from preconception to 10-years postpartum 

similar to methods used in non-pregnant hypertensive individuals; identify risk factors for 

cardiovascular complications and their modification. 

• 	 Develop career development programs should be developed to enhance research capabilities 

of scientists interested in hypertension in pregnancy. 

New Directions and Approaches to Address Gaps 

Investigations in chronic hypertension and gestational hypertension should take into 

consideration the need for medications, as well as the effects of these medications on uteroplacental and feto-placental circulations, fetal growth, and long-term outcomes. The research 

Appendix B-8 
should also focus on pregestational control of maternal blood pressure, as well as on the longterm cardiovascular morbidities and mortality. Such a study should include a group of women 

who never had a pregnancy beyond 20 weeks’ gestation, and a group of age-matched women 

who had a normotensive pregnancy. In addition, the effects of subsequent pregnancies and the 

role of weight gain, lifestyle changes, cigarette smoking, presence of gestational diabetes, or 

subsequent diabetes can be assessed longitudinally. Finally, some of these women have acute 

morbidity in the form of stroke, heart failure, renal, and liver failure; there is urgent need to study 

the long-term outcomes for these women. 

THROMBOPHILIAS 

Thrombophilic conditions have been associated with an increased risk of a variety of adverse 

pregnancy outcomes, including: severe, preterm preeclampsia; abruption; IUGR; late first 

trimester or second and third trimester fetal loss; and rare conditions, such as in utero fetal 

stroke. Collectively, these conditions complicate 8 percent of pregnancies and have tremendous 

personal, familial, societal, and economic impact in the United States. As in the case of the 

importance of thrombophilic conditions and maternal thromboembolic disease, controversy 

exists regarding thrombophilias and adverse pregnancy outcomes. For example, Infante-Rivard 

(NEJM 2002) did not find an association between thrombophilic conditions and IUGR; in fact, 

the authors of this large Canadian case-control study found that one of the mutations, MTHFR 

was protective of IUGR in the newborn. On the other hand, Kupferminc (NEJM 1999) found 

that the three most-common inherited conditions (FVL, MTHFR, Prothrombin gene mutation 

20210A) were responsible for one half of the cases of IUGR in the Israeli population. 

Research Gaps 

There is a tremendous research gap between the presence of these conditions and their 

association with maternal and fetal pathology; the pathways linking circulating maternal 

prothrombotic and proinflammatory markers to placental pathology must be defined. Future 

research should focus on these key areas: pathogenesis of disease in patients with these 

thrombophilic conditions; detailed epidemiologic studies to assess the magnitude of the risk to 

women of childbearing age; screening strategies, if appropriate; and surrogate circulating blood 

markers indicative of the presence of a thrombophilic condition or a marker of increased risk of 

maternal, fetal, or neonatal risk. Levels of circulating coagulation activation markers increase 

with the number of prothrombotic conditions (Arkel 2002). 

Research Goals and Opportunities 

• 	 Understand the fundamental pathologic processes involved patients harboring these 

conditions, in order to: 

o Enable accurate counseling regarding personal, fetal, and neonatal risk assessment 

surrounding pregnancy;
 

o Stratify the at-risk patient population to assess risk for thromboembolic events and 

adverse pregnancy outcomes; and 

o Base prevention and treatment strategies based upon risk assessment. 

• 	 With the natural history of the individual thrombophilic mutations and pathologic 

mechanisms elucidated, focus on specific prevention and treatment strategies. 

Appendix B-9 
 

• 	 Develop a comprehensive database with epidemiologic information, tissue, biologic fluids, 

and biophysical components available for future investigations. 

• 	 Establish regional centers of excellence composed of scientists, researchers, and clinicians 

with special interest in these areas to optimize resources, patient care, and, most importantly, 

strengthen research. 

New Directions and Approaches to Address Gaps 

Basic research efforts should be directed toward understanding relevant physiologic changes that 

occur in pregnancy, in non-thrombophilic and thrombophilic conditions, such as the Protein C 

system and its derangements. The regulation of angiogenesis and thrombogenesis early in 

pregnancy must be defined in order to explain common antenatal events such as utero-placental 

thrombosis and hemorrhage, which have significant implications for the remainder of pregnancy. 

New relevant biologic markers that improve upon existing screens for thrombin generation will 

aid in monitoring disease progress and prognostication of undesired events. More efficient 

genetic screening strategies, using current and future genetic technologies such as gene-chip 

array and SNPs, will provide an initial step at identifying patients who may benefit from 

intervention. 

Priority of Area for PPB 

• 	 Who should undergo thrombophilia evaluation and the components of such screening? 

• 	 What are the appropriate treatment/ prevention strategy(ies) that are currently available to 

practitioners? 

• 	 What other evaluation is appropriate for patients identified with thrombophilic conditions? 

• 	 Based upon current understanding, what is the appropriate counseling regarding the patient 

and her offspring? 

