Pregnancy and Perinatology 

Branch (PPB)
 

NICHD
 

Report to the NACHHD Council
 

September 2008
 

U.S. Department of Health and Human Services
 

National Institutes of Health
 

Eunice Kennedy Shriver National Institute of Child Health and Human Development 
TABLE OF CONTENTS 

PPB MAJOR MILESTONES AND ADVANCES: 2004-2007 .................................................I

EXECUTIVE SUMMARY .......................................................................................................... 1

INTRODUCTION TO THE BRANCH...................................................................................... 2

BRANCH ACTIVITIES: RESEARCH PROJECT GRANTS AND CONTRACTS............ 5

MATERNAL RESEARCH ................................................................................................................ 5 

FETAL RESEARCH ...................................................................................................................... 10 

LABOR AND DELIVERY RESEARCH............................................................................................. 14 

NEONATAL RESEARCH............................................................................................................... 17 

SUDDEN INFANT DEATH SYNDROME (SIDS) RESEARCH ........................................................... 25 

BRANCH ACTIVITIES: COOPERATIVE AGREEMENTS .............................................. 32

NEONATAL RESEARCH NETWORK (NRN).................................................................................. 33 

MATERNAL LIFESTYLES STUDY (MLS)..................................................................................... 38 

MATERNAL-FETAL MEDICINE UNITS (MFMU) NETWORK........................................................ 39 

INFANT FEEDING PRACTICES STUDY (IFPS) II........................................................................... 46 

COLLABORATIVE HOME INFANT MONITORING AND EVALUATION (CHIME) STUDY ................ 47 

MATERNAL-FETAL SURGERY NETWORK ................................................................................... 48 

VAGINAL ULTRASOUND CERCLAGE TRIAL................................................................................ 48 

COMMUNITY CHILD HEALTH RESEARCH NETWORK (CCHN) ................................................... 48 

PRENATAL ALCOHOL IN SIDS AND STILLBIRTH (PASS) NETWORK .......................................... 49 

STILLBIRTH COLLABORATIVE RESEARCH NETWORK (SCRN)................................................... 50 

GENOMIC AND PROTEOMIC NETWORK FOR PRETERM BIRTH RESEARCH (GPN/PBR)............... 51 

BRANCH ACTIVITIES: TRAINING AND CAREER DEVELOPMENT 

PROGRAMS ............................................................................................................................... 52

OTHER BRANCH ACTIVITIES ............................................................................................. 52

INSTITUTE OF MEDICINE (IOM) PREGNANCY WEIGHT GUIDELINES .......................................... 52 

BEST PHARMACEUTICALS FOR CHILDREN ACT (BPCA)............................................................ 53 

DHHS INTERAGENCY COORDINATING COUNCIL ON LOW BIRTH 

 WEIGHT AND PRETERM BIRTH AND DISPARITIES SUBCOMMITTEE......................................... 53 

FUTURE DIRECTIONS FOR THE PPB ................................................................................ 55

PANEL DISCUSSION.................................................................................................................... 56 

POSSIBLE BRANCH ACTIVITIES .................................................................................................. 58 

FIGURES AND TABLES ...............................................................FIGURES AND TABLES-1

APPENDIX A: BIOSKETCHES OF BRANCH PERSONNEL ................... APPENDICES-1

APPENDIX B: PPB-SUPPORTED STUDIES THAT 

HAVE IMPACTED CLINICAL PRACTICE ................................................ APPENDICES-3

APPENDIX C: PPB-SUPPORTED CONFERENCES AND WORKSHOPS, 

FISCAL YEAR 2004 THROUGH FISCAL YEAR 2007............................... APPENDICES-7
APPENDIX D: BRANCH SOLICITATIONS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2007.................................................................. APPENDICES-15

APPENDIX E: PUBLICATIONS FROM PPB STAFF AND PPB-SUPPORTED 

NETWORKS, 2004 THROUGH 2008 ........................................................... APPENDICES-17

APPENDIX F: PPB STAFF AWARDS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2008.................................................................. APPENDICES-41

APPENDIX G: EXPERT PANEL MEMBERS........................................... APPENDICES-42
PPB MAJOR MILESTONES AND ADVANCES: 2004-2007 

2004 • January—NICHD-AAP Research & Training in Neonatology Workshop: Ariagno et al. (2005). 

Pediatrics, Feb;115(2), 475-479; Raju et al. (2005). Pediatrics Feb;115(2), 468-474.

• January—NICHD-USAID Periconceptional Nutrition and Pregnancy Outcome Workshop

• January—PPB Strategic Plan distributed to the NACHHD Council

• January—Fetal growth restriction RFA presented to NACHHD Council

• March—Border of Viability Workshop: Higgins et al. (2005). Pediatrics, 115, 1392-1396.

• March—Long-term Followup of Prenatal Drug Exposure: Challenges and Opportunities 

Workshop

• April—Condon et al. (2004). Surfactant protein secreted by the maturing mouse fetal lung 

acts as a hormone that signals the initiation of parturition. PNAS, 101, 4978-4983.

• May—Anand et al. (2004). Effects of preemptive morphine analgesia (NEOPAIN trial). 

Lancet, 363, 1673-1682.

• May—Poindexter et al. (2004). Parenteral glutamine supplementation does not reduce the 

risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics, 113, 

1209-1215.

• August—Fetal Treatment: Needs Assessment and Future Directions Workshop 

• November—Improving Maternal & Infant Nutrition: Development of a Research Plan

• December—Prenatal Screening: Incorporating the First Trimester Studies Conference: 

Reddy et al. (2006). Obstet Gynecol, 107, 167-173.

• December—Landon et al. (2004). Maternal and perinatal outcome in women undergoing trial 

of labor after cesarean delivery. NEJM, 351, 2581-2589. 

2005 • January—State-of-the-Science Conference: Maternal Request Cesarean Delivery (planning 

meeting)

• May—Hypothermia for Perinatal Asphyxia Workshop; Higgins et al. (2006). J Pediatr, 

Feb;148(2), 170-175.

• July—Near-term pregnancy and near-term newborn infant: Optimizing care and long-term 

outcomes: Raju et al. (2006). Pediatrics, Sep;118(3), 1207-1214; 17 papers in two issues of 

Seminars in Perinatology, February and March, 2006.

• July—Van Meurs et al. (2005). Inhaled nitric oxide for premature infants with severe 

respiratory failure. NEJM 7;353(1), 13-22. 

• August—Oxygen in Babies Conference: Higgins et al. (2007). Pediatrics, Apr;119(4), 790-

796.

• September—Infertility Treatment and Adverse Pregnancy Outcome Workshop: Reddy et al. 

(2007). Obstet Gynecol, 109, 967-977.

• October—Shankaran et al. (2005). Whole-body hypothermia for neonates with hypoxicischemic encephalopathy. NEJM, 13;353(15), 1574-1584.

2006 • February—Higgins et al. (2006). Hypothermia and perinatal outcome. Pediatr, 148(2), 170-

175.

• March—State-of-the-Science Conference: Cesarean Delivery on Maternal Request

• March—Mullany et al. (2006). Topical applications of chlorhexidine to the umbilical cord for 

prevention of omphalitis and neonatal mortality in southern Nepal: A community-based, 

cluster-randomised trial. Lancet, 18;367(9514), 910-988. 

• June—Silver et al. (2006). Maternal morbidity associated with multiple repeat cesarean 

deliveries. Obstet Gynecol, 107(6), 1226-1232. 

• June—Consensus Statement Maternal Request Cesarean Delivery. Obstet Gynecol, 107(6), 

1386-1397. 

• July—Landon et al. (2006). Risk of uterine rupture with a trial of labor in women with multiple 

and single prior cesarean delivery. Obstet Gynecol, 108(1), 12-20. 

i 
• July—Bloom et al. (2006). Decision-to-incision times and maternal and infant outcomes. 

Obstet Gynecol, 108, 6-11. 

• August—Perinatal Stroke Workshop: Raju et al. (2007). Pediatrics, Sep;120(3), 609-616.

• September—Prenatal Imaging: Ultrasound and MRI Workshop: Reddy et al. (2008).Obstet 

Gynecol, 112, 145-157.

• October—Bloom et al. (2006). Fetal pulse oximetry and cesarean delivery. NEJM 

23;355(21), 2195-2202. 

2007 • March—Egyptian Bilirubin Meeting: White paper submitted to the NACHHD Council (June) 

• August—Antepartum Fetal Monitoring Workshop

• August—PASS Network Phase II Patient Recruitment Begins

• August—Rouse et al. (2007). A trial of 17 alpha-hydroxyprogesterone caproate to prevent 

prematurity in twins. NEJM, 2;357(5), 454-461. 

• September—International Stillbirth Workshop: Research Definitions

• September—Wapner et al. (2007). Long-term outcomes after repeat doses of antenatal 

corticosteroids. NEJM, 20;357(12), 1190-1198.

• October—Northen et al. (2007). Followup of children exposed in utero to 17 alphahydroxyprogesterone caproate compared with placebo. Obstet Gynecol, Oct;110(4), 865-

872. 

• October—Vaginal Birth After Cesarean Consensus Development Conference (organizational 

meeting)

2008 • January—Initiation of Institute of Medicine Panel: Reevaluation of Pregnancy Weight Gain 

Guidelines

• March—Breastfeeding patterns, time to initiation, mortality risk among newborns in Southern 

Nepal. J Nutr, 138, 599-603. 

• April—Preconception Care Workshop

• April—Tyson et al. Intensive care for extreme prematurity: Moving beyond gestational age. 

NEJM, 358(16), 1672-1681. 

• April—PPB Expert Panel Review 

• April—Electronic Fetal Heart Rate Monitoring Workshop: A Reevaluation 

• June: Surgeon General’s Conference on the Prevention of Preterm Birth 

• August—Neonatal Infection Workshop

• August—Vaginal Birth After Cesarean Consensus Development Conference (planning 

meeting)

• August—Antenatal Testing: A Reevaluation, Special Issue of Seminars in Perinatology

• September—Neonatal Hypoglycemia Workshop 

ii 
EXECUTIVE SUMMARY 

The mission of the Pregnancy and Perinatology Branch (PPB), within the Center for 

Developmental Biology and Perinatal Medicine (CDBPM), Eunice Kennedy Shriver National 

Institute of Child Health and Human Development (NICHD), is to improve the health of mothers 

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

the developing child. The Branch seeks to acquire scientific information that supports its 

mission through basic and clinical research, including: determining basic mechanisms that 

underlie normal and disease processes; identifying new treatments, methodologies, and 

preventive strategies that arise from translational and evidence-based research; assessing the 

dissemination and impact of therapeutic and preventive interventions; and increasing scientific 

resources through recruitment and training of investigators. 

Since its last report to the National Advisory Child Health and Human Development (NACHHD) 

Council, Branch funding has remained relatively stable. The PPB utilizes many existing 

National Institutes of Health (NIH) funding mechanisms to support its activities, which extend 

from basic research to clinical trials (see Figure 1). 

During the past four years, the Branch has expanded significantly, making considerable strides in 

incorporating the obstetric, neonatal, and basic science fields. The Branch’s long-term efforts, 

the Neonatal Research Network (NRN) and Maternal-Fetal Medicine Units (MFMU) Network, 

continue to be very successful. Each year, Network researchers have each given more than 20 

national presentations, have had publications in top-tier journals, and have provided data used by 

professional organizations to guide clinical practice. In addition, through the success of a 

number of initiatives, the Branch has expanded its portfolio to extend and enhance research in 

fetal surgery, stillbirth, periconceptional alcohol exposure, sudden infant death syndrome (SIDS), 

health disparities and preterm birth, and perinatal genetics. (See Appendix B for a listing of 

PPB-supported studies and trials that have impacted clinical practice.) 

Branch activities are organized around five maternal-fetal emphasis areas, which complement 

each other and build a comprehensive approach to research during the pre-, peri-, and postnatal 

periods: High-risk pregnancy, fetal pathophysiology, preterm labor and birth, disorders of the 

newborn, and SIDS. 

The Branch has successfully launched and maintained several time-limited networks, including 

the Management of Myelomeningocele Study (MOMS) Network, the Community Child Health 

Network (CCHN), the Stillbirth Collaborative Research Network (SCRN), the Prenatal Alcohol 

in SIDS and Stillbirth (PASS) Network, and the Genomics and Proteomics Network for Preterm 

Birth Research (GPN/PBR). Several of these networks are the result of collaborations, including 

a few with other NICHD Centers (e.g., CCHN is done in conjunction with the Center for 

Population Research) and with other Institutes (e.g., PASS is maintained in conjunction with the 

National Institute on Alcohol Abuse and Alcoholism; CCHN in conjunction with the National 

Institute of Nursing Research). The Branch also has significant interactions and partnerships 

with many other agencies and NIH Institutes. 

1 Executive Summary 
The Branch members also serve as members of committees for other NIH Institutes, such as the 

Trans-NIH Liver Diseases Subcommittee for the National Institute of Diabetes and Digestive and 

Kidney Diseases, and the Pre and Probiotic Working Group for the National Institute of Allergy 

and Infectious Diseases. In 2006, one Branch member completed a detail at the NIH Office of 

Extramural Research. Branch members also serve as liaisons to major societies in their 

respective fields. 

In December 2002, the Branch held a two-day workshop to develop a strategic research plan for 

2005 to 2010. The results from this workshop were published as the Pregnancy and 

Perinatology Branch, NICHD, A Strategic Plan, 2005-2010. In 2008, as part of the Institute’s 

continued efforts to improve strategic planning for its components, the PPB sought advice and 

feedback from a panel of experts about its possible future research directions for 2009 through 

2013. The panel included experts in the fields of neonatology, pediatrics, maternal-fetal 

medicine, obstetrics, and epidemiology and included members of the NACHHD Council (see 

Appendix G for a list of members). The panel continued the review and analysis of the Branch 

portfolio that was initiated in 2002. The results of the panel’s analysis are included in the Future 

Directions for the PPB section of this report. 

The PPB is convinced that investing efforts and funds in basic and clinical research for mothers’ 

and infants’ health problems will result in significant savings of later expenses for the care of 

patients who develop preventable disabilities and/or diseases. Most importantly, these 

investments will help promote the birth of healthy infants, who are able to achieve their full 

potential for healthy and productive lives. 

INTRODUCTION TO THE BRANCH 

The Pregnancy and Perinatology Branch (PPB), within the Center for Developmental Biology 

and Perinatal Medicine (CDBPM), Eunice Kennedy Shriver National Institute of Child Health 

and Human Development (NICHD), seeks to improve the health of mothers and children by 

focusing on maternal health, pregnancy, fetal well-being, labor and delivery, and the developing 

child. The Branch seeks to acquire scientific information supporting its mission through basic 

and clinical research, including: determining basic mechanisms that underlie normal and disease 

processes; identifying new treatments, methodologies, and preventive strategies that arise from 

translational and evidence-based research; assessing the dissemination and impact of therapeutic 

and preventive interventions; and increasing scientific resources through recruitment and training 

of investigators. 

The PPB utilizes many existing National Institutes of Health (NIH) funding mechanisms to 

support its activities, which extend from basic research to clinical trials (see Figure 1). 

During the past four years, the Branch has expanded significantly, making considerable strides in 

incorporating the obstetrical, neonatal, and basic science fields. The Branch’s long-term efforts, 

the Neonatal Research Network (NRN) and Maternal-Fetal Medicine Units (MFMU) Network, 

Introduction to the Branch 2 
continue to be very successful. Each year, Network researchers have each given more than 20 

national presentations, have had publications in top-tier journals, and have provided data used by 

professional organizations to guide clinical practice. In addition, through the success of a 

number of initiatives, the Branch has expanded its portfolio to extend and enhance research in 

fetal surgery, stillbirth, periconceptional alcohol exposure, sudden infant death syndrome (SIDS), 

health disparities and preterm birth, and perinatal genetics. (See Appendix B for a listing of 

PPB-supported studies and trials that have impacted clinical practice.) 