Appendix B-10 
 

AREA OF OPPORTUNITY: NEONATOLOGY 

(SPECIFICALLY INTENSIVE-CARE ISSUES) 

Advances in the field of neonatal perinatal medicine include: care and diagnosis of fetal 

conditions; better understanding, application, and access to neonatal intensive care; the effect of 

prenatal steroids on lung and brain maturation; improved delivery-room care for the neonate; 

improved respiratory function and decreased mortality and morbidity with surfactant 

replacement therapy; and increased survival for smaller preterm infants <28 weeks’ gestation and 

< 1000 g birth weight. There has also been increased short-term and long-term morbidity such 

as BPD, cerebral palsy, mental developmental delay, and limitation in intellectual potential. The 

best outcomes for the newborn arise from successful collaboration among many subspecialties 

(e.g., genetics, pediatric/fetal surgery, cardiology, pediatric cardiovascular surgery, and others) 

and maternal fetal medicine in particular. In large part the neonatal-perinatal research effort has 

been directed to neonatal intensive care issues (e.g., modes of ventilation, the biology of lung 

surfactant deficiency) and acute problems (e.g., respiratory distress syndrome [RDS], meconium 

aspiration syndrome, persistent pulmonary hypertension of the newborn). Although follow-up 

studies, an important component of the NRN, have been done, the data are limited due to cost 

and the lack of availability of infants and families for later follow up at school ages. 

The incidence of preterm newborn births is increasing in the United States, in part, due to later 

maternity, more common multiple gestation pregnancies, and advances in and increased use of 

assisted reproductive technologies and methods. Infants born with complex anomalies and 

perinatal cardiorespiratory problems can respond to intensive care, which may include 

Extracorporeal Membrane Oxygenation (ECMO), renal dialysis, and experimental therapies. 

The field is evolving from addressing primarily acute developmental and intensive care issues, to 

addressing the longer-range implications of preterm birth and neonatal diseases, which require 

neonatal intensive care for later health and function. 

RESEARCH GAPS AND OPPORTUNITIES 

Long-term childhood morbidity (e.g., blindness, deafness, cerebral palsy, mental delay and 

limitation, and physical handicaps) are all sufficiently common; for instance, the incidence of 

cerebral palsy is less than 15 percent for preterm infants < 1250 g birth weight. At the present 

time, we are limited in determining whether the morbidity occurs prenatal, intrapartum or 

postpartum. Research regarding cause, prevention, and treatment would lead to improvement in 

the neurological outcome for the infant. Basic research in neuroscience and translational 

research should be priorities. Early identification of infants at high risk for long-term 

neurodevelopmental impairment is needed (See Area of Opportunity: Fetal/neonatal brain 

development and damage, including prenatal, perinatal, neonatal, infant periods). 

In general, the effect of stress and demand for more mature function from immature organ 

systems, often associated with neonatal intensive care, must also be studied to determine if the 

ultimate level of function and maintenance of function over time is comparable to control infants 

and children. If not comparable, can it be modified or improved? The effectiveness of neonatal 

intensive care over the last three decades has improved survival rates; it is now appropriate and 

Appendix B-11 
 

 

timely to raise questions about lifetime health issues. Basic and translational research on organ 

development, the effect of intensive care interventions, and the effect of prenatal and postnatal 

influences on development and long term potential for function should be a priority. 

Many low birth weight (< 1,500 g) preterm infants who are appropriate size for gestational age 

or small for gestational age at birth are growth retarded at the time of discharge. Basic and 

translational research in fetal nutrition and gastrointestinal development should be a priority to 

prevent extrauterine growth retardation, and malnutrition, and to address developmental issues 

in organ development during a critical window of development. 

Appendix B-12 
 

 

 

 

 

 

 

AREA OF OPPORTUNITY: PRENATAL SCREENING,
 

DIAGNOSIS, AND FETAL THERAPY
 

RATIONALE 

The primary goal of the PPB is to support research that improves pregnancy outcome and infant 

health. An important aspect of this goal is to develop tools for prenatal diagnosis and screening 

that help to identify pregnancies at risk. Historically, prenatal diagnosis research has been 

funded through the through the Intellectual and Developmental Disabilities (IDD) Branch, 

formerly the Mental Retardation and Developmental Disabilities (MRDD) Branch, of the 

NICHD. Some examples of this research include: the U.S. Amniocentesis Trial (circa 1976); 

the U.S. Chorionic Villus Sampling (CVS) Trial (circa 1983); the Early Amniocentesis vs. -

Transabdominal CVS Trial (circa 1999); Fetal Cells in Maternal Blood or NIFTY Trial (1994 

2002); and the First and Second Trimester Evaluation of Risk for Aneuploidy (FASTER) Trial 

(1999-2004). 

PRIORITY OF AREA OF OPPORTUNITY WITHIN PPB 

To date, the NICHD has supported research in prenatal diagnosis and screening, but this work 

has been primarily performed under the aegis of the MRDD Branch. One could argue that this 

area might belong under the category of Maternal/Clinical research. One example is the 

FASTER trial, in which ultrasound and biochemical markers are being analyzed to detect 

pregnancies at risk for both Down syndrome, and congenital heart disease, although congenital 

heart disease is not necessarily associated with mental retardation. There will undoubtedly be 

new markers of fetal well-being developed over the next decade that could be applied to broad 

populations of pregnant women. Prenatal diagnosis is a huge clinical area in which clinical 

obstetric practice is altered on the basis of the published literature, but not necessarily through 

careful evaluation or through randomized prospective clinical trials. 

AREAS OF INQUIRY 

Prenatal screening and diagnosis can be grouped into three broad areas of inquiry: 1) Imaging 

studies of the fetus and/or placenta; 2) Biochemical testing of the blood or urine in a pregnant 

woman, to identify products of the fetus and/or placenta; and 3) Genetic studies through analysis 

of fetal material obtained invasively and non-invasively. 

The ultimate goal of prenatal diagnosis is to be able to treat the underlying abnormality in utero 

to minimize symptoms or even correct the underlying disorder. Thus, fetal therapy (e.g., 

medical, surgical, and minimally invasive) could also arguably fit into this category. 