Branch activities are organized around the following five maternal-fetal emphasis areas, which 

complement each other and build a comprehensive approach to research during the pre-, peri-, 

and postnatal periods: 

• High-risk pregnancy is concerned with those factors, both normal and abnormal, 

influencing the course and outcome of pregnancy; factors include maternal physiology, 

environmental variables, conditions, and treatments that occur during pregnancy, all of which 

contribute to adverse outcomes (e.g., low birth weight). Studies in this area include (but are 

not limited to) elucidating: mechanisms involved in the pathophysiological states of 

pregnancy; health impact of pregnancy-related disorders on mother and infant; pathogenesis 

of symptomatic and asymptomatic maternal infections and their effects on fetal development, 

with the aim of improving treatment and prevention; effects of maternal medications and 

mother’s use and abuse of drugs on fetal development; and adolescent pregnancy. 

• Fetal pathophysiology includes studies of the physiologic, metabolic, endocrine, and 

pharmacologic events related to abnormal development of the fetus; such events include 

morphology, function, and metabolism of the placenta and uterine blood flow. The Branch 

encourages studies in this area to improve existing methodologies for antenatal diagnosis 

regarding fetal status, growth, position, maturity, and well-being. 

• Preterm labor and birth promotes studies of the factors affecting the initiation and 

completion of labor, as well as the physiology, endocrinology, and pharmacology of 

parturition. Of special concern are causes and prevention of preterm labor, threatened and 

habitual pregnancy loss (miscarriage), prolonged and dysfunctional labor, and dystocia. 

• Disorders of the newborn includes basic and clinical studies concerned with the etiology, 

pathophysiology, therapy, and followup of conditions, such as adaptation to extrauterine life, 

hyperbilirubinemia, and sequelae of prematurity (i.e., asphyxia, respiratory distress, 

bronchopulmonary dysplasia, hypoglycemia, anemia, and infection), that are associated with 

the perinatal and neonatal period. 

• SIDS encompasses studies to elucidate underlying mechanisms of SIDS and its probable 

cause(s). Additional research strives to identify infants at risk for SIDS and to develop 

preventive approaches. 

Since its last report to the National Advisory Child Health and Human Development (NACHHD) 

Council, the Branch has successfully launched and maintained several time-limited networks, 

including the Management of Myelomeningocele Surgery (MOMS) Network, the Community 

Child Health Network (CCHN), the Stillbirth Collaborative Research Network (SCRN), the 

Prenatal Alcohol in SIDS and Stillbirth (PASS) Network, and the Genomics and Proteomics 

Network for Preterm Birth Research (GPN/PBR). Several of these networks are the result of 

3 Introduction to the Branch 
collaborations with other NICHD Centers (e.g., CCHN efforts is in conjunction with the Center 

for Population Research) and with other Institutes and agencies (see below). 

The Branch members also serve as liaisons to major societies in their respective fields, including: 

Section on Perinatal Pediatrics of the American Academy of Pediatrics (AAP); the AAP 

Committee on the Fetus and Newborn; the Society for Maternal-Fetal Medicine (SMFM); the 

American College of Obstetricians and Gynecologists (ACOG); the Liaison Committee for 

Obstetricians and Gynecologists. Branch members have also served in advisory capacities for 

professional groups, such as the Cochrane Collaboration Child Health Advisory Board and the 

Vermont Oxford Network. 

The Branch has had significant interactions and partnerships with other Institutes and agencies, 

including (but not limited to): 

• U.S. Department of Health and Human Services (DHHS) Interagency Coordinating Council 

on Low Birth Weight and Preterm Birth 

• Centers for Disease Control and Prevention (CDC)—NRN Cytokine Analysis and Early 

Onset Sepsis Surveillance Study, Stillbirth Research, and Preconception Care 

• U.S. Food and Drug Administration (FDA) 

o With the NIH Office of Research on Women’s Health (ORWH)—Best Pharmaceuticals 

for Children Act (BPCA) Activities, the Breastfeeding Survey, Pregnancy Food Pyramid 

(part of http://MyPyramid.gov) 

o With the MFMU Network and the NRN—Development and Testing of Equipment and 

Investigational Drugs 

o Infant Feeding Practices Study II: NICHD co-funded this study, which was led by the 

FDA; the study was completed in 2007, and the first set of 13 papers will be published in 

a supplement to Pediatrics in October 2008. 

• National Institute of Mental Health (NIMH)—co-sponsor of the program announcement (PA) 

Women’s Mental Health in Pregnancy and the Postpartum Period 

• National Institute of Neurological Disorders and Stroke (NINDS)—co-sponsor of MFMU 

Network studies 

• National Heart, Lung, and Blood Institute (NHLBI)—co-sponsor NRN and MFMU Network 

studies 

• National Eye Institute (NEI)—co-sponsor of NRN studies 

• NIH ORWH—co-sponsor of MFMU Network studies 

• National Institute on Alcohol Abuse and Alcoholism (NIAAA)—co-funder of the PASS 

Network 

• National Institute of Nursing Research (NINR)—co-funder of the CCHN 

• National Institute on Drug Abuse (NIDA)—co-funder of the Maternal Lifestyles Study 

The Branch is among the largest sources of support for research on pregnancy and perinatology. 

Using a combination of funding and training mechanisms, the PPB supported 302 projects for a 

total of more than $94 million (see Table 1, Figure 1, Figure 2, and Figure 3) in fiscal year 2007. 

Introduction to the Branch 4 
In addition to the extensive strategic planning process the Branch went through in 2002, in 2008, 

the PPB also relied on an expert panel to review its portfolio, analyze its activities, and 

recommend future research directions for the Branch. The panel included experts in fields 

relevant to Branch-supported research, public and patient advocates, and members of the 

NACHHD Council (see Appendix G for a list of panel members). The results of the panel’s 

analysis are included in the Future Directions for the PPB section of this report. 

The remainder of this report describes the Branch’s activities, including Branch-supported grants 

and contracts in the five research areas explained above, cooperative agreements, research 

networks, and other activities since the Branch’s last report to the NACHHD Council. 

BRANCH ACTIVITIES: RESEARCH PROJECT GRANTS AND CONTRACTS 

The following section highlights a few of the advances in each Branch research category; due to 

space limitations, all the advances could not be included in this report. Highlights from Branchsupported research networks are summarized separately. 

MATERNAL RESEARCH

This portfolio includes basic, translational, and clinical research studies, which address a myriad 

of issues in pregnancy to understand normal and abnormal physiological events and the effects of 

maternal, acute, or chronic diseases on pregnancy and fetal development. 

Preeclampsia 

Preeclampsia is a major and potentially serious disorder of pregnancy. This hypertensive disease 

affects approximately 7 percent of first pregnancies and 3 percent of all pregnancies. 

Preeclampsia contributes significantly to preterm deliveries in the United States, and, its severest 

form, eclampsia, is a leading cause of maternal morbidity and mortality. Although its exact 

mechanism(s) is unknown, preeclampsia is widely believed to result from poor vascular 

development between the placenta and the uterus. In a normal pregnancy, trophoblastic cells, the 

main type of cell in the placenta, invade deep within the uterus and remodel small uterine arteries 

into large-diameter vessels. In preeclampsia, the trophoblastic cells fail to invade the uterus 

adequately, preventing the normal remodeling process of the uterine vessels. In turn, the poorly 

perfused placenta releases factors into the maternal circulation that result in the systemic 

symptoms of the disease. 

SOLUBLE FMS-LIKE TYROSINE KINASE-1(SFLT-1)

sFlt-1 is thought to play a major role in the pathophysiology of preeclampsia, a disease 

characterized by severe endothelial dysfunction. Levels of sFlt-1 are dramatically increased in 

preeclampsia, and the increase precedes disease manifestation. Furthermore, exogenous 

expression of sFlt-1 in a rodent model leads to a preeclampsia-like syndrome. sFlt-1 is a soluble 

5 Branch Activities: Research Project Grants and Contracts 
form of the receptor that binds vascular endothelial growth factor (VEGF), an essential growth 

factor necessary for the normal functioning of endothelial cells. An abnormally high circulating 

level of sFlt-1 disrupts VEGF by binding to the membrane-bound form of Flt-1 on endothelial 

cells, leading to endothelial dysfunction. It has long been assumed that the major source of 

sFlt-1 production was the trophoblast cells of the placenta. 

Based on the observation that rinsing placental biopsies in saline to remove excess blood resulted 

in an eight-fold decrease in the level of sFlt-1 mRNA, a researcher (supported through another 

PPB-supported investigator’s grant) pursued the reason behind this serendipitous finding. He 

hypothesized that peripheral blood mononuclear cells (PBMCs) could be a significant source of 

extra-placental sFlt-1. He demonstrated that the PBMCs of normal pregnant women could 

produce sFlt-1, and that its production could be further stimulated under hypoxic conditions—a 

known inducer of sFlt-1 via the hypoxia-inducible factor-1 alpha pathway. The researcher 

further demonstrated that PBMCs obtained from women with preeclampsia, under normoxic 

conditions, produced twice the sFlt-1 of those from normal women; under hypoxic conditions, 

the production could be further stimulated an additional two-fold in PBMCs obtained from both 

normal women and women with preeclampsia. Furthermore, analysis of PBMCs obtained from 

women with a history of preeclampsia showed elevated production of sFlt-1 even after one year 

postpartum. Thus, this researcher provided the field with important information on an extraplacental source of sFlt-1. 

However, many important unresolved questions about preeclampsia remain. What is the 

contribution of PBMCs derived sFlt-1 to the total circulating sFlt-1? Are PBMCs activated to 

produce abnormally high levels of sFlt-1 because of their exposure to a hypoxic placental 

environment, or are PBMCs of women predisposed to preeclampsia already sensitized to over 

react to a hypoxic placental environment? How important are activated PBMCs in driving the 

systemic maternal syndrome? Based on the work described above, the talented researcher is now 

a PPB-supported investigator who received his first NIH grant in fiscal year 2007 to answer 

these important questions. 

THE RENIN/ANGIOTENSIN SYSTEM 

This system is an important regulator of systemic blood pressure that is mediated through the 

production of angiotensin II (Ang II), a potent vasoconstrictor, through the action of kidneyderived renin. However, a local renin/angiotensin system is also present in many other tissues, 

including the placenta. Because the level of Ang II increases concomitant with sFlt-1 during 

pregnancy, an investigative team hypothesized that Ang II may promote the expression of sFlt-1. 

They demonstrated that infusing pregnant mice with Ang II resulted in an increased level of 

circulating sFlt-1. Furthermore, Ang II stimulated sFlt-1 production in human villous explants, 

as well as in purified human trophoblast cells in culture. The team also demonstrated that Ang 

II-mediated sFlt-1 production was mediated through the Ang II type 1 receptor. Thus, this team 

discovered a previously unrecognized signaling pathway involved in sFlt-1 production. The 

team speculates that this pathway may be important in the pathophysiology of preeclampsia. 

Although it is known that the levels of sFlt-1 are elevated in women with preeclampsia, while the 

level of Ang II is not, women with preeclampsia often show activation of autoantibodies to the 

Ang II type-1 receptor, which mimics the action of Ang II. 

Branch Activities: Research Project Grants and Contracts 6 
DISCOVERY OF BIOLOGICAL MARKERS 

Biological markers that signal impending disease and its severity are critically important for the 

effective clinical management of the patient, as well as for providing a research tool that can 

increase the specificity of studies. One investigative team has been particularly active in 

studying the biological markers of preeclampsia. Hyperuricemia is common in preeclampsia and 

is manifested early in pregnancy. In addition, uric acid is known to promote inflammation, 

oxidative stress, and endothelial dysfunction, all of which are associated with preeclampsia. The 

investigative team hypothesized that the measurement of uric acid might be an additional marker 

of adverse pregnancy outcome in gestational hypertension. 

They examined fetal outcome data from 972 pregnancies. Subjects were nulliparous with no 

known medical complications prior to pregnancy. Analytes were measured from specimens 

taken at admission for delivery. The frequency of preterm birth, the duration of pregnancy, 

frequency of small-for-gestational-age (SGA) infants, and birth weight centile were examined in 

the presence or absence of combinations of hypertension (H), hyperuricemia (U), and proteinuria 

(P). The relative risk (RR) for a preterm birth was significantly increased in the groups of 

women with HU (RR = 3.3) and HPU (RR = 9.7), but no significant difference was found in the 

other groups (H, P, U, HP, PU) compared to controls. The relative risk for an SGA infant, at less 

than the 5th percentile, was significantly increased in the groups of women with HU (RR = 4.6), 

PU (RR = 7.4), and HPU (RR = 2.2); however, researchers found no significant difference in the 

other groups (H, P, U, HP) compared to controls. In addition, the mean gestational age (GA) in 

weeks at delivery was also significantly reduced in women with HU (GA = 38.7), 

PU (GA = 38.0), and HPU (GA = 35.4) compared to all the other groups. Hence, the risk of 

these adverse outcomes increased with the incidence of hyperuricemia. The utility of the 

measurement of uric acid for the prediction of adverse pregnancy outcomes warrants further 

examination, especially for measurements taken early in pregnancy. 

Exercise and Pregnancy 

Regular physical activity during pregnancy and its potential to redistribute blood flow away from 

the uterus and viscera and to affect placental morphology and function are other areas of study 

for PPB-funded investigators. Pregnant women are often advised not to engage in supine 

exercise out of concern that direct pressure of the gravid uterus on the inferior vena cava will 

decrease venous return, cardiac output, and uterine blood flow. With the use of Doppler 

ultrasound, a PPB-supported team measured uterine artery diameter and flow rates for pregnant 

women (at 28 weeks to 38 weeks of gestation) at rest on their left sides and in the supine 

position. In addition to documenting a decrease in uterine blood flow while supine, these 

researchers also documented a concomitant decrease in the uterine artery luminal diameter. This 

unexpected finding suggests that the uterine vasculature may be more vasoreactive than 

previously assumed. During supine exercise (e.g., stomach crunches and leg lifts), uterine blood 

flow increased to a level not significantly different from that resulting from the left lateral 

position. These results suggest that the proscription against supine exercise in pregnancy may 

need to be reconsidered. 

In another study, this same team examined the placentae of a group of women who engaged in 

frequent moderate- to high-intensity running throughout pregnancy, and a group of pregnant 

women who were physically active, but who did not participate in regular weight-bearing 

7 Branch Activities: Research Project Grants and Contracts 
exercise. They found that regular running was associated with increased cellular proliferation 

and increased villous vascular volume in the placenta. Avenues for further research include 

study of the mechanisms by which regular weight-bearing exercise stimulates placental growth, 

and whether an exercise regimen could be of benefit for preventing or treating anomalous 

fetoplacental growth. 

Pregnancy and Subsequent Health 

A growing body of evidence indicates that women who experience preeclampsia during 

pregnancy are at increased risk for cardiovascular disease later in life. Preeclampsia may arise in 

women who have underlying cardiovascular risk factors, such as insulin resistance and chronic 

inflammation, that are unmasked by the physiological stress of pregnancy, and that persist after 

delivery. Other pathophysiologic mechanisms involved in preeclampsia and potential targets for 

prevention and therapy are under active pursuit by PPB-funded investigators. Earlier work 

indicated that a majority of preeclamptic women experienced an abnormal immune response, 

called autoimmunity, in which their bodies produced antibodies against one of their own 

proteins; these antibodies are called autoantibodies. Autoantibodies target a receptor, designated 

AT-1, that is involved in mediating the effects of Ang II, described earlier and involved in the 

contraction of blood vessels. In contrast to most antibodies that neutralize their targets, 

autoantibodies actually activate AT-1 receptors. Researchers speculate that these autoantibodies 

are responsible for the hypertension associated with preeclampsia because of the ability of these 

substances to contract blood vessels. 

Agonistic Ang II type-1 receptor autoantibodies (AT1-AA) have been detected in women with 

preeclampsia and may contribute to the syndrome through activation of the Ang II type-I 

receptor, causing vasoconstriction and hypertension. It is not clear whether these autoantibodies 

remain in the maternal system after delivery, or whether they contribute to later cardiovascular 

risk. A PPB-funded group of researchers examined serum levels of AT1-AA and other factors at 

18 months postpartum in women who had preeclampsia and in women who had normal 

pregnancies. AT1-AA were present in a significantly higher proportion of women who had a 

history of preeclampsia than in normal controls. Women with autoantibodies had higher sFlt-1 

levels, lower VEGF levels, and higher insulin resistance compared to women without 

autoantibodies. AT1-AA have already been linked to a variety of cardiovascular conditions, 

meaning they may also be a marker for future development of cardiovascular disease in women 

who had preeclampsia. 

Microchimerism refers to the presence of two distinct cell populations, originating from two 

different individuals, that co-exist in a single person. Fetal cell microchimerism arises from the 

transfer of fetal cells into the maternal circulation during pregnancy. This transfer occurs in all 

pregnancies, and fetal cells are known to persist in maternal blood and tissues for many years. A 

number of studies have implicated fetal microchimeric cells as factors related to later 

autoimmune illness, such as systemic sclerosis, in parous women. Recent evidence, however, 

indicates that fetal microchimeric cells have the potential to differentiate into hepatic, epithelial, 

and leukocyte phenotypes, meaning they may be involved in maternal tissue repair. To explore 

potential beneficial effects of fetal microchimerism, a PPB-funded investigator assessed the 

presence and quantity of fetal cells in the maternal livers of parous mice exposed to chemical or 

surgical hepatic injury and of control animals. Polymerase Chain Reaction (PCR) results showed 

Branch Activities: Research Project Grants and Contracts 8 
that, after chemically induced hepatic injury, but not after surgically induced hepatic injury, fetal 

cells were detectable in the maternal liver and spleen, and that the number of fetal cells increased 

significantly over time post-injury. These findings suggest a novel role for fetal microchimeric 

cells in maternal health, with possible dynamic involvement in injury type-specific tissue repair. 

Further studies to assess the fetal cells’ phenotype, whether they migrate to the site of injury or 

proliferate locally, and whether they improve tissue recovery and function are warranted. 

Mood Disorders in Pregnancy and Postpartum 

Peripartum mood disorders are common and cause substantial morbidity in women, their infants, 

and families. Depression affects approximately 10 percent to 15 percent of pregnant women. A 

history of antenatal depression increases the risk of postpartum depression, which also affects 

10 percent to 15 percent of women postpartum. The treatment of antenatal depression is 

challenging because it is not yet clear how best to balance antidepressant medication and 

untreated depression in terms of risk to mother and infant. A PPB-funded researcher conducted a 

prospective study of groups of pregnant women, with mild to moderate depression, who were or 

were not using antidepressants compared to a group of healthy controls. Women using 

antidepressants were significantly more likely to experience preterm birth and had a lower mean 

gestational age at delivery (GAD) than women with untreated depression and than normal 

controls. There seemed to be an inverse relationship between dose of antidepressant and GAD. 

There was no difference in GAD or preterm birth rate between untreated women and healthy 

controls. Though questions still remain, this study provides important information for clinicians 

to consider when counseling pregnant women who have depression. 

Obesity is a well-described risk factor for depression. Given the dramatic rise of obesity among 

women of childbearing age, could an epidemic of perinatal mood disorders also be developing? 

To address this question, one PPB-funded investigator conducted a population-based study of the 

relationship between self-reported prepregnancy body mass index (BMI) and depressive 

symptoms in a cohort of women at two months to four months postpartum. Moderate or greater 

depressive symptoms were more commonly reported by women at the extremes of BMI, i.e., 

those who were underweight (BMI < 19.8) or obese (BMI > 29). This preliminary work 

suggests that further research into the possible association between postpartum depression and 

extremes of BMI is warranted. 

Mechanisms of Abnormal Placentation 

Preeclampsia is thought to result from abnormal placental development early in pregnancy. 

Better understanding of the mechanisms of early placental development may lead to novel 

preventive or therapeutic measures for preeclampsia and other placental disorders. Under 

normal conditions, specialized cells of the placenta (called cytotrophoblasts) aggressively invade 

the uterus to graft the embryo onto the maternal blood supply. This process is more akin to 

tumorigenesis than to organogenesis. The invasive property of the cytotrophoblast is normally 

limited and, once the maternal-fetal blood supply is established, the cytotrophoblasts 

differentiates to a non-invasive cell type. The mechanism by which this switch from an invasive 

to non-invasive cell type occurs is unknown. PPB-funded researchers have shed light on this 

important process. They demonstrated that the switch from an invasive to non-invasive cell type 

is associated with aneuploidy, specifically an increased number of specific chromosomes. 

Aneuploidy also correlated to reduced cell proliferation. This finding is a conundrum because 

9 Branch Activities: Research Project Grants and Contracts 
aneuploidy is a condition in which the chromosome number of a cell is abnormal and is generally 

a characteristic of an abnormal or tumor cell. The researchers speculate that aberrations in 

chromosome number are a normal part of cytotrophoblast differentiation, rather than an anomaly, 

and that these aberrations limit the cells’ invasive and proliferative potential. This finding may 

be a plausible mechanism for holding these fetal cells with tumor-like properties in check. In 

addition, abnormalities in this process may be associated with a number of pregnancy disorders 

due, in part, to either poor cytotrophoblast invasion (i.e., fetal growth restriction and 

preeclampsia) or excessive invasion (i.e., placental increta and percreta). 

Another PPB-funded team has also been studying the mechanisms underlying abnormal 

placental development and impaired trophoblast invasion. This investigative team hypothesized 

that viral infections of the placenta induce pathological changes, which impair trophoblast 

invasion into the uterine wall, resulting in adverse pregnancy outcomes due to placental 

dysfunction. Generally, approximately 40 percent to 80 percent of adults are infected with the 

adeno-associated virus-2 (AAV-2). In earlier work, the investigators used detection of AAV-2 

IgG antibodies to determine that approximately 83 percent of pregnant women had been 

previously infected by AAV-2; however, previous exposure to AAV-2 before pregnancy was not 

associated with poor pregnancy outcome. In contrast, active infection during pregnancy, either 

due to a first exposure or to activation of the virus from a previous infection, was associated with 

severe preeclampsia and other adverse pregnancy outcomes. 

Extending this work, the research team recently demonstrated that trophoblast cells in vitro can 

be easily infected with AAV-2, resulting in an inhibition of their invasive properties. 

Furthermore, AAV-2 DNA was found five-times (55 percent) more frequently in trophoblast 

cells from the placentas of women who had severe preeclampsia than in those of normal women 

(18 percent). These results indicate that a common virus is associated with a frequently observed 

poor pregnancy outcome, and that its mechanism of action targets the trophoblast cells of the 

placenta to cause impaired trophoblast function. This research suggests that viral infection may 

play a more significant role in poor pregnancy outcomes than previously recognized. Additional 

research is warranted to determine the susceptibility of the placenta to other types of common 

viral infections and their effects on pregnancy outcome. 

FETAL RESEARCH

Prenatal Diagnosis 

Fetal research, including prenatal diagnosis, remains a key area of interest for the PPB and its 

supported researchers. The recent explosion in high-throughput genotyping technologies may 

offer important advances in prenatal diagnostics. However, current microarrays used for many 

clinical conditions, such as cancer, are too expansive for prenatal testing. Recent work has 

shown that significant genomic variations, including relatively large deletions, are common 

between normal individuals; therefore, only microarrays crafted to minimize incorrect or 

uninterpretable results, yet capable of maximizing identification of clinically relevant mutations 

will be acceptable for accurate prenatal testing. Studies will also require analyses of large 

numbers of pregnancy samples to not only confirm diagnostic equivalency to cytogenetic testing, 

but also to develop sufficient knowledge of the clinical significance of additional findings 

Branch Activities: Research Project Grants and Contracts 10 
resulting from a given method. Although researchers have conducted preliminary studies using 

novel diagnostic methods on children who have clinical conditions suspicious for a 

microdeletion, these studies typically have not addressed the unique questions raised in relation 

to prenatal testing. These and other issues need to be addressed before any new diagnostic 

method is incorporated into regular practice. 

One PPB-supported study is exploring the accuracy and efficacy of Comparative Genomic 

Hybridization Microarrays (CGH-MA) compared to the present clinical standard of prenatal 

cytogenetic diagnosis. This study will evaluate the use of CGH-MA on a cohort of pregnancies 

with abnormal pregnancy outcomes, such as congenital anomalies, stillbirth, growth restriction, 

or repeat miscarriages. It is likely that CGH-MA may identify subtle small deletions, insertions, 

or duplications, which could eventually lead to knowledge about the origins of these conditions 

and facilitate future counseling. Successful demonstration of the accuracy of CGH-MA in 

prenatal diagnosis could also allow for its routine use in clinical care and could significantly 

increase access to the technology by all pregnant women. CGH-MA also has un-assessed 

potential for revealing common changes in the genome that do not have clinical significance, but 

that if not completely evaluated, could result in incorrect or false-positive diagnoses and patient 

anxiety. It is important, then, to determine the appropriate application of the method and the 

genetic counseling that should accompany it before making it standard practice. 

Fetal Origins of Adult Diseases 

A significant portion of the PPB portfolio deals with research in the area of the fetal origins of 

adult diseases. Much of this research stems from the early epidemiological work of Barker that 

showed a relationship between low birth weight and the development cardiovascular disease. 

During the last decade, this research area has burgeoned; substantial epidemiological and animalbased research has not only supported the original concept, but has also expanded it. Currently, 

research posits that an inadequate prenatal environment, leading to either a low birth weight, 

(e.g., due to poor maternal nutrition, placental insufficiency or dysfunction), high birth weight 

(e.g., due to gestational diabetes), or fetal stressors (e.g., resulting in elevated fetal cortisol 

production), may permanently alter and program the fetus for the onset of many diseases later in 

life. The diseases associated with this process are broad and include hypertension, diabetes, 

cardiovascular disease, and obesity, as well as psychiatric and behavioral disorders. The gross 

phenomena are well documented; the challenge now is to understand the molecular mechanisms 

behind the processes of fetal programming. Although it is not possible to describe all the work 

of PPB-supported investigators in this area due to space limitations, the following section 

highlights some of these efforts. 

One research team studied the effect of administering antenatal glucocorticoids on offspring 

development of hypertension in adulthood. Using a sheep model, pregnant ewes at 80 days 

(0.6 gestational interval) of gestation were treated for two consecutive days with betamethasone 

or placebo. Fetal kidneys were analyzed at 81 days and 135 days (0.9 gestational interval) of 

gestation. The investigators showed that certain key renal regulatory molecules were acutely and 

chronically affected following betamethasone treatment. At day 81 of gestation, the levels of 

Na/H exchanger 3 (NHE3) were increased, levels of Ang II receptor (AT2R) were decreased, 

and there was no change in the Na, K-ATPase pump (NKAP), angiotensin 1 receptor (AT1R), or 

type 1 dopamine receptor (T1DR). At day 135 of gestation, levels of AT2R remained decreased, 

11 Branch Activities: Research Project Grants and Contracts 
but T1DR was increased, and there was no change in the levels of NKAP, NHE3, or AT1R. In 

addition, at 135 days of gestation, the kidneys of fetuses exposed to betamethasone had a 

26-percent decrease in the number of glomeruli but no difference in kidney weight. In 

betamethasone-treated young adults at six months of age, the mean systolic and diastolic blood 

pressures were significantly elevated compared to non-treated young adults, but there was no 

significant difference in heart rate. These results suggest that even a transitory increase in the 

glucocorticoid exposure levels in the fetus can have long-lasting effects and can lead to 

hypertension in adulthood. Thus, fetuses exposed to stressors that increase the fetal production 

of cortisol may also be at higher risk for adult-onset hypertension. These results may also have 

important implications for human neonates who are exposed to antenatal steroids as a way to 

accelerate fetal lung maturity prior to delivery. 

Another PPB-supported team used a non-human primate model to study the effect of maternal 

nutrient restriction in early gestation on the fetal kidney. Pregnant baboons were nutrient 

restricted by feeding them 70 percent of their normal diet on a weight-adjusted basis from 

30 days (0.2 gestational interval) through 90 days (0.5 gestational interval) of gestation. At 

90 days, researchers collected fetal kidneys and conducted global mRNA expression analysis and 

histology. Findings indicated that nutrient restriction resulted in a down-regulation of genes in 

pathways related to RNA, DNA, and protein biosynthesis, metabolism, and catabolism. In 

contrast, genes in cell signal transduction, communication, and transport pathways were upregulated. Histology indicated decreased tubule density within the kidney cortices of nutrientrestricted fetuses. Because glomerular cross-sectioning per unit area was unaffected by nutrient 

restriction, it could be that tubule tortuosity and/or tubule length was decreased. Taken together, 

the changes indicated that nutrient restriction results in accelerated fetal renal differentiation, 

thus shortening critical phases of renal growth. This shortening may lead to decreased functional 

capacity of the kidney, resulting in hypertension later in life. 

A Branch-funded investigative team studied the effect of nutrient restriction on fetal heart 

development. Using a sheep model, researchers studied placental insufficiency caused by 

umbilicoplacental embolization (UPE). After undergoing UPE at 115 days of gestation 

(0.8 gestational interval), instrumented fetal sheep were weighed and measured 10 days and 

20 days later. UPE-treated fetuses weighed less (10 days = -20 percent; 20 days = -27 percent) 

than control fetuses, but their heart dimensions and weight were appropriate for their reduced 

weights. Results indicated that 10 days of UPE did not significantly alter the proportion of 

binucleated myocytes or cell-cycle activity in either ventricle. In contrast, 20 days of UPE 

treatment resulted in a 16-percent decrease in the proportion of binucleated myocytes in both 

ventricles and reduced cell cycle activity in both ventricles by 70 percent. These findings are 

indicative of a less mature myocardium, which may lead to cardiac problems later in life. 

Fetal Growth 

Normal fetal growth requires the fetus to effectively interface with maternal circulation to ensure 

that it receives an adequate supply of nutrients and to maintain the proper exchange of gases and 

waste products. This interface occurs at the level of the placenta. Perturbed or abnormal 

placental development is associated with a number of serious pregnancy conditions, such as 

miscarriage, fetal growth restriction, and preeclampsia. One PPB-supported investigative team 

studied the role of a specific gene during pregnancy within the context of fetal growth. The gene 

Branch Activities: Research Project Grants and Contracts 12 
codes for a protein called adrenomedullin, whose function in pregnancy was poorly understood. 

The blood level of this protein increases to very high levels during pregnancy; in the last 

trimester, the level is 500 percent higher than in the non-pregnant state. To learn more about the 

protein’s function, the investigators genetically engineered mice to have only one copy of the 

gene and mated them to one another or to normal mice, which have two copies of the gene. The 

genetically engineered pregnant female mice with only one copy of the gene had more placental 

defects and growth-restricted fetuses than did normal mice. Fetuses lacking all copies of the 

adrenomedullin gene were more severely affected. These results indicate that adrenomedullin 

plays an important role in pregnancy, and that maternal-derived and fetal-derived 

adrenomedullin are both important for normal placental development and the proper growth of 

the fetus. This research suggests that lower levels of adrenomedullin gene expression can 

adversely impact pregnancy. Identifying individuals with such defects before pregnancy and 

treating them during pregnancy with potential therapies to restore normal adrenomedullin levels 

could be beneficial. 