Appendix B-13 
RESEARCH GAPS AND OPPORTUNITIES 

Sonography and Fetal Imaging 

• 	 Some major limitations of current approaches include the need for specialized training and 

quality assurance with regard to sonographic markers of fetal anomalies. Who should 

perform sonography, and what should they be studying in the fetus at each trimester? Should 

sonographic studies be performed only (or primarily) in centers of expertise, as suggested by 

the RADIUS trial? What can be done to assess fetal well-being in the primary care obstetric 

setting? What is appropriate quality assurance? 

• 	 What additional fetal anatomic markers can be seen on ultrasound examinations that correlate 

with fetal well-being? What role will 3-D (or 4-D) ultrasound studies have in routine 

prenatal care? What novel indications exist for fetal MRI or fetal functional MRI? What 

other imaging technologies is on the horizon that merit assessment by the PPB? 

A relatively large number of fetuses are found to have “soft markers” for aneuploidy (i.e., nuchal 

thickening, pyelectasis, echogenic cardiac focus, and short limbs). The management of these 

patients has not been well defined. This issue currently generates significant patient anxiety and 

potentially unnecessary testing and interventions, with all the accompanying morbidity and cost. 

Studies are needed to accurately determine the likelihood ratios of these findings in a large and 

nationally representative population. Methods and mechanisms are needed to use this 

information clinically in counseling and management of these patients, in a process similar to 

what is in place for serum markers. 

The appropriate method of delivery for some fetal structural defects (i.e., abdominal wall, neural 

tube) remains controversial. Randomized studies are not available and may only be possible if a 

large multicenter trial is funded. 

Noninvasive Markers in Maternal Serum and Urine 

Maternal serum screening approaches to the detection of fetal Down syndrome are limited by a 

sensitivity of detection of about 70 percent and a calculated false-positive rate of 5 percent. How 

can the false-positive rate be minimized, while assuring adequate sensitivity of detection of 

Down syndrome? What new aspects of the underlying biology of pregnancy can be learned from 

the study of placental and fetal biochemical markers? 

What can non-invasive markers tell us about complications of pregnancy besides aneuploidy? 

Fetal cell-free DNA is elevated in the blood of pregnant women who will develop preeclampsia, 

unstoppable preterm labor, hyperemesis gravidarum, or placenta accreta, and in women who 

carry a fetus with Down syndrome or trisomy 13. Furthermore, cell-free fetal DNA is useful in 

the diagnosis of single-gene disorders such as Rhesus D incompatibility and congenital adrenal 

hyperplasia. Insight regarding the trafficking of nucleic acids (including RNA) between fetus 

and mother may lead to a new understanding of perinatal biology, while providing novel clinical 

applications. 

• 	 Novel technologies to increase the amount of information obtained from standard obstetric 

procedures are needed. 

Appendix B-14 
• 	 Novel technologies are in development that could be used to study fetal material acquired 

through conventional methods of prenatal diagnosis, CVS, and amniocentesis. Fetal gene 

expression and an expanded karyotype using cDNA and genomic DNA-based microarrays 

are available on a research basis. These technologies could expand prenatal diagnosis from 

primarily a study of aneuploidy to an assessment of fetal developmental biology. 

With the return to first trimester diagnosis, chorionic villi could serve as a source of novel 

biochemical data that could improve our understanding of early fetal metabolism. 

The traditional metaphase karyotype may eventually be replaced with molecular analysis of the 

entire genome using bacterial artificial chromosomes (BACS) and a competitive genomic 

hybridization (CGH) approach. This analysis will present new opportunities to study the effect 

of genetic microdeletions and/or duplications on the developing fetus. 

Similarly, as microarray technology becomes routinely applied to the fetus and placenta, there 

will be additional clinical and biological information available that will presumably improve 

perinatal care. 

Preimplantation Genetic Diagnosis (PGD) 

PGD presents an opportunity to “prevent” genetic disease by transferring only unaffected 

embryos for implantation. To date, research in this important, cutting-edge area does not have a 

formal “home” in a branch of the NICHD. 

With the increase in the use of assisted reproductive technologies, many in older gravidas, 

aneuploidy screening in multiple gestations is becoming relatively common. Investigations into 

methods for screening in established pregnancies are needed. In addition, advances in molecular 

analysis of the entire genome may provide a way for PGD. 

PGD presents an opportunity to improve selection of embryos for transfer in assisted 

reproductive technology. Currently, embryos are selected based upon morphologic criteria, 

which does not accurately identify aneuploidy. Microarray, cytogenetic, and biochemical data 

could be combined with morphology to better predict the embryos that are likely to successfully 

implant, leading to a clinical pregnancy. Furthermore, this technology presents an outstanding 

opportunity to study the early developing human embryo. 

Fetal Therapy 

A broad-based approach to fetal treatment should be encouraged and explored. This approach 

should encompass a systematic evaluation of fetal medical treatment, minimally invasive 

treatment (i.e., endoscopy, laser ablation), and open surgical clinical trials with outcome 

assessment. 

In the next decade, it is reasonable to expect that in utero gene therapy will become feasible via 

the administration of stem cells. The PPB would allow an ideal collaboration between 

perinatologists, who would administer the cells, and the neonatologists, who would study the 

effects of the therapy upon the developing infant. 

Appendix B-15 
Infrastructure Resources Needed 

• 	 Research funding 

• 	 Data-analysis resources 

• 	 Tissue and specimen banks with corresponding clinical data 

• 	 Linkage of medical records between fetus, newborn, and child 

Health Disparity 

It is well known that socio-economic disparity exists in the utilization of prenatal screening and 

diagnostic services. How can this disparity be minimized? 