Intrauterine growth restriction (IUGR) is a major cause of perinatal morbidity, death, and longterm complications, such as diabetes and hypertension in adulthood. IUGR often arises in a 

setting of uteroplacental insufficiency, a situation in which inadequate oxygen delivery results in 

chronic fetal hypoxia. A PPB-supported investigative team is examining hypoxia’s influence on 

key fetal growth factors and on gene expression. For example, the action of insulin-like growth 

factor 1 (IGF-1), a major growth promoter in fetal tissues, is blocked by binding to insulin-like 

growth factor binding protein 1 (IGFBP-1). Using an animal model, this team showed that 

exposure to chronic hypoxia significantly increased fetal IGFBP-1 expression, which may 

directly impair fetal growth, or may block growth by inhibiting the action of IGF-1. Studies of 

time-dependent fetal-tissue gene expression revealed that hypoxia results in tissue-specific 

alterations that differ by the duration of hypoxic exposure. For instance, growth-related genes 

were consistently suppressed, regardless of hypoxia duration, and genes involved in glycolysis, 

calcium homeostasis, and inflammation were induced by hypoxia of varying duration. 

Understanding the mechanisms by which hypoxia produces growth failure is key to development 

of interventions to prevent or treat IUGR. 

Prenatal diagnosis of fetal hematologic and genetic disorders offers the opportunity for 

therapeutic intervention before birth. In utero hematopoietic-cell transplantation (IUHCT) refers 

to the introduction of hematopoietic stem cells into the fetus, ideally serving as a donor tissue 

graft or inducing donor-specific tolerance to facilitate postnatal cellular and organ 

transplantation. Consistent and high-level donor-cell engraftment in such cases is often 

hampered by host-cell competition and dominance in hematopoietic tissues. Researchers 

supported by the PPB are investigating mechanisms by which donor cells could be given a 

competitive advantage over host cells and, thus, establish longer-term engraftment. Using a 

mouse model, the research team is focusing on the process by which donor cells home in on fetal 

hematopoietic tissues. This research focuses on CD26, a membrane-bound exopeptidase 

expressed on some hematopoietic stem cells and progenitor cells, which impair donor-cell 

homing by cleaving a chemokine (SDF-1α) involved in attracting circulating donor cells to the 

bone marrow cavity. By injecting donor cells, in which CD26 activity was inhibited, into 

recipient animals, researchers not only significantly increased donor-cell homing, but also 

significantly enhanced donor-cell engraftment and establishment of macrochimerism. This study 

13 Branch Activities: Research Project Grants and Contracts 
demonstrates that the goal of establishing longer-term hematopoietic allografts during fetal life 

may be addressed by improving donor cells’ ability to home in on host hematopoietic tissues. 

LABOR AND DELIVERY RESEARCH

Labor is a complex and interwoven physiological process involving fetal, placental, and maternal 

signals. A number of stimulatory and inhibitory mechanisms that play different roles in uterine 

contractility, fetal membrane integrity, and cervical maturation have been identified. The Branch 

promotes studies of the physiology, endocrinology, and management of preterm, term, and postterm deliveries. 

Understanding the normal physiological and biochemical events that occur during parturition is 

essential for successful interventions for and prevention of preterm labor. Preterm births are 

increasing in the United States and occur in more than 12 percent of all births, accounting for 

more than 75 percent of all perinatal morbidity and mortality. Excluding congenital 

malformations, preterm birth accounts for approximately 70 percent of all neonatal deaths and 

nearly 50 percent of long-term neurological problems. These long-term neurological problems 

include serious physical and mental disabilities, such as cerebral palsy, intellectual and 

developmental disabilities, and vision and hearing loss. Delaying a very preterm birth even by 

days or weeks has profound effects on reducing neonatal mortality and morbidity. The PPB and 

the NICHD have made significant research investments in understanding the causes and 

mechanisms that underlie preterm labor and delivery. The brief descriptions below highlight 

some findings from PPB-funded efforts related to labor and delivery, including preterm labor and 

delivery. 

One of the prerequisites for a successful birth is that the newborn be able to breathe on its own 

following delivery. The ability to breathe is critically dependent on the production of 

surfactant—a mixture of proteins and lipids that prevents the lungs from collapsing during 

normal breathing—by the lungs. During the last trimester of pregnancy, surfactant production is 

initiated by the fetal lungs and reaches maximal levels just before birth. Hence, it would make 

sense that the ability to breathe and the timing of birth would be coordinated, although no 

evidence has demonstrated such a relationship. A PPB-supported researcher has shown, 

however, that a surfactant protein, SP-A, may be involved in the timing of delivery. Using a 

mouse model of parturition, the researcher demonstrated that increasing levels of SP-A, secreted 

by the fetal lung into the amniotic fluid, induce an inflammatory response in the uterus by 

activating macrophages present in the amniotic fluid. The activated macrophages migrate to the 

uterine wall, where they produce inflammatory cytokine interleukin-1, which activates a 

transcription factor, called nuclear factor-kappa beta (NF-kB), in uterine muscle cells. The 

activation of NF-kB turns on a molecular cascade, resulting in increased uterine contractility and 

parturition. 

Further research also indicated a role for SP-A in mediating parturition; compelling evidence 

suggested that the injection of SP-A into the amniotic fluid induces preterm delivery, and that the 

injection of an SP-A neutralizing antibody delays delivery. The discovery that SP-A secreted by 

the fetal lung can act as a signal for the initiation of parturition serves as a valuable paradigm 

Branch Activities: Research Project Grants and Contracts 14 
illustrating the intricate relationship between the maturation of the fetus and the timing of 

delivery. Thus, the fetus can signal the uterus to indicate that its lungs are sufficiently mature to 

switch from an aqueous to an air environment. Blocking or reversing this signal, then, may be a 

way to delay parturition, even after the process has begun. 

During 95 percent of human pregnancy, the uterus is maintained in a state of almost complete 

quiescence by elevated levels of circulating progesterone. Myometrial levels of the progesterone 

receptor (PR) remain elevated throughout pregnancy and into labor. Spontaneous labor, then, is 

likely mediated by a concerted series of biochemical events that negatively impacts the ability of 

PR to regulate target genes, which maintain myometrial quiescence. One investigative team has 

been actively studying the molecular mechanisms involved in this process. They hypothesized 

that progesterone/PR inhibits uterine contractility by blocking NF-kB and the induction of 

cyclooxygenase-2, a contractile gene that is up-regulated during labor. The investigators 

identified a novel role for PR as a potent anti-inflammatory factor in the myometrium. They 

found that progesterone acts through PR to play a major anti-inflammatory role in human 

myometrial cells by antagonism of NF-kB activation and the subsequent induction of COX-2, the 

crucial and rate-determining enzyme in prostaglandin biosynthesis. Because prostaglandins play 

a critical role for inducing myometrial contractions, prostaglandin activity likely underlies the 

action of progesterone/PR to maintain myometrial quiescence throughout pregnancy. 

Research to understand preterm birth, which accounts for approximately 500,000 births annually, 

is ongoing. Approximately 50 percent of preterm births occur spontaneously following the 

premature onset of labor. In addition, many pregnant women experience false preterm labor, i.e., 

preterm contractions that do not result in a preterm delivery. An effective screening method to 

determine which women are in spontaneous preterm labor and which ones are simply having 

preterm contractions would allow clinicians to start necessary treatment for those having true 

preterm labor and to avoid unnecessary treatment and hospitalizations for those who are not. To 

develop such a screening method, one PPB-supported investigative team used uterine 

electromyography (EMG), placement of electrodes on the abdomens, to measure the uterine 

activity of women in preterm labor, in term labor, and not in labor. The researchers then used an 

artificial intelligence neural-network computer program to analyze the data and classify the 

various groups based on their EMGs. This method correctly differentiated more than 90 percent 

of the women in preterm labor from those in labor at term and from those not in labor. This noninvasive method may provide clinicians with a new tool for properly treating women who are in 

labor and women who are not. 

Approximately 10 percent of preterm births occur because of preterm premature rupture of 

membranes (pPROM), which leads to either a spontaneous or medically induced delivery. In 

addition, African American women have a two-fold increase in the risk of pPROM compared to 

Caucasians. A PPB-supported investigative team studied whether genetic differences between 

the two groups could account for this health disparity. Using a candidate-gene approach, 

researchers previously showed that certain single nucleotide polymorphisms (SNPs) increase the 

promoter activity of genes encoding matrix metalloproteinases, enzymes which break down 

collagen; this increased activity is associated with an increase risk of pPROM in African 

Americans. Using a similar approach, the team hypothesized that a particular SNP at position 

-656 in the promoter of the SERPINH1 gene, which codes for a chaperone protein essential for 

15 Branch Activities: Research Project Grants and Contracts 
collagen synthesis, may be associated with an increased rate of pPROM in African Americans 

because the polymorphism is more common in people of African descent. The research 

confirmed that the -656 T minor allele, compared to the -656 C major allele, is 2.7 times to 

5.8 times more common in certain African populations than in Western European Caucasians. In 

African Americans, the -656 T allele was increased by 1.7 times compared to European 

Americans. Using functional genetic-construct studies of amnion fibroblasts, the same group 

also demonstrated that the -656 T allele construct had much less promoter activity than the major 

-656 C allele construct. Furthermore, the -656 T allele was increased three fold in African 

American neonates born from pregnancies complicated by pPROM compared to controls. 

Together, these results suggest that differences in allele frequencies between populations may be 

responsible, in part, for the health disparity observed in the incidence of pPROM. 

Most of the infant mortality and morbidity of preterm birth is associated with the 1 percent to 

2 percent of infants born extremely preterm (birth at less than 32 weeks of gestation). A 

significant percentage of preterm births that occur less than 32 weeks of gestation are associated 

with infection. Unfortunately, tocolysis or antibiotic treatments are ineffective for preventing or 

significantly delaying delivery in these cases. Using a non-human primate model (rhesus 

macaque), a PPB-supported investigative team has focused on this problem. They have shown 

that antibiotic treatment before the onset of uterine contractile activity eliminated group B 

streptococcus (GBS)-induced infection, prevented elevations of inflammatory mediators 

(IL-1beta, -6, and -8; TNF-alpha; prostaglandins), and prevented preterm delivery. Antibiotic 

treatment given after the onset of uterine contractions eliminated the infection; however, it 

prevented neither the elevations of inflammatory mediators nor preterm delivery. These results 

indicate that, once inflammatory mediators are elevated by infection and reach a threshold, the 

inflammatory process can no longer be reversed by antibiotic treatment alone. 

The investigators then hypothesized that a combination of both antibiotics and anti-inflammatory 

agents may be effective in preventing or at least significantly delaying an infection-induced 

preterm delivery. As a proof of principle to test the hypothesis, a small number of pregnant 

rhesus monkeys were inoculated with GBS to induce uterine contractions; monkeys then 

received no treatment, were treated with antibiotic (ampicillin) alone, or were treated with 

antibiotic in combination with anti-inflammatory agents (dexamethasone and indomethacin). 

The mean interval from contraction onset to delivery was 1.4 days in the untreated group, 

3.4 days in the antibiotic-treated group, and 8.9 days in the antibiotic/anti-inflammatory-treated 

group. As expected, antibiotic and anti-inflammatory agent treatment significantly suppressed 

the level of inflammatory mediators in the amniotic fluid compared to either the control or 

antibiotic group. Therefore, antibiotic treatment, in combination with anti-inflammatory agents, 

may be a useful intervention to prevent infection-induced preterm labor. More research is 

clearly warranted in this promising area. 

Reproductive epidemiology—specifically research on the rising rates of cesarean section 

deliveries in the United States—has also been a focus of PPB-funded researchers. Despite the 

Healthy People 2010 goal of decreasing cesarean births, the cesarean delivery rate in the United 

States has risen steadily since 1996, reaching an all-time high (more than 30 percent) in 2005. A 

major driving force behind the increase in cesarean births is the declining rate of vaginal birth 

after cesarean (VBAC). In 1996, delivery by VBAC peaked at 28.3 percent; by 2004, VBAC 

Branch Activities: Research Project Grants and Contracts 16 
rates had dropped to 9.2 percent. PPB-supported researchers have studied the safety of VBAC, 

which is associated with risks of uterine rupture, need for hysterectomy or transfusion, and 

endometritis. Investigators reviewed more than 25,000 records from women who had prior 

cesarean deliveries; the data included women served by tertiary and community hospitals and at 

facilities with and without obstetrics/gynecology residency programs, making the results more 

generalizable to a wider spectrum of obstetric patients. Data showed that the incidence of uterine 

rupture among women who had a prior cesarean and who attempted VBAC was less than 

1 percent; this figure is important because some have suggested that the occurrence of uterine 

rupture is on the rise in the United States. Researchers also found that a prior vaginal delivery 

was associated with a 60-percent reduction in the likelihood of rupture. However, uterine 

rupture in those attempting VBAC delivery, in general, could not be accurately predicted. This 

large, generalizable, observational study of maternal VBAC safety found that the overall 

incidence of uterine rupture in those attempting VBAC was quite low, less than 1 percent in 

2000. The investigators concluded that women who had a prior cesarean should be offered 

VBAC, and that women with a prior cesarean and prior vaginal delivery should be encouraged to 

use VBAC. 

The Branch also funds a diverse portfolio on the circumstances of parturition, with projects that 

use physiological, biochemical, and molecular approaches to elucidate the various mechanisms 

involved, including (but not limited to): the role of the hypothalamic-pituitary-adrenal axis in 

both preterm and term labor; the involvement of hormones such as corticotropin-releasing 

hormone, adrenocorticotrophic hormone, cortisol, and androgens in parturition; mechanisms, 

such as infection, cytokine production, and extracellular matrix biology, involved in pPROM; 

and uterine relaxation and contraction factors, such as nitric oxide (NO), oxytocin, relaxin, 

steroids, and prostaglandins, and their mechanisms of action. This research will provide a better 

understanding of the mechanisms responsible for parturition to help promote successful labor 

and deliveries. In addition, the clinical, translational, and epidemiological research funded by 

the Branch augments its basic science research in the development of preventive and therapeutic 

measures necessary to optimize pregnancy outcomes. 

NEONATAL RESEARCH

The Branch supports basic and clinical studies concerned with the etiology, pathophysiology, 

therapy, and followup of conditions associated with the perinatal and neonatal period; these 

include adaptation to extrauterine life, hyperbilirubinemia, and sequelae of preterm birth, such as 

asphyxia, respiratory distress, bronchopulmonary dysplasia, hypoglycemia, anemia, and 

infection. In addition to the PPB, other NICHD Branches and NIH Institutes support neonatal 

research. Funded projects share the common aim of clarifying neonatal physiology and 

pathology to permit further developments in the care of these infants. Results from some 

Branch-supported activities are described below. 

17 Branch Activities: Research Project Grants and Contracts 
Estrogen Receptors and Endothelial Cells 

New blood vessel development in the ovary, uterus, and placenta is regulated by estradiol-17β

(E2) acting through estrogen receptor α (ERα). The underlying processes include direct actions 

of E2 on endothelial cells to promote growth and migration. These mechanisms also mediate 

cardiovascular protection by E2 for many years after the childbearing age. Investigators funded 

by the NICHD have shown that E2 stimulates endothelial NO synthase via the activation of 

plasma membrane-associated ERα, and that the non-genomic function of these receptors entails 

G-protein coupling. Using pull-down experiments with purified recombinant proteins, the 

investigators demonstrated that ERα binds directly to Gαi and Gβγ. Mutagenesis and the 

addition of blocking peptide revealed that this binding occurs via amino acids 251–260 and 

271–595 of ERα, respectively. Through direct interactions, ERα mediates a novel mechanism of 

G-protein activation that provides greater diversity of function for both the steroid hormone 

receptor and G proteins. This work enables researchers to segregate genomic and non-genomic 

estrogen action, with the ultimate goal of harnessing the non-genomic mechanisms for 

cardiovascular benefit without perturbing oncogenic processes. 