Research Risk/Ethical Aspects of Research 

• 	 As in other areas of obstetric research, there are two patients whose well-being needs to be 

considered. 

• 	 In particular, in areas of fetal therapy, there are risks to the fetus and to the pregnant woman. 

• 	 Genetic screening studies may identify issues that do not directly impact fetal well-being, but 

may “label” the fetus in unintended ways. For example, newborn screening for cystic 

fibrosis in Massachusetts has the intended goal of detecting newborns with cystic fibrosis to 

maximize therapeutic options, but the screening may also identify newborns who are carriers 

of a single cystic fibrosis mutation. Sonographic studies that identify subtle fetal anomalies 

with little or no clinical significance may have an unintended impact on the long-term care of 

the child. 

• 	 The impact of the Health Insurance Portability and Privacy Act on clinical perinatal and 

neonatal research needs to be explored. 

Appendix B-16 
AREA OF OPPORTUNITY: FETAL/NEONATAL BRAIN DEVELOPMENT AND DAMAGE 

(INCLUDING THE PRENATAL, PERINATAL, NEONATAL, AND INFANT PERIODS) 

During the past five decades, marked clinical research has led to major advances in fetal 

monitoring and diagnosis, and in perinatal intensive care; simultaneously, basic research has 

provided an ever-broadening understanding of cerebral development from the molecular to the 

behavioral plane. The Workshop participants believe that the most vexing issues for PPB are in 

the implementation of translational research that targets problems common to the developing 

brain. Almost 1 percent of all live births weigh <1000 g at birth; 0.2 percent to 0.4 percent of 

term infants born each year suffer hypoxic ischemic encephalopathy; the incidence of fetal 

stroke, xenobiotic exposure, and other conditions that impact neurobehavioral outcome remains 

largely unknown. Nonetheless, all of these children are at high-, and potentially preventable risk 

for neurodevelopmental handicap. 

RESEARCH GAPS AND OPPORTUNITIES 

I. Interaction of the environment and the genome in developing brain (i.e., molecular, 

cellular, animal models of injury and repair): 

• 	 Broaden understanding of unique features of the immature brain that impact vulnerability and 

response to stress; understand the normal developmental pattern and function of expression 

and activity of neurotransmitters, growth factors, metabolic capacity, cell death/apoptotic 

activity, etc. 

• 	 Identify common pathways of injury to developing brain (i.e., metabolic, infectious, and 

xenobiotic agents). 

• 	 Determine genomic factors that render the developing brain resistant and/or susceptible to 

injury. 

• 	 Identify environmental factors that promote plasticity or enhance defect. 

• 	 Develop strategies to prevent injury and promote neural repair. 

Examples: Growth factors are known to promote angiogenesis and neurogenesis both in vitro 

and in vivo in animal models of disease. The chronic hypoxemia and nutritional deficits 

associated with IUGR and with postnatal conditions such as premature birth, BPD, etc., result in 

elevated levels of these growth factors and, thus, merit study in the developing brain. The 

association of environmental intervention with alterations in neurogenesis and in enhanced 

learning and neurobehavioral outcomes in animal models warrants further research. 

II. Translation of the basic science data to the newborn unit and beyond 

• 	 Broaden collaborative use of the MFMU Network and the NRN to validate animal models of 

injury and repair. 

• 	 Develop intervention and prevention trials for these populations. 

Example: Collaboration in translational research is exemplified by the ongoing Beneficial 

Effects of Antenatal Magnesium Sulfate in the Prevention of Cerebral Palsy (BEAM) trial. In 

Appendix B-17 
this extraordinary study, the MFMU Network and the NRN work together to test hypotheses 

derived from animal studies that examine strategies for prevention of injury to the brains of 

preterm infants. 

III. Improved methodologies for assessment of normal neurobehavioral development, for 

diagnosis of injury, for documentation of efficacy of therapies, and for repair of 

developmental injury applicable in the clinical situation 

• 	 Implement comprehensive infant follow-up studies as projected for the National Children’s 

Study. 

• 	 Develop behavioral methodologies and probes to evaluate continuities and trajectories 

relevant to long-term outcomes. 

• 	 Develop improved fetal-imaging strategies (i.e., fetal MRI, DWI, fMRI, volumetric studies). 

• 	 Develop improved neonatal-imaging strategies (i.e., MRI, DWI, MRS, DTI). 

• 	 Develop standardized strategies to assess early language abilities. 

Examples: Neuroimaging in the immediate perinatal period is now the standard of care for 

fetuses and infants with encephalopathy; numerous recent studies have documented the 

importance of MRI, DWI, and MRS for the diagnosis of hypoxic ischemic encephalopathy, and 

for prognostication and monitoring clinical interventions/treatment strategies. Further, DWI 

shows promise for preterm infants, in whom abnormal early DWI studies may reflect an 

increased risk for cystic periventricular leukomalacia (PVL), at a time when intervention 

therapies may be considered. Similarly, fMRI studies may be able to document plasticity in the 

injured developing brain. Finally, fetal MRI and fMRI provide a window into the structure and 

function of the developing brain, yet these techniques are not widely employed. 

Appendix B-18 
 

 

 

AREA OF OPPORTUNITY: TRAINING
 

This section is structured to answer three questions, which are important in training, both for 

physician and non-physician scientists: (1) How do we attract potential trainees in the field? (2) 

How do we maintain the involvement of trainees over the course of training? (3) How do we 

assure success of the process through generation of independent investigators? 

The statement of each question is followed by a series of suggested changes that might be 

implemented by PPB to address the problem. There are a series of training problems for which 

the solutions rely primarily on bodies other than NIH. This section discusses all such problems; 

however, the proposed solutions are divided into those that have relevance for the PPB, and 

those that will necessitate action by other organizations. 

These questions are based on the premise that existing training structure and funding have failed 

to develop an adequate cadre of scientists in perinatal medicine who can perform the basic, 

translational, and clinical research required to answer the most pressing questions and to advance 

the field. 

PHYSICIAN-SCIENTIST 

How to attract them? 

The field does not provide sufficient exposure, generate interest, or excite students/clinical 

trainees at a sufficiently early stage to generate a pool of talented individuals committing to 

research careers in the field. These individuals need to get an understanding of the field, its 

problems, its complexities, and its intellectual challenges. The field does not provide 

opportunities for them to experience various aspects of perinatal medicine, as these aspects occur 

in the real world; the field does not enable them to follow through on possible career paths, 

neither by exploring clinical and research perinatology, nor by providing guides, mentors, or role 

models. Given this problem, discussants were in agreement that a variety of methods could 

provide a greater initial pool of trainees. 

Action Steps for PPB 

Increase research exposure, involvement, and interest among medical students through support 

of perinatal research programs in: 

• Summer research 

• Research electives 

• Year-out programs 

Programs such as these should be developed by first identifying a pool of mentors who are 

willing to participate, and then matching the most appropriate mentor for the student interest. 

Similarly, for residents, increased research exposure should be sought through support of: 

• Resident research educational programs 

• Year-out programs 

Appendix B-19 
 

Action Steps for Other Resources 

• 	 Evaluate the model used by Five School Program. 

• 	 Assist interested medical students in matching for residency in perinatal research-oriented 

departments. 

How to maintain involvement? 

The pathway to a research career in perinatal medicine can be daunting, and the end-point is 

often seen as unattractive. The length of time required for specialist/subspecialist clinical and 

research training by standard pathways often exceeds seven to 10 years, after medical school. 

Clinical training time is encumbered by the non-educational service element. Competing 

residency training requirements preclude substantive research experience. Research training 

time in subspecialty fellowship is insufficient to produce independent physician scientists. 

Action Steps for PPB 

Maintain interest in research by: 

• 	 Providing funding to reduce clinical service demands in exchange for greater research 

training time 

• 	 Developing programs that will facilitate continuing research by MD, PhD, and other trainees 

who have already been involved in, and wish to continue in the perinatal research track 

Action Steps for Other Resources 

• 	 Utilize flexibility in residency training for research training. 

• 	 Incorporate and fund PhD, MPH, MSCE tracks in training. 

• 	 Assist finishing residents in identifying appropriate post-residency training programs. 

• 	 Consider a new model for training in research. Perhaps the best time for training is after the 

fellowship training in a subspecialty; however, for this plan to succeed, this training period 

be made more attractive, both in terms of ease of obtaining support (K awards) and of 

reducing the monetary burden (loan payments). In addition, an easier way to make the 

period more attractive may be to allow supplemental awards to all R01s, which would allow 

interested individuals to obtain excellent mentored training from established scientists, 

independent of a formal training program. 

How to assure success? 

• 	 Salary levels for continuing a research-oriented career are low, when compared to private or 

academic clinical practice. This disincentive is further exaggerated by rising medical school 

debt, rising medical liability costs, and salary caps for research components of effort. 

• 	 Changing environment after clinical training, but before completing independent research 

training may result in disruption of research and mentorship. Research training frequently 

consists of 18 to 24 months in fellowship, with limited research goals and training. Trainees 

often do not have the support mechanisms necessary to succeed. Often, departments cannot 

or will not provide adequate support for protected research time for new faculty. Faculty 

require clinical involvement to maintain and refine skills, as well as to generate research 

questions and materials, but new faculty are buried under clinical demands. 

• 	 Current research funding levels are insufficient to assure protection from competing clinical 

demands. There is a lack of financial support from departments for new faculty that would 

allow them to pursue research goals in the early part of their careers. These faculty never get 

Appendix B-20 
 

 

as far as the R03; they need a bridging grant, seed money to start them off, based on the 

presence of experienced, funded faculty mentors, not based on a project. Seed money should 

come with a protected time requirement. 

• 	 The follow through in the latter part of training or after training is frequently inadequate. 

Many new clinical research faculty have had wholly inadequate training to prepare them for 

the role of independent investigator. One of the most important elements is the presence of 

basic scientists with whom they can collaborate, and through whose expertise they can 

continue to learn. These researchers frequently have no mentors within their new 

departments, neither clinically, nor for their research. Often there is little or no oversight of 

their progress in the first crucial years. 

Action Steps for PPB 

Maintain interest in research by: 

• 	 Expanding loan forgiveness programs 

• 	 Increasing levels of funding for research training to compete with clinical compensation 

• 	 Implementing rigorous oversight and quality control of training programs 

• 	 Providing increased flexibility of programs, such as Women’s Reproductive Health Research 

(WRHR) awards and programs 

Action Steps for Other Resources 

• 	 Ensure that liability costs do not necessitate a volume of clinical practice that precludes 

substantive research time. 

• 	 Assure consistent and capable mentoring. 

NON-PHYSICIAN SCIENTISTS 

How to attract them? 