Hypoxia/Asphyxia in the Fetus and Newborn 

The Branch supports a number of research teams studying hypoxia/asphyxia, namely in trying to 

understand the mechanisms of the condition, its causes, and its effects on the outcomes of 

infants. Some of this research includes the following: 

• Researchers in the White Mountains of California found that the cerebral vascular tone of the 

fetus goes through a spectrum of acclimatization changes, including increased media 

thickness due to increases in smooth muscle cell layers, marked increase in the size of 

perivascular nerves, and a number of pharmaco-mechanical couplings, in response to longterm hypoxia (LTH). Results from this and other research suggest that in the fetus, LTH is 

associated with decreased vascular tone, which may play a key role in optimizing cerebral 

blood flow under hypoxic conditions. LTH seems to accelerate maturation of many fetal 

cerebrovascular mechanisms and serves to illustrate the concept of “developmental 

plasticity”—that is, a fetus that matures more quickly enhances the chances for survival for 

both mother and fetus. From a teleological point of view, these changes serve to optimize 

cerebral blood flow and, thus, O2 delivery in the face of decreased O2 levels. 

• Researchers are working to understand the mechanisms of long-term effects of stress during 

pregnancy, and of fetal low birth weight, on disease in the adult. Using ovine placentomes, 

researchers demonstrated that LTH from high altitude was associated with an approximately 

40-percent increase in capillary density and caused significant changes in ovine placentome. 

The same team also noted that a number of genes in the mouse placenta were up- or downregulated in response to 48 hours of hypoxic stress (from embryonic day 15.5 to day 17.5). 

In response to maternal protein deprivation (50-percent protein with normal calories, 

vitamins, and minerals), another subset of genes were up- or down-regulated. For the most 

part, the stress-induced gene-expression changes were unique to each state, hypoxia or 

protein deprivation. 

• A large body of Branch-supported research has produced several basic discoveries to explain 

the mechanisms of neuronal cellular death due to asphyxia in the newborn period. These 

findings offer an opportunity to intercept the cell-death pathway and facilitate the 

development of strategies to prevent or attenuate neuronal injury. For example, one research 

Branch Activities: Research Project Grants and Contracts 18 
• Research is also striving to understand the basic processes involved in the etiology of 

hypoxia-mediated pulmonary hypertension in newborn infants. For instance, endothelin-1 

(ET-1) mediates hypoxia-mediated pulmonary vascular remodeling (HPVR), and an 

endothelin-A receptor (ET-AR) blockade prevents HPVR in newborn mice. Researchers 

determined the postnatal effects of chronic hypoxia and/or ET-AR blockade on lung ET-1, 

ET-AR, endothelin-B receptor, and vascular collagen and elastin. By exposing newborn 

C57BL/6 mice to air or hypoxia (12-percent oxygen) from birth for 1 day, 3 days, or 14 days, 

and then assessing vascular collagen, elastin, and endothelin, investigators found that: 

o Hypoxia attenuated the normal postnatal decrease in ET-1 and collagen content. 

o The ET-AR blockade reduced collagen independent of oxygen. 

o Hypoxia increased elastin mRNA expression and attenuated the normal postnatal 

decrease in elastin content. 

o BQ610 reduced elastin mRNA but not elastin content. 

Cerebrovascular Smooth Muscle Maturation and Contractility 

• Blood vessels are conglomerates of many different cell types in continuously varying stages 

of maturation. NICHD-funded researchers studied the contractility and the distribution of 

multiple markers of smooth-muscle phenotype in the carotid and cerebral arteries of 

developing animals. This work revealed that, as arteries mature during the postnatal period, 

their expression of synthetic markers (such as non-muscle myosin) is gradually supplanted by 

increased expression of contractile proteins (such as the SM2 isoform of myosin). These and 

other findings indicated that contractility is regulated through fundamentally different 

mechanisms in fetal and adult cerebral arteries. The overall contribution of this research 

provides a basis to better understand maturational aspects of cerebral vasculature, as well as 

to begin to study mechanisms of ischemic damage to the blood vessels through the lifespan. 

Lung Development 

As mentioned earlier, one of the prerequisites for a successful birth is that the newborn be able to 

breathe on its own following delivery. The following are findings from PPB-supported research 

on lung-related topics of the newborn: 

• To understand the mechanisms of persistent pulmonary hypertension (PPHN) in newborns, 

researchers showed that the increase in pulmonary blood flow that normally occurs at birth is 

related to an increase in synthesis and release of adenosine triphosphate (ATP), which is 

released in response to increased postnatal oxygen concentrations. They also found that 

increased ATP acted as a signal to increase pulmonary blood flow. Normally, ATP interacts 

with nitric oxide synthase (NOS) to stimulate NO release into the pulmonary circulation; in 

models of PPHN, however, this mechanism is altered so that other enzymes (not NOS) were 

19 Branch Activities: Research Project Grants and Contracts 
involved in the release of superoxide, a vasoconstrictor. These findings may assist future 

development of therapeutic agents, which could help correct the imbalance in NOS function. 

• To define the phenotype of congenital alveolar capillary dysplasia (ACD) as a first step 

toward mapping the responsible gene(s), investigators analyzed pathology reports and 

microscopic slides of 23 subjects with ACD and conducted sequence analyses of two 

candidate genes. The investigators delineated the natural history of ACD and its associated 

anomalies and corroborated the likely autosomal recessive nature of this condition in some 

families. Using sequence analysis, the investigators were able to exclude mutations in the 

coding region of two candidate genes, bone morphogenetic protein type II receptor (BMPR2) 

and endothelial monocyte-activating polypeptide II (EMAP II), as candidates for ACD. 

• One unique PPB-supported study is developing a step-by-step approach to resuscitation in an 

animal model (fetal/neonatal lambs), enabling testing and fine tuning of methods to 

determine which approach is least damaging to the lungs. Investigators simulated the actual, 

real-life method of resuscitating preterm infants in a sheep model and varied the amount of 

air and oxygen mixture delivered into the lungs with and without keeping the placental 

circulation intact. Preterm lambs delivered at 129 days of gestation (about 30 weeks’ in 

humans) were resuscitated in a way that simulates the way human babies are typically 

resuscitated: a tube inserted in the trachea, large volumes of air/oxygen mixture (called 

hand-bag-ventilation at 15 ml/kg) blown through the tube for 15 minutes, no positive endexpiratory pressure. After the initial 15 minutes, the lambs were given standard intensive 

care given to babies (surfactant and additional ventilatory support for two hours, 45 minutes). 

The control group received no resuscitation and was maintained with placental support. 

Following analysis of lung fluid and other biological specimens, researchers found that 

within 15 minutes of “routine” method of resuscitation, the lungs were already damaged with 

inflammatory cells and normal and abnormal protein leakage into the lung spaces. Thus, the 

current “standard method of ventilation” can initiate an injurious process in the preterm lung. 

• Using preterm animal models, a group of PPB-supported researchers is attempting to 

understand the factors that enhance fetal and neonatal lung injury from inflammatory 

mediators, in an effort to develop treatment strategies that reduce the burden of chronic lung 

disease. The researchers induced amniotic fluid inflammation in experimental pregnant 

sheep using injections of endotoxin and then delivered the lambs on the day 130 of gestation 

(equivalent to 34 weeks of human pregnancy); lambs were supported by various ventilatory 

strategies. The results showed that endotoxin-exposed lungs required higher ventilation 

pressures, although ventilation per se did not increase lung injury. However, the trachea and 

lungs of the ventilated endotoxin-exposed animals contained six to 12 times more 

inflammatory cells than controls, indicating that fetal lung inflammation has a very serious 

effect on the developing immature lungs. 

• In a different set of experiments, the same group of investigators sought to determine 

whether continuous positive airway pressure (CPAP) ventilation minimized lung injury. In 

preterm lambs delivered at day 133 of gestation and randomized to three groups (e.g., no 

ventilation, conventional mechanical ventilation, or CPAP), researchers found that the 

CPAP-treated lambs breathed without distress to maintain normal blood carbon dioxide 

levels. These findings, when validated in human infants, could help reduce the long-term 

burden of chronic lung disease. 

Branch Activities: Research Project Grants and Contracts 20 
Neonatal Pain 

The Branch supported the following studies on pain and pain control during the neonatal period: 

• The Branch funded the NEOPAIN Study, a multi-center, controlled trial of prophylactic, 

preemptive analgesia in high-risk newborn infants (born at 24 weeks’ to 32 weeks’ gestation) 

who were receiving mechanical ventilation support. The findings of this study, published in 

The Lancet, showed that preemptive analgesia markedly reduced pain experience, but it also 

increased the incidence of adverse side effects. There was a strong correlation between a 

need for any analgesic support and poor outcome. The study also concluded that continuous 

infusion of opioid analgesic was associated with more systemic side effects than intermittent 

use of the same treatment, as clinically needed. The findings of this important study will 

have a significant impact on clinical practice. The investigators are planning a followup of 

surviving children from this study. 

• In another PPB-supported study, the researchers found links between cumulative exposure to 

pain in the Neonatal Intensive Care Unit (NICU) and programming of the hypothalamicpituitary-adrenal (HPA) axis. The findings are important because the end product of the 

HPA axis—cortisol—is the body’s primary stress hormone, important in cognitive 

functioning, learning, memory, and immune functions. In a mixed cross-sectional and 

longitudinal study of 225 infants, researchers examined the developmental trajectory of basal 

salivary cortisol concentrations at three months, six months, eight months, and 18 months 

corrected age. Infants born at extremely low GA (less than 28 weeks’ gestation) showed 

down-regulation of cortisol levels at three months, then a shift over time to up-regulation 

from eight to 18 months. This resetting of basal HPA activity, relative to infants born 29 

weeks’ to 32 weeks’ gestation and full-term infants, suggests one possible mechanism for 

altered neurodevelopment in this vulnerable population. 

• The same researchers also found that repeated exposure to neonatal procedural pain among 

neurodevelopmentally immature preterm infants could contribute to modulation of HPA-axis 

functions, especially at sites where hormonal responses to pain are processed. Immature 

infants may be at greater risk for long-term deleterious consequences from cumulative pain 

exposure. These findings underscore a continued need for studies to develop methods to 

prevent pain and therapeutic options to treat procedural pain for acutely ill newborn infants. 

Neonatal Skin 

Because the skin of an infant in the newborn period is very thin and is less acidic compared to 

adult skin, it becomes an important portal for infections. NICHD-funded researchers have been 

studying the biology of newborn skin in an effort to enhance its maturation. In one study, they 

determined the effect of a topical application of group of proteins, called liver X-receptor 

activators, to see if acidification of skin layers in the neonatal period could be enhanced, thereby 

reducing functional abnormalities in permeability barriers, homeostasis, and integrity and 

cohesion of the skin. In the newborn rat model, they found that such topical applications 

accelerated the acidification of the skin layer and stimulated the formation of an acidic stratum 

corneum; these changes are deemed to provide a protective buffer against invading bacteria. 

They also studied the mechanisms by which these processes are governed. This type of research 

has potential for developing agents to enhance skin-barrier functions in the newborn period to 

prevent infections acquired through the skin. 

21 Branch Activities: Research Project Grants and Contracts 
Newborn Antiseptic Washing and Neonatal Mortality in Nepal 

Investigators funded through the Branch tested the effects of cleansing the newborn baby soon 

after birth and of umbilical cord care on infection survival rates. Using a community-based 

cluster randomization design in rural Nepal, researchers recruited 17,299 newborn infants into 

the skin-cleansing group (cleaned with a dilute antiseptic solution of 0.25-percent chlorhexidine) 

and 13,724 infants into the cord-care group (cleaned the umbilical cord site with 4-percent 

chlorhexidine) for 10 days and compared results to those of infants given the standard care, 

namely, the soap-and-water cleansing and “dry cord care” of the umbilical region. The 

chlorhexidine skin-cleansing intervention led to a 13-percent reduction in neonatal mortality 

compared with the standard care group. Among the low birth weight infants in the chlorhexidine 

skin-cleansing group, there was a 30-percent reduction in neonatal mortality. In the umbilical 

cord-care arm, there was a 23-percent to 63-percent reduction in the rates of infection at the 

umbilical cord site in the chlorhexidine care group compared to controls. The Lancet editorial 

strongly endorsed implementing this strategy globally. 

Early Breastfeeding and Infant Mortality Risks 

Initiation of breastfeeding within one hour after birth has been associated with reduced neonatal 

mortality in a number of rural communities. However, the time for initiation of breastfeeding is 

not uniform; in some cultures, mothers, fearing that the colostrum is “unhealthy,” do not begin 

breastfeeding until up to 48 hours after birth. To examine the trends in the time of initiation of 

breastfeeding and early neonatal outcomes, the investigators who conducted the chlorhexidine 

study in Nepal (mentioned above) prospectively collected longitudinal data on breastfeeding 

patterns and infant outcomes in the Nepalese cohort. Based on 22,838 breastfed newborns who 

survived to 48 hours after birth, they estimated the association between breastfeeding initiation 

and death. Within one hour of birth, 3.4 percent of infants were breastfed; 56.6 percent were 

breastfed within 24 hours of birth. Partially breastfed infants (72.6 percent) were at higher 

mortality risk (RR = 1.77; 95% Confidence Interval [CI] = 1.32-2.39) than those who were 

exclusively breastfed. Mortality was higher among those who initiated breastfeeding late 

(> 24 hours) compared with those who initiated early (< 24 hours) (RR = 1.41; 95% 

CI = 1.08-1.86) after adjusting for low birth weight, preterm birth, and other covariates. The 

authors concluded that between approximately 7.7 percent and 19.1 percent of all neonatal 

deaths may be avoided with universal initiation of breastfeeding within the first day of life or 

hour of life, respectively. Although the relevance of these data for the U.S. population needs to 

be studied, it seems that programs to promote breastfeeding in rural areas need to focus on early 

initiation, in addition to exclusivity and duration of breastfeeding. 

Fetal and Neonatal Environment and Later Health Problems 

Prenatal viral infection is associated with development of schizophrenia and autism spectrum 

disorders (ASDs) later in life. One study funded by the PPB showed that late first-trimester 

administration (embryonic day [E] 9 or E9) of influenza virus caused deleterious effects on brain 

structure and function in mouse offspring. The investigators hypothesized that late secondtrimester infection (E18) in mice may lead to different patterns of brain gene expression and 

result in structural defects in the developing offspring. Mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offspring of 

the infected mice were collected at postnatal day 0, postnatal day 14, postnatal day 35, and 

postnatal day 56 (which correspond to human birth, childhood, adolescence, and adulthood, 

Branch Activities: Research Project Grants and Contracts 22 
respectively); the brains were removed and the prefrontal cortex, hippocampus, and cerebellum 

were dissected and flash frozen. Microarray, qualitative real-time PCR, diffusion-tensor imaging 

and magnetic resonance imaging (MRI) scanning, western blotting, and neurochemical analysis 

were performed to detect differences in gene expression and brain atrophy. Expression of 

several genes associated with schizophrenia or ASDs, including Semaphoring 3A, Transferrin 

Receptor 2, and Very Low Density Lipoprotein Receptor, were altered, as were protein levels of 

Forkhead Box P2. Imaging revealed significant atrophy in several brain areas as well as whitematter thinning in the corpus callosum. Neurochemical analysis also revealed significantly 

altered levels of serotonin (in postnatal day 14 and 35 samples), 5-Hydroxyindoleacetic acid (in 

postnatal day 14 samples), and taurine (in postnatal day 35 samples). The investigators propose 

that maternal infection in the mouse provides an heuristic animal model for studying the 

environmental contributions to the geneses of schizophrenia and ASDs. 

In addition, a large body of evidence suggests that adult-onset coronary artery disease, diabetes, 

and hypertension may have developmental origins. For example, when glucose and other 

nutrient supplies are deficient in the fetus, the fetus does not grow adequately. Thus, abnormal 

fetal metabolism of glucose may be related to poor fetal growth, as may be adult-onset diabetes. 

A number of investigators supported by the Branch are studying fetal insulin production, the size 

of the pancreatic islet cells, factors affecting fetal growth, and the relation of these factors to later 

glucose homeostasis. One study addressed how pancreatic cells of fetal sheep responded to 

changing blood glucose levels. The researchers found that after prolonged hypoglycemia 

(14 days) followed by recovery to normal blood glucose levels, the fetal insulin response was 

inherently weaker compared to adult controls, and to those with short-term hypoglycemia. 