There is little or no appeal to basic scientists to enter the field. There is also a dearth of good 

scientists at the graduate student and postdoctoral levels who are interested in the field. Finding 

candidates for postdoctoral positions is extremely difficult, even when considering including 

foreign scientists. This situation is made all the more difficult given the restrictions on the 

recruitment of non-U.S. citizens to various positions, such as National Research Service Award 

postdoctoral fellowships. There are no short-term training programs designed to give potential 

trainees some understanding of the field. There are very few programs that offer graduate 

studies designed to emphasize or to appeal to those interested in reproductive biology. 

Action Steps for PPB 

Increase research exposure, involvement, and interest amongst undergraduate and graduate 

students through support of perinatal research programs in: 

• 	 Summer research 

• 	 Laboratory rotations 

• 	 Year-out programs 

Appendix B-21 
 

 

 

Action Steps for Other Resources 

• 	 Encourage interdisciplinary programs that include reproductive biology. 

• 	 Develop graduate studies programs in reproductive biology. 

How to maintain interest/involvement? 

The process by which training is funded is currently cumbersome and lengthy. The time 

between establishing contact and the start of a training grant can be 18 months or more, with no 

guarantees that funding will ensue. The small number of training programs, usually associated 

with major university centers, limits the number of positions available. Substantial resources are 

required to establish and maintain additional institutional training programs. The WRHR and 

Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) programs have been 

developed without an understanding of the needs for training of non-physician scientists. It is 

assumed that postdoctoral positions will be found from research grant funding. In this way, 

much of the emphasis on training is lost, since the trainee is required produce research results to 

justify the research grant funding, whether or not this provides training for independent 

investigator status. Training stipends need to be continually updated to avoid industry recruiting 

the most promising trainees. 

Action Steps for PPB 

• 	 Simplify methods for obtaining funding for pre-doctoral and postdoctoral positions. 

• 	 Allow principal investigators to apply for a pre-doctoral or postdoctoral award without 

having a named candidate. 

• 	 Remove U.S. citizen/permanent resident requirement. 

• 	 Allow a supplement to R01 grants to allow addition of a training position. 

• 	 Establish WRHR-type programs for non-physician scientists in reproductive biology. 

• 	 Establish loan-forgiveness program for non-physician scientists. 

How to assure success? 

Developing independent basic scientists is problematic because of continued dependence on 

poorly funded postdoctoral positions, the lengthy time required to obtain necessary experience, 

and the need to publish sufficiently to attain R01 funding. Although there is some non-NIH 

postdoctoral funding, usually it is for specified topics, and only includes salary support. 

Preference is usually given to physician-scientists by industry and private foundations. 

Establishing a track record of funding is commonly restricted to those who are already have 

faculty appointments. Yet, obtaining a faculty position without extant funding is difficult. 

Current funding mechanisms for new/junior faculty are inadequate. The R03 does not provide 

sufficient funding for salary and technical assistance. The R01 "new investigator" designation is 

insufficient to allow a new/junior faculty member to compete against established investigators, 

the result being that the new/junior faculty member must often spend years accumulating enough 

data and support to submit a competitive R01. 

Action Steps for PPB 

• 	 Provide postdoctoral grants for salary, supplies, and technical support for which trainees can 

apply during the postdoctoral training period. 

• 	 Fund a bridge grant to include salary, supplies, and technical support for which a 

postdoctoral applicant can apply. Evaluate bridge grant applications on credentials, 

Appendix B-22 
postdoctoral research, and research plan, such that grant can be taken up at a suitable 

institution once the trainee has accepted a new faculty position. 

• 	 Re-establish a starter grant mechanism similar to R29 to foster development of new/junior 

faculty. 

Appendix B-23 
AREA OF OPPORTUNITY: OBSTETRICAL, FETAL AND NEONATAL 

INTERVENTIONS AND INFANT/CHILD OUTCOMES
 

Recent evidence from epidemiological studies in humans located in several different parts of the 

world, and from studies in animals provides strong support for the concept of imprinting and 

programming during development and early childhood. In this context, the fetus, neonate, and 

child represent a continuum, influenced by genetics and environment at every stage of 

development. At each of these stages, growth and development is determined by genetics and is 

influenced by the environment (i.e., metabolism, endocrine, nutrition, infections). 

The consequence is a change in patterning or imprinting that not only has an impact on the health 

of the individual during adulthood, but also 

may be transmitted to the future generation 

(epigenetic). 

FETAL GROWTH AND ITS LONG-TERM 

CONSEQUENCES 

The data from human studies strongly suggests 

that “thinness” at birth is associated with 

chronic diseases in adulthood, such as type II 

diabetes, coronary artery disease, etc. 

However, a number of inconsistencies in the reported data, conflicting data, selection bias, and 

ecological trends have raised some concern regarding this hypothesis and will need to be 

addressed in the future. Additionally, the mechanism(s) of IUGR and the mechanism of 

development of chronic disease have not been addressed. These topics are particularly important 

because identification of various mechanisms will allow development of intervention strategies 

and examination of their effectiveness. 

While a large body of data has accumulated to relate small size at birth with various diseases in 

adults, the relationship between large-for-gestational-age infants and adult disease has not been 

carefully examined. In human studies, maternal diabetes, both type I and gestational diabetes, 

has been used as the major paradigm for examining the impact of maternal metabolic 

environment on fetal growth. However, the impact of other metabolic/nutritional perturbations 

during pregnancy on fetal growth and on the neonate remains to be examined. In this context, 

the influence of maternal obesity, energy, and protein intake on metabolic imprinting of the 

developing fetus requires detailed evaluation. 