Recovery responses were also less optimal in animals exposed to long-term hypoglycemia. 

Fetuses subjected to chronic starvation did not respond to glucose infusion by producing insulin, 

as occurs in a normal fetus. The programming of pancreatic insulin secretion in response to fetal 

glucose deprivation may be a mechanism for adult-onset (type 2) diabetes, meaning this lack of 

insulin response may underlie the origin of diabetes in later life. 

Bilirubin and Neonatal Jaundice 

Glucuronidation and transporter-mediated efflux into bile are important in the elimination of 

xeno- and endobiotics, including the natural biladienone pigment bilirubin. The mechanisms of 

these processes and the structural factors dictating whether cholephilic compounds are excreted 

directly in bile or whether they require prior glucuronidation are poorly understood. To 

investigate effects of molecular shape and intramolecular hydrogen bonding on the interplay 

between direct excretion and glucuronidation in the liver, Branch-supported researchers studied a 

series of novel synthetic exploded and homologated bilirubin analogues. Metabolism studies 

were done in rats, including Gunn rats, which are congenitally deficient in UGT1 glucuronosyl 

transferases, and TR- rats, which are deficient in the canalicular transporter Mrp2 (Abcc2). The 

results showed strikingly that minor, seemingly inconsequential changes in constitution, 

amplified by their influence on hydrogen bonding and molecular conformation, can profoundly 

influence competing clearance pathways in the liver, an effect that is unlikely to be restricted to 

bis-dipyrrinone carboxylic acids. Exposed carboxyl groups seemed to favor the direct route of 

elimination, whereas the potential for carboxyl infolding by hydrogen bonding seemed to favor 

glucuronidation. The results also showed that molecular shape is less important than once 

assumed for the hepatic glucuronidation and biliary excretion of bilirubin. 

23 Branch Activities: Research Project Grants and Contracts 
Level and Volume of Neonatal Intensive Care and Mortality in Very Low Birth Weight 

(VLBW) Infants 

Community hospitals have seen a large increase in both the number of NICUs and the 

complexity of the cases treated in these units. Investigators examined differences in neonatal 

mortality among VLBW (< 1,500 g) infants among NICUs of various care levels and with 

different volumes of VLBW infants. Researchers linked birth certificates, hospital discharge 

abstracts, and fetal and infant death certificates to assess neonatal rates among 48,237 VLBW 

infants born in California hospitals between 1991 and 2000. The mortality rates varied 

according to both the level of care at the delivery hospital and the volume of VLBW patients; 

compared with high levels of care and a high volume of VLBW infants (more than 100 such 

deliveries each year), lower levels of care and lower volumes of these patients were associated 

with higher odds ratios for death, ranging from 1.19 to 2.72 (95% CI = 1.04-3.12). However, 

fewer than 25 percent of VLBW deliveries occurred in facilities with NICUs that offered a high 

level of care and had a high volume of these patients. The authors estimated that increased 

regionalization of NICUs had the potential to prevent 21 percent of deaths among VLBW 

infants. 

Mortality Differentials and Ethnicity 

A group of Branch-supported investigators studied health outcomes of neonates in nine 

subgroups of the U.S. Asian population (e.g., Cambodian, Chinese, Filipino, Indian, Japanese, 

Korean, Laotian, Thai, and Vietnamese) using a cross-sectional comparison model. Researchers 

assessed and compared outcomes for births to mothers from these subgroups and from nonHispanic white mothers for all California births between January 1991 and December 2001. The 

unadjusted mortality rate for births to non-Hispanic white mothers was 2.0 deaths per 1,000 

births. The unadjusted mortality rate for births to Chinese and Japanese mothers was 

significantly lower (1.2 per 1,000, P < 0.001; 1.2 per 1,000, P = 0.004, respectively), while the 

rate for births to Korean mothers was significantly higher (2.7 per 1,000, P = 0.003). After 

adjusting for risk, infants born to Cambodian, Japanese, and Korean mothers had significantly 

lower neonatal mortality rates compared with infants born to non-Hispanic white mothers 

(adjusted odds ratios: 0.58 for infants of Cambodian mothers, 0.67 for infants of Japanese 

mothers, and 0.69 for infants of Korean mothers); infants of Thai mothers had higher neonatal 

mortality rates (adjusted odds ratio: 1.89; P < 0.05). The researchers noted significant variations 

in neonatal mortality between subgroups of the Asian American population that are not entirely 

explained by differences in observable risk factors. Efforts to improve clinical care that treats 

Asian Americans as a single, homogeneous group, then, may miss important opportunities for 

improving infant health in specific subgroups. 

Development of Cytomegalovirus (CMV) Vaccine in Animal Model 

Researchers supported by the PPB are working on an experimental vaccine to reduce stillbirths 

among rodents born to mothers infected with CMV—a common virus that can also cause 

intellectual and developmental disabilities and hearing loss in newborn children who are infected 

in early fetal life. Female guinea pigs, given the CMV vaccine before becoming pregnant, gave 

birth to fewer dead pups and were less likely to transmit the infection to their offspring than were 

female guinea pigs that did not get the vaccine. The experimental vaccine differs from 

traditional vaccines, which are made from a whole-killed virus, because it uses an altered virus 

Branch Activities: Research Project Grants and Contracts 24 
(called a vector) to deliver one gene from the viral DNA to the animals’ cells. Once injected, the 

cells begin manufacturing the viral protein. Cells of the guinea pigs’ immune system detected 

the viral protein and launched an attack against it, thus learning to recognize CMV. The gene 

used in the experimental guinea pig CMV vaccine—UL83, also called pp65—contains the 

information needed to make a protein involved in the infection process; the virus used to make 

the vector vaccine (Venezuelan Equine Encephalitis Virus) was altered to prevent it from 

reproducing and infecting new hosts. 

The young female guinea pigs in the study were vaccinated three times at two-month intervals 

before they became pregnant and were injected with the guinea pig form of CMV early in their 

third trimester. Tests showed that rodents given the experimental vaccine had acquired 

immunity to guinea pig CMV. The vaccinated guinea pigs also showed T-cell activity against 

the virus, a step critical to the response against disease-causing organisms. Results in the animal 

model will provide the basis for developing a version of the vector vaccine to possibly test in 

humans. 

Cochrane Neonatal Review Group (CNRG) 

The NICHD-funded CNRG conducts systematic reviews of randomized controlled 

trials in neonatal medicine. The 245 full-length reviews, posted on the NICHD 

Web site at http://www.nichd.nih.gov/cochrane/default.cfm, make the CNRG 

second among the 50 Cochrane Review Groups in number of reviews. Unlike the 

National Library of Medicine’s PubMed database system, which provides only 

abstracts of reviews, the NICHD Cochrane Web site provides full-length papers for 

download at no cost. 

Reviews are performed by experts, who are identified by a group of international editors. The 

CNRG is also planning to develop and implement training on systematic reviews and in metaanalysis. In addition to the Web site noted above, the CNRG reviews are published in the 

Cochrane Library, Issue 1, 2008. The CNRG Web page is one of the most frequently visited 

pages on the NICHD Web site. 

SUDDEN INFANT DEATH SYNDROME (SIDS) RESEARCH

The NICHD, led by the PPB, has been the primary federal resource for research on SIDS since 

the SIDS Act of 1974 was passed. Its efforts have included and still include studies on the 

causes and etiology of SIDS, ranging from basic research with animal models to more applied 

methods involving responses to environmental risk factors; research on the incidence and 

prevalence of SIDS, especially among certain portions of the U.S. population; and outreach 

designed to educate parents and caregivers about ways to reduce SIDS risk, especially among 

those populations with a higher incidence of SIDS. The following sections describe some 

highlights from the PPB’s SIDS research portfolio. 

25 Branch Activities: Research Project Grants and Contracts 
Etiology and Pathogenesis 

STUDIES OF BRAIN ABNORMALITIES AMONG SIDS INFANTS

Researchers have studied the underlying processes that may lead to SIDS for many years. 

Recently, investigators reported important findings—a body of work that has resulted from 

almost 20 years of NICHD- and PPB-supported research—regarding the brains of infants who 

die of SIDS. Researchers had previously reported that infants who died from SIDS had a unique 

deficit in a neural network within the medullary raphe of the brainstem; this network uses the 

neurotransmitter serotonin and controls heart rate, breathing, blood pressure, temperature, and 

arousal from sleep. By comparing the brains of infants who died from SIDS to those of infants 

who died from other known causes, researchers found that the serotonin system deficit was more 

widespread than previously realized. Specifically, researchers found (JAMA, 2006; 296, 2124-

2132) that: 

• Brainstem tissue from SIDS infants contained more serotonin-using neurons than did the 

tissue from infants who died from other known causes. 

• These serotonin-using neurons from SIDS infants seemed to contain fewer serotonin 

receptors than did tissue from infants who died of other known causes. Specifically, tissues 

from SIDS infants had very little of a serotonin receptor known as “Subtype 1A,” which 

inhibits nerve-cell firing when serotonin binds to it. 

• Relative to the increased number of serotonin-using neurons in SIDS infants, the tissues had 

fewer proteins that recycle serotonin than the tissues of infants who died from other known 

causes, meaning that the infants who died of SIDS had significantly impaired ability to use 

serotonin. 

• Brainstem abnormalities were observed in about three-fourths of SIDS infants. 

Researchers are now trying to develop tests to identify infants with these abnormalities at birth, 

and to improve strategies for preventing death among these infants. To accomplish these goals, 

researchers need to understand how the abnormalities alter an infant’s physiology. If they can 

understand how these abnormalities develop, researcher may also be able to design interventions 

to prevent the abnormalities from occurring in the first place. 

Although SIDS infants’ tissues in the research described above showed more serotonin neurons, 

the neurons were morphologically immature and functionally abnormal. Such abnormalities are 

likely to originate in pregnancy, while the fetus is developing in utero. To determine when such 

development might occur, the same group of investigators studied the development of the human 

medullary 5-HT system, whose neurons are normally distributed throughout the medullary raphe. 

Using immunocytochemical techniques in animal models, researchers found that the medullary 

5-HT system began to form in the embryo, with the raphe primordia appearing as early as seven 

weeks’ gestation; by 20 weeks’, the topography of the medullary 5-HT system was in place 

(Auton Neurosci, 2007; 132, 92-102). These findings provide evidence that early prenatal 

insults, such as exposure to alcohol or tobacco, could cause abnormalities in the medullary 5-HT 

system. 

The Aberdeen Area Infant Mortality Study (AAIMS), conducted in collaboration with the 

Aberdeen Area Tribal Chairman’s Health Board and was funded by the NICHD, the Indian 

Branch Activities: Research Project Grants and Contracts 26 
Health Service (IHS), and the CDC, sought to understand why the SIDS rates are so high among 

Northern Plains Indians, who have among the highest SIDS rates in the United States. The study 

was the first to link epidemiological findings with neurochemical deficits in the developing 

human brain. Researchers observed that serotonin-receptor binding abnormalities in the 

brainstem regions of SIDS cases in the AAIMS were similar to those observed in other 

populations. In addition, among AAIMS infants, the abnormalities in the arcuate nucleus were 

more frequent if the mother smoked cigarettes and used alcohol during early pregnancy, or 

before or throughout pregnancy. This finding supports outcomes reported in the previous 

section that describe the development of the medullary 5-HT system early in fetal growth. 

Researchers from the AAIMS collaborated with investigators on another NICHD-funded SIDS 

study in Northern Plains Indians to report on a unique case that was common to both studies. A 

Northern Plains Indian baby boy was enrolled in a prospective study, which took measurements 

of nervous system control of the heart at two days of age; the boy became part of the AAIMS 

when he died from SIDS at age two weeks. Upon review of the case, researchers discovered that 

the boy had abnormal regulation of the heart rate during sleep in response to the “tilt test” 

(described in the previous section) at age two days compared to other infants in the prospective 

study who lived. At autopsy, the infant’s brain showed the same serotonin-receptor 

abnormalities in the brainstem neural network observed in other SIDS infants in other 

populations. To the researchers, this case demonstrated that abnormalities in the brainstem 

common to infants who die from SIDS may be detectable by physiological tests before death. 

These findings need to be replicated in larger populations to develop predictive screening tools 

for identifying infants at possible increased risk of SIDS (J Neuropath Exp Neurol, 2005; 64, 

689-694). 

Another PPB-supported research project is using an animal model to examine the role of 

serotonin in regulating breathing responses to high levels of carbon dioxide as a way to 

understand a possible cause of SIDS. Researchers found that if they raised serotonin levels in 

the medullary raphe, shown in research described above to have serotonin-receptor deficits in 

SIDS infants, the breathing response to elevated carbon dioxide was increased (J Appl Physiol, 

2004; 97, 1763-1773). This finding supports previous findings that serotonin-activated neurons 

in the medullary raphe may play a role in causing SIDS because of that brain region’s 

involvement in breathing response, body temperature regulation, and arousal. 

Other research has shown that some infants who die from SIDS have other brain abnormalities, 

such as having less myelin—a lipid-rich insulation covering nerve fibers and commonly known 

as “white matter”—in their brains. Myelination, necessary for normal functioning of the brain, 

starts in fetal life and continues through the first two years of life. The patterns of undermyelination in SIDS infants suggest a delay in the development of myelin; this situation occurs 

in other disorders in which the growth of the infant is impaired. To learn more, researchers used 

animal models to study the outcomes of those periodically deprived of oxygen for short periods 

of time, and then given oxygen, in an effort to mimic what happens in SIDS infants, who may 

have breathing problems or who may not respond properly to hypoxia. Results indicated that 

oxygen-deprived tissue tries to improve its ability to get oxygen by making more blood vessels, 

but creates less myelin compared to brains never deprived of oxygen. When oxygen was 

completely returned, the extra blood vessels disappeared, but the myelin never developed to the 

27 Branch Activities: Research Project Grants and Contracts 
extent that it should have. Thus, early short-term hypoxia results in permanent long-term 

developmental brain injury (Am J Physiol Regul Integr Comp Physiol, 2006; 290, R1105-

R1114), a finding that reinforces the importance of identifying infants with breathing problems 

as early in life as possible. 

STUDIES OF ENVIRONMENTAL FACTORS AND SIDS 

Other Branch-funded researchers are working to understand how environmental factors might 

influence autoresuscitation, the failure of which may contribute to SIDS. Some have proposed 

that stomach sleeping increases the likelihood that the infant, face down in the bedding, will 

rebreathe expired air low in oxygen (hypoxia) and rich in carbon dioxide. In addition, some 

theorize that an infant sleeping on the stomach is more likely to overheat (hyperthermia) because 

his or her face and/or head are more likely to become covered. Researchers exposed mice to 

either condition or to a combination of the two conditions. Although neither hypoxia nor 

hyperthermia alone affected autoresuscitation, researchers noted an increased frequency of 

autoresuscitation failure at first exposure to hypoxia when the temperature was higher. In 

addition, they found decreased ability to recover from multiple exposures to hypoxia when the 

temperature was higher. These studies suggest that hypoxia and hyperthermia in combination 

may increase the risk posed by stomach sleep condition and by the head covered by bedding 

(J Appl Physiol, 2004; 97, 669-674). 

Previous research has shown that infants who are not accustomed to sleeping on the stomach are 

at significantly higher risk of SIDS when they are placed on the stomach for sleep. To 

understand more about this increased risk, researchers compared the protective behaviors of 

infants who were experienced sleeping on their stomachs with those of infants inexperienced 

with this sleep position. Infants with experience stomach sleeping had the best protective 

responses, turning the head or lifting the head, possibly to reach more oxygen-rich air or to 

reduce overall temperature. Not only did inexperienced infants move and lift their heads less 

often, they also spent more time with their faces in the bedding (Pediatrics, 2004; 114, 1634-

1639). These findings also indicate that some protective factors are learned, bolstering the 

theory that some infants who succumb to SIDS do not learn these behaviors. This absence of 

learning may result from deficits in the brain’ components involved in learning, or from deficits 

in the ability to sense elevated carbon dioxide levels, preventing them from learning any type of 

protective behavior for the situation. The latter theory is consistent with the findings explained 

earlier related to abnormalities in the tissues of the brainstem, which mediates response to carbon 

dioxide levels. 