This topic is particularly important because obesity in adolescents and adults is rapidly reaching 

epidemic proportions. Obesity could have its origins during fetal life as a consequence of the 

intrauterine environment. Data from a number of studies have shown that obese mothers, even 

those who do not develop glucose intolerance during pregnancy, give birth to macrosomic 

babies. The mechanism of macrosomia and its long-term consequences are not known. Only 

Appendix B-24 
carefully performed studies examining the molecular and environmental mechanisms involved in 

these pattern formations will help in the development of intervention strategies. 

INTERVENTIONS IN THE NEONATE 

Although short-term impact of nutritional and other interventions in the neonate are well known, 

their impact on health during adolescence and adulthood is not known. Studies in animals (rats) 

provide strong evidence that nutritional experiences during the newborn period can have 

consequences in the adult. The data of Patel and colleagues have clearly demonstrated that 

newborn rats, exposed to a high carbohydrate diet until weaning develop hyperinsulinemia as 

adults, become obese, and develop resistance to insulin action. Of significance, the pups of these 

obese mothers, although of normal size at birth, become obese as adults. Such animal models 

provide unique opportunities for the study of nutritional/hormonal and other factors that 

influence the phenotype, perhaps via epigenetic mechanisms. 

Research Gaps 

Prospective studies in humans, using state-of-the-art methods in a carefully identified 

contemporary cohort are required to distinguish the genetic, nutritional, metabolic, and hormonal 

influences during pregnancy that impact fetal growth, and to examine the relationship between 

size at birth and adolescent and adult health. It should be underscored that, by influencing the 

expression of multiple genes at appropriate times in development, the intrauterine environment 

during pregnancy may have a major impact on both physical and functional phenotypes. 

In order to accomplish such goals, the development of new, innovative, non-invasive, and safe 

methodologies (i.e., isotopic tracers, NMR, PET scan, and molecular biology method) will be 

required, which will allow physiological and functional assessments of whole body and organ 

systems, such as the placenta and fetus in utero. 

A major emphasis should be placed on developing sophisticated techniques for animal models. 

Recent research using animal models has primarily focused on genetic influences, but not on 

physiological phenotypes. This situation has resulted from the small size of the commonly used 

animals, mice and rats. The development of newer, non-invasive methods should allow easy 

access to important physiological data. 

Health Disparity 

Multiple studies have demonstrated an association between experiences of socioeconomic 

disadvantage (disparity) and health during reproductive life, childhood, and adulthood. The 

physiological mechanisms remain to be elucidated. The influence of health disparity on 

neurodevelopment has also been suggested. 

Evaluation of Interventions 

A number of intervention strategies, including nutritional and pharmaceutical, have been used in 

the care of pregnant mothers and newborn infants. Many of these strategies have not been 

carefully evaluated for their effectiveness and long-term impact. Future studies should be 

directed at examining the biological basis of these interventions, and the impact of timing of the 

Appendix B-25 
intervention (i.e., early or late in pregnancy, intrapartum, or the neonatal period). The latter is 

particularly important for the prematurely born infant. 

Outcome Measures 

There is now a recognized need for the development of new algorithms to examine outcome. 

This development will require new, sensitive techniques to address functions, including 

functional imaging methods (MRI), anthropometric studies (body composition measurements), 

and other methods to assess neurodevelopment early in life. 

OTHER AREAS OF FUTURE EMPHASIS 

• 	 Evaluation of intrauterine genetic environment, including fetal polymorphism, and its 

relation to IUGR, preeclampsia, hypertension, and stroke 

• 	 Examination of congenital anomalies, including fetal therapy 

• 	 Identification of infections not related to prematurity that continue to result in significant 

fetal and neonatal morbidity, such as hepatitis C, HIV, CMV, etc. 

Appendix B-26 
 

APPENDIX C: PPB STAFF AND 

PPB PLANNING WORKSHOP PARTICIPANTS 

PPB STAFF (IN ALPHABETICAL ORDER) 

Nancy Chescheir, M.D. 

Scientific Responsibility: Maternal-fetal surgery; fetal interventions; and high-risk obstetrics 

E-mail: Nancy_Chescheir@med.unc.edu 

Rosemary Higgins, M.D. 

Scientific Responsibility: Neonatology; NRN; disorders of the neonate and infant; and neonate 

and infant follow up; NICHD liaison to AAP 

E-mail: higginsr@mail.nih.gov 

John V. Ilekis, Ph.D. 

Scientific Responsibility: Genetics, molecular biology, physiology, and biochemistry dealing 

with the placenta, uterus, and cervix; basic research dealing with preeclampsia and premature 

birth; basic research involving psychosocial stressors and their physiological effects on 

pregnancy 

E-mail: ilekisj@mail.nih.gov 

Susan Pagliaro 

Program Support Specialist and Network Coordinator, MFMU Network 

E-mail: pagliars@mail.nih.gov 

Carolyn Petrie 

Program Support Specialist and Network Coordinator, NRN 

E-mail: petrie@rti.org 

Tonse Raju, M.D. 