Infants who sleep on their stomachs are reportedly slower to wake up in response to arousing 

stimuli compared to those who sleep on their backs and that stomach-sleeping infants spend 

more time in quiet or deep sleep. Such features could be related to deficits in the medullary 

system, which helps mediate arousal from sleep. In fiscal year 2005, researchers extended their 

findings related to stomach sleeping. They found that, even when stomach-sleeping infants are 

in active sleep (also called Rapid Eye Movement [REM] sleep), which is supposed to be easier to 

arouse from, their brain wave activity is slower in frequency, more closely resembling quiet 

sleep (Arch Dis Child Fetal Neonatal Ed, 2005; F311-F315). So infants who sleep on their 

stomachs are more often in a deeper sleep than infants who sleep on their backs, a finding which 

could explain why they take loner to arouse than their back-sleeping peers. 

Branch Activities: Research Project Grants and Contracts 28 
More than 90 percent of SIDS deaths occur in infants younger than six months of age, with peak 

incidence between two and four months of age. Researchers consider this timeframe to be a 

developmental period of unique vulnerability to environmental factors, such as sleeping on the 

stomach, that increase the risk of SIDS. To learn more about this timeframe, researchers 

examined life-sustaining functions controlled by the brainstem using the “tilt test”—rapidly 

tilting infants from the horizontal to the head-up position. When newborns were rapidly tilted to 

the head-up position, their reflexes increase the heart rate in response to the tilt. Recordings of 

brain waves done at the same time as the tilt showed an increase in electrical activity in the 

cerebral cortex, the area of the brain that integrates signals from all parts of the brain, including 

the brainstem. The heart rates of infants between two months and four months of age did not 

increase in response to the head-up tilt, and these infants showed a smaller increase in electrical 

activity in the brain compared to newborns (Acta Pediatr, 2005; 94, 1756-1763). This 

developmental difference in response could result from a variety of reasons, which are now 

being investigated. Researchers suggest that the tilt test may be a good way to assess the brain’s 

control of heart rate and blood pressure during the peak age of SIDS (Acta Pediatr, 2006; 95, 77-

81). 

GENETICS AND SIDS 

Although the risk for SIDS does not seem to have a large genetic component, some deaths 

diagnosed as SIDS may have defined genetic causes. Prior work supported by the NICHD found 

that 5 percent and 10 percent of SIDS cases had mutations in the SCN5a, a cardiac sodiumchannel gene involved in long-QT syndrome. Recently, researchers detected other rare 

mutations in channel-associated proteins that result in cardiac-channel malfunction in some cases 

diagnosed as SIDS. Three new genes with different molecular pathologies are implicated in 

cases diagnosed with SIDS; the findings include CAV3, which encodes caveolin -3, a structural 

protein found in plasma membranes of muscle. The mutations observed in SIDS cases resulted 

in late sodium currents, a phenotype similar to that seen with mutations of SCN5a, that lead to 

prolonged QT. Of interest is that researchers isolated all three mutations from 50 SIDS cases 

among African American infants, but found none of the mutations in 83 cases of SIDS in white 

babies (Heart Rhythm, 2007; 4, 161-166). 

Mutations in the glycerol-3-phosphate dehydrogenase 1-like (GDP1-L) gene disrupt the 

trafficking of the SCN5a protein, resulting in a loss of sodium-channel function. Three 

mutations of GDP1-L were detected in 222 SIDS cases. When co-expressed with sodiumchannel protein, the mutations significantly reduced sodium current; when transfected in cell 

culture, the mutations reduced sodium current density, which could lead to pro-arrhythmogenic 

conditions (Circulation, 2007; 116, 2253-2259). 

A different mutation in the RyR2-encoded cardiac ryanodine receptor causes lethal 

catecholaminergic ventricular tachycardia (CPVT), which is sometimes miscategorized as SIDS. 

When these mutations are present, cardiac calcium channels exhibit increased activity in 

response to sympathetic stimulation, making channels leaky and resulting in fatal cardiac 

arrhythmia. Such sympathetic stimulation can result from physiological stress, such as exertion, 

hypoxia, thermal stress, or even the sympathetic surge during REM sleep. Out of 143 unrelated 

SIDS deaths, two female SIDS infants had RyR2 mutations and both died in their sleep. Both of 

29 Branch Activities: Research Project Grants and Contracts 
the mutated proteins, under simulated in vitro biochemical stress conditions, resulted in a gain of 

function in cardiac calcium channel consistent with prior-characterized CPVT-associated RyR2 

mutations Heart Rhythm, 2007; 4, 733-739). This type of “molecular autopsy” is proving to be 

an important strategy in unraveling the pathophysiology of deaths diagnosed as SIDS. 

COLLABORATIVE HOME INFANT MONITORING EVALUATION (CHIME) STUDY

The CHIME Study, now complete, was a multi-center cooperative study of home monitoring to 

determine whether the monitoring could detect SIDS and other life-threatening events in highrisk infants. Almost 1,200 infants were enrolled in the following subject groups: healthy term 

infants; preterm infants weighing less than 1,750 grams at birth; and siblings of babies who had 

died from SIDS or who experienced an idiopathic apparent life-threatening event. The PPB, 

CHIME researchers, and industry collaborated in the development of new monitoring 

technology, which was being tested for its potential to detect and record life-threatening 

cardiorespiratory episodes. 

The technology incorporated new, advanced computer capabilities, inductance 

plesthysmography, electrocardiogram (ECG), pulse oximetry, and an accelerometer to detect 

motion and infant position. In addition to event recording, which captured physiology for a 

period before, during, and after an event, monitors were programmed to store continuous RR 

intervals from the ECG, continuous breath-breath intervals, and normative three-minute epochs 

at hourly intervals. Findings from CHIME published in 2001 indicated that cardiorespiratory 

events (e.g., apnea, bradycardia, etc.) meeting conventional alarm thresholds were quite 

common, even in healthy term infants. More severe events were common only in preterm 

infants, and the timing of the events suggested that they were likely not immediate precursors of 

SIDS (JAMA, 2001; 285, 2199-2207). However, further research showed an association between 

infants who had five or more events exceeding conventional or extreme alarm thresholds and 

lower scores on the Bayley Scale at one year of age compared to infants who had fewer or no 

events (J Pediatr, 2004; 145, 465-471). 

To prevent occurrences of these events and poor long-term outcomes, it is necessary to 

understand their origins. Recently, CHIME investigators reported on in-depth analyses of 

cardiorespiratory and oxygen saturation changes in the two hours prior to an event. The duration 

of respiratory pauses and of periodic breathing progressively increased just before conventional 

events; respiratory rate variability increased immediately before a conventional event and at one 

hour before an extreme event; and oxygen saturation decreased immediately before both 

conventional and extreme events. Thus, apnea and bradycardia are preceded by autonomic 

instability of the cardiorespiratory system (Pediatr Pulmonol, 2008; 43, 87-98). 

Risk Reduction 

Established by the NICHD in 1994, the Back to Sleep campaign is a partnership 

with the AAP, First Candle/SIDS Alliance, the Association of SIDS and Infant 

Mortality Programs, the Maternal and Child Health Bureau at the Health 

Resources and Services Administration, and other organizations for the support 

of a public health education campaign to educate parents and caregivers about 

ways to reduce the risk of SIDS based on the recommendations from the AAP 

Task Force on SIDS. When it was initiated, the campaign’s primary message 

Branch Activities: Research Project Grants and Contracts 30 
was that healthy babies be placed on their back or sides to reduce the risk of SIDS; today, Back 

to Sleep’s main message is that all babies be placed wholly on their backs for every sleep to 

reduce the risk of SIDS. 

In 2005, the AAP Task Force on SIDS added a recommendation against bed sharing as a result 

of evidence related to the hazards of this practice in relation to SIDS and infant mortality 

(Pediatrics, 2005; 116, 1245-1255). Findings from the Infant Care Practices Study, a 

longitudinal prospective study of more than 15,000 mother-infant dyads enrolled at birth in 

Massachusetts and Ohio from 1995 to 1998, provided information about bed-sharing practices in 

the United States. The study indicated that the proportion of women who reported bed sharing 

for most of the previous night decreased from 22 percent when the infant was one month old to 

13 percent and 14 percent when the infant was three months old and six months old, respectively. 

Breastfeeding was a strong predictor of bed sharing at all infant ages; this association was 

strongest for Asian and while women. The likelihood of bed sharing was high among African 

American dyads independent of breastfeeding. This finding was concerning for researchers 

because the risk of SIDS associated with bed sharing seems to be greatest for the youngest 

infants (J Dev Behav Pediatr, 2004; 25, 141-149). 

The AAP Task Force also added a recommendation about using a clean, dry pacifier in its 2005 

recommendations. In addition to a large body of evidence from international studies that 

pacifiers reduce the risk of SIDS, a population-based case-controlled study conducted in 11 

counties in California provided further support for this recommendation. The study which 

evaluated SIDS risk since the start of the Back to Sleep campaign, reported a 0.08 adjusted odds 

ratio (95% CI: 0.03-0.21) for SIDS associated with pacifier use during last sleep. These statistics 

mean that the risk of SIDS among infants who used pacifiers was one-twelfth that of infants who 

did not use pacifiers. Pacifier use was associated with risk reduction in every sociodemographic 

category and risk factor evaluated (BMJ, 2006; 332, 18-22). 

In order to evaluate changes in infant care practices in response 

to the AAP recommendation and to the Back to Sleep

campaign, the NICHD has supported the National Infant Sleep 

Position (NISP) Study. This annual telephone survey of 

nighttime caregivers in households with infants younger than 

eight months of age has documented a decline in the number of infants placed to sleep on their 

stomachs; this decline correlates with the decline in SIDS rates (see Figure 7). In the era of the 

campaign, the SIDS rate has dropped by more than 50 percent, and, according to NISP data, 

about three-fourths of caregivers indicate placing infants to sleep on their backs. According to 

the National Center for Health Statistics, the SIDS rate for 2004 was about 0.5 deaths per 1,000 

live births, a decline of more than 50 percent since the Back to Sleep campaign began. 

However, although SIDS rates have dropped at similar rates in all race/ethnicities, a disparity in 

SIDS rates remains—namely, the rate of SIDS among African Americans is more than twice that 

of whites. The NICHD is conducting research to understand why this and other disparities in 

SIDS rates exist. For example, researchers conducted interviews at Special Supplemental 

Nutrition Program for Women, Infants, and Children (WIC) clinics in Boston, Dallas, Los 

Angeles, and New Haven. WIC is a federally funded program for low-income women who are 

31 Branch Activities: Research Project Grants and Contracts 
pregnant, breastfeeding, and/or postpartum and for children who are younger than five years of 

age and are from low-income families. Findings from this study (Pediatrics, 2006; 118, e243-

250) include the following: 

• Approximately two-thirds of women attending the clinics in this study were African 

American. 

• 59 percent of all women reported that they placed the baby on his or her back to sleep. 

• There were differences among locations, with 78 percent of all women usually placing 

infants on their backs to sleep in New Haven, 61 percent in Boston, 52 percent in Los 

Angeles, and 45 percent in Dallas. 

• Only 36 percent overall reported that a doctor recommended that they place the baby on its 

back to sleep. 

• Women were more likely to place the baby to sleep on its back if they trusted the doctor or if 

they received a recommendation from the doctor or nurse. 

• About half of women were concerned that the baby would choke while sleeping on its back, 

and these women were less likely to place the infant on the back to sleep. 

• Advice from a relative or female friend and perceived comfort for the baby were most 

influential in determining the sleep position for the baby. 

This study revealed that it is possible to achieve high rates of back sleeping among African 

Americans. The study also reinforced what the NICHD and other agencies are currently doing—

that is, conducting community education programs that focus on disseminating safe sleep 

messages so that friends and family members embrace them and share them. Other NICHD 

programs focus on educating doctors and nurses to provide advice in an atmosphere of trust. A 

key aspect of these programs is information to help dispel myths about choking. 

BRANCH ACTIVITIES: COOPERATIVE AGREEMENTS 

The PPB has a number of cooperative agreements to facilitate and encourage large-scale research 

requiring multi-center networks. 

In 1986, in response to the need for well-designed clinical trials in maternal-fetal medicine and 

neonatology, the NICHD established two large-scale Networks—the NRN and the MFMU 

Network—as administrative frameworks in which to conduct multi-center, randomized clinical 

trials and other prospective clinical studies in obstetrics and neonatology. Each Network is 

guided by a Steering Committee, which consists of representatives from each clinical site, from 

the PPB, and from the data coordinating center. These Networks allow for timely and costeffective responses to urgent clinical questions. Currently, the NRN has 16 sites, and the MFMU 

Network has 14 sites. Sites are selected every five years following an open competition. 

Typically, each Network has two or three randomized controlled trials and two or three 

observational studies ongoing at any given time. Network investigators agree to use common 

Branch Activities: Cooperative Agreements 32 
protocols, definitions, and data forms and are linked by their common data centers and common 

data-entry systems. Investigators, together with the PPB and the data coordinating center staff, 

develop protocols that are reviewed by advisory boards, external reviewers, and Data Safety and 

Monitoring Committees, which are established for each Network to ensure that the trials are safe 

and scientifically significant. 

Advantages to doing clinical trials within the Networks include the following. 

• The Networks provide large populations with which to conduct studies that have adequate 

statistical power to resolve many research questions; inadequate sample size is a common 

limitation of many published clinical trials. Approximately 140,000 births occur per year in 

the MFMU Network, and 105,000 infants are born each year in the NRN. 

• Because the study populations are diverse, a therapy or management strategy shown to be 

effective across an array of ethnic and socioeconomic backgrounds and health care settings 

within the Networks is more likely to prove effective in real-world clinical practice. 

• The data coordinating centers attached to the Networks have sufficient resources to assure 

excellent study management and data quality. 

• The administrative systems of the Network are efficient and cost effective. To ensure their 

cost effectiveness, the Networks are funded through a combination of a minimum base 

budget and capitated funds for enrollment in specific protocols. New trials can begin 

relatively rapidly because the infrastructure is already in place. 

The Networks address the need for clinical trials in neonatology and obstetrics, especially trials 

related to preventing low birth weight (< 1,500 grams) and to the management of low birth 

weight infants. The Networks build upon contributions to the clinical trial field and are unique 

in that they rely, to a greater extent, on shared responsibility and commitment. 

In addition to the long-term Networks, the PPB has implemented five additional time-limited 

Networks since 2005. These projects were designed to address specific questions and are time 

limited, meaning once the questions specific to their missions are addressed, the Networks will 

not recompete. The successes of these Networks are measured by their study and trial designs, 

the impact and number of their publications, and the incorporation of their findings into clinical 

practice and as the basis for additional studies. The following section describes PPB-supported 

Networks and other efforts funded through cooperative agreements.

NEONATAL RESEARCH NETWORK (NRN)

As explained earlier, the primary 

objective of the NRN is to advance the 

field of neonatal-perinatal medicine by 

establishing and maintaining a network of academic centers that perform multi-center clinical 

protocols in a rigorous manner to investigate the safety and efficacy of treatment and 

management strategies to care for newborn infants, including low birth weight infants. This 

model of multi-site clinical centers for research is the gold standard for conducting clinical 

research; the infrastructure is set up for the ideal randomized double-blinded placebo-controlled 

33 Branch Activities: Cooperative Agreements 
trials and provides the ability to follow short-term (clinical effect) and long-term 

(neurodevelopmental outcome) measures. The Network is also set up for observational, 

longitudinal studies in the NICU setting. This scientific partnership has become an influential 

and successful enterprise in neonatal research. NRN members and co-investigators present 

regularly at national and international scientific meetings (see Figure 8 and Figure 9). 