Scientific Responsibility: General neonatology; acute and chronic disorders of newborn infant; 

neonatal brain injury and repair; long-term follow-up; Cochrane Neonatal Review Collaboration; 

NICHD liaison to the Committee on Fetus and Newborn, AAP 

E-mail: rajut@mail.nih.gov 

Diane Scholl 

Secretary 

E-mail: scholld@mail.nih.gov 

Catherine Y. Spong, M.D., PPB Chief 

Scientific Responsibility: Maternal-fetal medicine, obstetrics, MFMU Network, National 

Children’s Study: Pregnancy and the Infant Working Group, American College of Obstetricians 

and Gynecologists Committee on Obstetric Practice 

E-mail: spongc@exchange.nih.gov 

Appendix C-1 
Marian Willinger, Ph.D. 

Scientific Responsibility: SIDS; stillbirth; fetal and infant development; health disparities; and 

National Children's Study: Pregnancy and the Infant Working Group 

E-mail: mw75q@nih.gov 

PARTICIPANTS IN PPB PLANNING WORKSHOP 

CHAIR 

Mary E. D’Alton, M.D. 

Professor of Obstetrics and Gynecology 

Department of Obstetrics and Gynecology 

Director, Maternal-Fetal Unit 

622 West 168th Street, PH16 

College of Physicians and Surgeons 

Columbia University 

New York, NY 10032 

Phone: 212-305-6293 

Fax: 212-305-3869 

E-mail: md511@columbia.edu 

PARTICIPANTS 

Ronald L Ariagno, M.D. 

Stanford University School of Medicine 

750 Welch Road, Suite 315 

Palo Alto, CA 94304 

Phone: 650 723 5711 

E-mail: rla@stanford.edu 

Diana W. Bianchi, M.D. 

New England Medical Center 

The Natalie V. Zucker Professor 

Tufts University School of Medicine 

136 Harrison Avenue 

Boston, MA 02111 

Phone: 617-636-7000 

E-mail: DBianchi@Lifespan.org 

Avroy A Fanaroff, M.D. 

Case Western Reserve University 

Rainbow Babies and Children’s Hospital 

11100 Euclid Avenue 

Cleveland, OH 44106 

Phone: 216 844 3387 

E-mail: aaf2@po.cwru.edu 

Nick Illsley, Ph.D. 

UMD-New Jersey Med School 

Dept of Ob/Gyn & Women’s Health 

185 South Orange Avenue 

Newark, NJ 07103-2714 

Phone: 973-972-4456 

E-mail: illsleni@umdnj.edu 

Satish C. Kalhan, M.D. 

Professor, Department of Pediatrics 

School of Medicine 

Case Western Reserve University 

Director, Schwartz Center 

MetroHealth Medical Center, BG-774 

2500 MetroHealth Drive 

Cleveland, OH 44109-1998 

Phone: 216-778-8643 

Fax: 216-778-8644 

E-mail: sck@po.cwru.edu 

Mark Klebanoff, M.D. 

Director, Epidemiology Branch 

Division of Epidemiology, Statistics, and 

Prevention Research, NICHD 

6100 Executive Boulevard, Room 7B03 

Rockville, MD 20852 

Phone: 301-496-6155 

Fax: 301-402-2084 

E-mail: klebanom@exchange.nih.gov 

Appendix C-2 
 

Charles Lockwood, M.D. 

Professor and Chair, Department of 

Obstetrics and Gynecology 

Yale University 

333 Cedar Street 

New Haven, CT 06510 

Phone: 203-737-2970 

E-mail: cjl43@email.med.yale.edu 

Michael Mennuti, M.D. 

Chairman and Professor of Obstetrics and 

Gynecology 

Department of Obstetrics and Gynecology 

University of Pennsylvania Medical Center 

3400 Spruce Street 

Philadelphia, PA 19104 

Phone: 215-662-3234 

Fax: 215-349-5893 

E-mail: mmennuti@obgyn.upenn.edu 

Laura Ment, M.D. 

Professor of Pediatrics and Neurology 

Department of Pediatrics 

School of Medicine 

Yale University 

New Haven, CT 06520 

Phone: 203-785-5708 

Fax: 203-737-2236 

E-mail: laura.ment@yale.edu 

George Saade, M.D. 

The University of Texas Medical Branch 

Department of OB/Gyn 

301 University Boulevard 

Galveston, TX 77555-0587 

Phone: 409-747-0482 

Fax: 409-772 2261 

E-mail: gsaade@utmb.edu 

Baha Sibai, M.D. 

Professor and Chairman 

Department of Obstetrics and Gynecology 

The University of Cincinnati College of 

Medicine 

231 Bethesda Avenue 

Cincinnati, OH 45267 

Phone: 513-558-6587 

E-mail: Baha.sibai@uc.edu 

Raymond I. Stark, Ph.D. 

Professor of Pediatrics and Perinatology in 

Obstetrics and Gynecology 

Columbia College of Physicians and 

Surgeons 

622 W 168th Street 

PH 4W-465-D 

New York, NY 10032 

Phone: 212-305-0954 

Fax: 212-305-0956 

E-mail: ris2@columbia.edu 

Kent L. Thornburg, Ph.D. 

Professor and Director 

Oregon Health and Science University 

3181 S.W. Sam Jackson Park Road 

Portland, OR 97201-3098 

Phone: 503-494-2382 

Fax: 503-494-4352 

E-mail: thornbur@ohsu.edu 

PARTICIPATING IN ABSTENTIA 

Elena Fuentes-Afflick, M.D., M.P.H. 

Associate Professor 

Department of Pediatrics 

San Francisco General Hospital 

University of California, San Francisco 

1001 Potrero Avenue (MS 6E) 

San Francisco, CA 94110 

Phone: 415-206-4196 

Fax: 415-206-3686 

E-mail: efuentes@sfghpeds.ucsf. 

Appendix C-3