Randomized Controlled Trials 

Since 2004, the PPB-supported NRN has conducted a number of clinical trials (see Figure 9); 

several of these trials and their outcomes are described below: 

• The Network completed a high-impact trial of whole-body hypothermia for reducing death or 

disability in term infants who had acute perinatal asphyxia at 18 months of age (n = 208). 

Whole-body cooling reduced death and disability from 62 percent to 44 percent at 18 months 

of age (NEJM, 2005; 353: 1574). This landmark study led the AAP to issue practice 

recommendations (Pediatrics, 2006; Mar;117[3]: 942-948) following publication of the 

beneficial finding. 

o Among neonates diagnosed as having hypoxic-ischemic encephalopathy (HIE), the 

classification and regression tree model, but not the scoring system, was superior to early 

neurologic examination in predicting death/disability. The three models were 

comparable in predicting death. Only a few components of the early neurologic 

examination were associated with poor outcomes. These scoring systems and 

classification trees, if validated, may help assess prognosis and may prove useful for riskstratification of infants with HIE for clinical trials (Pediatrics, 2006; Nov;118[5]: 2084-

2093). 

o School age followup (ages six to seven years) is underway for the valuable cohort of 

children included in the whole-body cooling trial. Long-term followup is currently 

scheduled to be completed in spring 2010. Several secondary analyses are also being 

performed. 

o Following completion of the previous study, the researchers will conduct an amplitudeintegrated electroencephalogram study utilizing a cohort from the whole-body cooling 

trial and infants with HIE at NRN sites as followup of children at 18 months of age. 

o A new hypothermia trial testing the efficacy and safety of whole-body cooling in infants 

with HIE who present at 6 hours to 24 hours of age (just beyond the window of the 

previous study) began in 2008. 

• The Network published its findings from a trial utilizing inhaled NO in sick, preterm infants. 

The results showed no benefit of inhaled NO in infants at < 1,500 grams birth weight also 

had respiratory failure (NEJM, 2005; Jul7;353[1]: 13-22). 

o Following cessation of the trial due to an interim analysis, cranial ultrasounds underwent 

a rigorous process of evaluation by a central reader. The results showed increased 

intraventricular hemorrhage (IVH) in infants exposed to inhaled NO, but the increase did 

not remain statistically significant after all subjects were evaluated. The findings 

demonstrate reliability and accuracy of highly unfavorable cranial ultrasound findings, 

but suggest caution when interpreting mild to moderate IVH or white-matter injury 

(J Pediatr, 2007; Jun;150[6]: 592-596, 596.e1-e5). 

Branch Activities: Cooperative Agreements 34 
o Followup showed that, among this extremely ill cohort, inhaled NO did not reduce death 

or neurodevelopmental impairment, nor did it improve neurodevelopmental outcomes 

(J Pediatr, 2007; Jul;151[1]: 16-22, 22.e1-e3). 

• The Network previously completed a trial to evaluate the effect of parenteral glutamine 

supplementation on the risk of death or late-onset sepsis in extremely low birth weight 

(ELBW) infants (n = 1,433). Results indicated that such supplementation had no effect on 

death or sepsis (Pediatrics, 2004; 113). 

o Secondary studies are utilizing this important dataset to evaluate nutritional information 

for ELBW infants. Early provision of amino acids is associated with better growth at 

36 weeks’ post-conceptual age (J Pediatr, 2006; Mar;148[3]: 300-305). Higher fluid 

intake and less weight loss during the first 10 days of life were associated with an 

increased risk of bronchopulmonary dysplasia (BPD) (J Pediatr, 2005; Dec;147[6]: 786-

790). Beneficial effects of breast milk on neurodevelopment were evident at 18 months’ 

(Pediatrics, 2006; Jul;118[1]: e115-e123) and 30 months’ (Pediatrics, 2007; Oct;120[4]: 

e953-e959) corrected age in ELBW infants. Nutrition management remains a significant 

problem for this population. 

o A cytokines study was conducted concurrently with this previous trial. Measurements of 

cytokine values in ELBW infants may give insight into short- and long-term 

complications of preterm birth. 

• The NRN completed a CPAP delivery room pilot study of ELBW infants (n = 103) 

(Pediatrics, 2004; Sep;114[3]: 651-657) that showed the feasibility of applying CPAP 

following stabilization after delivery. This pilot study led to a large multi-center trial called 

the Surfactant Positive Airway Pressure and Pulse Oximetry (SUPPORT) Trial in ELBW 

infants. This large-scale, factorial design CPAP/surfactant and oxygen-saturation level trial 

has recruited approximately two-thirds of the needed 1,300 infants and is co-funded by 

NHLBI. 

o Secondary studies attached to this trial include a neuroimaging study, an antenatal 

consent study, a growth study, and a breathing outcomes study, as well as followup at 

18 months’ to 22 months’ corrected age. 

• The Network completed a benchmarking protocol to reduce BPD in VLBW infants (< 1,250 

grams) (Pediatrics, 2007; May;119[5]: 876-890). Benchmarking and multimodal quality 

improvement changed practices, but did not reduce BPD rates. Multiple secondary studies 

have been performed including those listed below: 

o NRN researchers developed a significant finding, utilizing a physiologic definition of 

BPD that relied on oxygen saturation criteria reduced the overall rate of BPD and reduced 

the variation among centers. Researchers found significant center differences in terms of 

the impact of the physiologic definition; differences between centers remained even with 

the use of this standardized definition. The magnitude of the change in BPD rate was 

comparable to the magnitude of treatment effects seen in some clinical trials of BPD. 

The physiologic definition of BPD facilitates the measurement of BPD as an outcome in 

clinical trials and the comparison between and within centers over time (Pediatrics, 2004; 

Nov;114[5]: 1305-1311). 

35 Branch Activities: Cooperative Agreements 
o Researchers found that cumulative exposure to hypocarbia, but not hyperoxia was 

independently related to risk of periventricular leukomalacia in low birth weight infants 

(Pediatrics, 2006; Oct;118[4]: 1654-1659). 

o Prescription of oxygen with combinations of flow rates and concentrations that delivered 

a low-dose of effective Fraction of Inspired Oxygen (FiO2) is common in patients who 

receive nasal canula oxygen in the nursery. Routine calculation of effective FiO2 values 

may prompt earlier trials of room air and, thus, reduce unnecessary days of oxygen 

therapy (Pediatrics, 2005; Oct;116[4]: 857-861). 

• Retinopathy of prematurity (ROP) is a devastating disease that causes severe visual 

impairment and/or blindness in very preterm infants. The NRN is conducting a series of 

studies, including documentation of inositol blood levels and single- and multiple-dose 

pharmacokinetic studies, that will lead to a large clinical trial to determine if inositol is useful 

as a preventive agent for ROP. This study is co-funded by the NEI. 

• The Early Onset Sepsis (EOS) Surveillance Study is being performed in collaboration with 

the CDC. The objectives of this study are to: establish current hospital-based rates of EOS 

among term and preterm infants in the era of intrapartum antibiotic prophylaxis; monitor the 

organisms associated with EOS and meningitis in neonates of all birth weights and GAs; 

compare asymptomatic and symptomatic infants by GA and pathogen; and monitor sepsisassociated mortality rates for infants with EOS by pathogen group. 

• Inhaled Prostaglans E1 pilot study is a randomized, placebo-controlled, clinical trial to test 

the safety of using intravenous prostaglandin E1 (PGE1) in an inhaled form for treatment of 

hypoxemic respiratory failure in term newborns. The study will enroll 50 infants diagnosed 

with hypoxemic respiratory failure at nine NRN sites and will randomly assign them to 

receive one dose over a 72-hour period of either high-concentration PGE1, low-concentration 

PGE1, or placebo. In addition to determining the safety, optimal dose, and duration of the 

therapy, this pilot trial will evaluate the feasibility of conducting a larger, multi-center 

randomized, blinded placebo-controlled trial of the same treatment. 

• A randomized trial of phototherapy for jaundice in ELBW infants was recently completed 

and analyses and manuscripts are in process. 

Observational Studies 

In addition to clinical trials, the NRN has completed a number of observational studies, including 

those listed below: 

• One NRN observational trial of necrotizing enterocolitis (NEC) showed that survival to 

hospital discharge after surgery for NEC or intestinal perforation was poor at 51 percent. 

Followup at 18 months showed continued poor outcome and a high rate of impairment in 

survivors. Surviving children who underwent laparotomy were less likely to have 

neurodevelopmental impairment (38 percent) than those who underwent intestinal drain 

placement (63 percent). Differences between the drain and laparotomy groups included GA 

and birth weight, providing evidence for a randomized trial of peritoneal drain versus 

laparotomy with 18-month neurodevelopmental outcome as a primary endpoint. This second 

trial is under development in the NRN. 

• The Network recently completed enrollment in an observational trial of Candida infection; 

data entry and analyses are forthcoming. 

Branch Activities: Cooperative Agreements 36 
• An observational trial of a pneumococcal vaccine conjugate in VLBW infants recently 

completed enrollment. Followup is completed and analyses are forthcoming. 

• The NRN has a database of preterm infants who were admitted to Network sites and a 

follow-up program for infants born at ELBW. One of the most important Network efforts 

using these resources is the development and implementation of a standardized follow-up 

protocol for evaluating outcomes of ELBW infants at 18 months’ to 22 months’ corrected 

age. The follow-up protocol provides the largest standardized follow-up assessment of 

ELBW infants to date. Seminal publications from the last four years include the following: 

o Sepsis in VLBW infants resulted in higher rates of neurodevelopmental impairment than 

was seen in an uninfected cohort of infants. Results from this large cohort study 

(n = 6,093) suggest that neonatal infections among ELBW infants are associated with 

poor neurodevelopmental and growth outcomes in early childhood. Additional studies 

are needed to elucidate the pathogenesis of brain injury in infants with infection so that 

novel interventions to improve these outcomes can be explored (JAMA, 2004; 

Nov17;292[19]: 2357-2365). 

o Evidenced-based outcome information for infants born at 22 weeks’ to 25 weeks’ 

gestation showed that multiple factors in addition to GA can determine resultant outcome 

for ELBW infants. Use of multiple factors, including sex, estimated birth weight, single 

versus multiple gestation, and antenatal corticosteroid administration in addition to GA 

gives better survival and impairment-free survival estimates for infants at 22 weeks’ to 25 

weeks’ gestation (NEJM, 2008; 358[16]: 1672-1681). This study resulted in a Webbased tool for outcome data that is available on the NICHD Web site, at 

http://www.nichd.nih.gov/about/org/cdbpm/pp/prog_epbo/index.cfm, for medical staff 

and lay persons to use to make informed decisions regarding care among ELBW infants. 

• Additional highlights of published information from observational studies include: 

o Researchers saw no significant increases in survival without neonatal and long-term 

morbidity among VLBW infants between 1997 and 2002. They speculate that improving 

survival without morbidity requires not only determining, disseminating, and applying 

best practices using therapies currently available, but also identifying new strategies and 

interventions (Am J Obstet Gynecol, 2007; Feb; 196[2]: 147.e1-e8). 

o Histamine type 2-blocker therapy was associated with higher rates of NEC, a result which 

agreed with a previous randomized trial of acidification of infant feeding resulting in a 

decreased incidence of NEC. In combination, these data support the hypothesis that 

gastric pH level may be a factor in the pathogenesis of NEC (Pediatrics, 2006; 

Feb;117[2]: e137-e142). 

o Researchers found significant neurodevelopmental impairment in preterm birth survivors 

despite significant strides in the care and management of these vulnerable infants: 

Perinatal, neonatal, and early childhood factors confer similar incremental risk or 

protection to boys and girls, but boys appear to have inherently greater baseline risk. 

Unmeasured biological variables likely contribute to the neurodevelopmental outcome 

disadvantage of preterm males. (Acta Paediatr, 2006; Oct;95[10]: 1239-1248). 

o One study showed that childhood neurodevelopmental outcomes among infants younger 

than 25 weeks of estimated GA are not improving in the post-surfactant era, despite more 

aggressive perinatal and neonatal treatment (Pediatrics, 2005; Jun;115[6]: 1645-1651). 

37 Branch Activities: Cooperative Agreements 
o Among ELBW infants, receiving surgical management of NEC (SurgNEC) was 

associated with significant growth delay and adverse neurodevelopmental outcomes at 

18 months’ to 22 months’ corrected age compared with receiving no treatment for NEC 

(NoNEC). Medical management of NEC (MedNEC) conferred additional risk. 

SurgNEC was also likely to be associated with greater severity of disease (Pediatrics, 

2005; Mar;115[3]: 696-703). 

o At 18 months’ to 22 months’ corrected age, ELBW infants born with major anomalies 

had nearly twice the risk for neurodevelopmental impairment, as well as increased risk of 

poor growth and more than three times greater risk of rehospitalization when compared to 

ELBW infants without major anomalies. This information may be valuable for 

counseling parents regarding the outcomes of these infants and for the facilitation of 

appropriate support and intervention services (Pediatrics, 2007; Dec;120[6]: e1512-

e1519). 

o Preterm infants were at increased risk for rehospitalization after discharge. Although 

racial disparities are known to exist in pediatric health care, in a cohort of ELBW infants 

recruited from 1998 to 2000, race was not a predominant variable in the risk for 

rehospitalization. Medical morbidities and low family income seemed to be the major 

risk factors for rehospitalization. 

Data from the following completed NICHD NRN studies are available upon request: 

• Intravenous gamma globulin trial in ELBW infants 

• Randomized trial of parenteral glutamine supplementation for ELBW infants 

• Inhaled NO for preterm infants with severe respiratory failure 

• Randomized controlled trial of induced hypothermia for HIE in term infants 

The NRN has also conducted several trials with the following industry partners: 

• INO Therapeutics, Inc., provided inhaled NO for the NO studies. 

• Natus Medical, Inc., provided NeoBlue light emitting diode phototherapy lights for use in the 

phototherapy trial. 

• Abbott Laboratories’ Ross Products Division provided the study drug for the ROP crosssectional and single-dose studies. It will also provide inositol for the upcoming multi-dose 

studies. 

The NRN Data Coordinating Center underwent competitive review and was awarded in 2008. 

The NRN will undergo competitive review in 2011; additional information on the Network is 

available at http://neonatal.rti.org. 

MATERNAL LIFESTYLES STUDY (MLS)

MLS is the largest clinical, prospective, longitudinal study of prenatal drug exposure and child 

outcomes to date. It is conducted at four NRN sites: University of Miami, University of 

Tennessee at Memphis, Wayne State University, and Brown University. The cohort includes 

Branch Activities: Cooperative Agreements 38 
658 exposed and 730 comparison mother/child dyads. In addition to PPB support, NIDA has 

consistently co-funded the MLS effort since it began. 

In Phase I of the MLS, 19,079 pregnant mothers were recruited just before or immediately after 

they gave birth. Of these, 16,988 (89 percent) met basic eligibility criteria, and 11,811 

(70 percent) agreed to participate in the study. Drug use was confirmed by an interview with the 

mother and by gas chromatography/mass spectroscopy for cocaine/opiate metabolites in the 

meconium of the infant. Based on this information, 1,185 infants (10 percent) were exposed to 

either cocaine or opiates during pregnancy. A total of 7,442 infants (63 percent) were confirmed 

as not having been exposed to either cocaine or opiates; the exposure status of 3,184 infants 

(27 percent) was not confirmed. The use of alcohol, tobacco, and/or marijuana by the mother 

occurred in all three of these groups. 

Phase II of the study tracked the development of infants who had been exposed to illicit drugs 

and compared the results to those for infants who were not exposed to illicit drugs. A total of 

1,388 subjects were recruited for this phase of the MLS. Of these, 658 infants were exposed to 

cocaine, opiates, or both in utero, while 730 infants had been exposed to neither. All of these 

infants were initially assessed at one month of age; mothers or caretakers were encouraged to 

participate in visits when the child was four months, eight months, 10 months, 12 months, 

18 months, 24 months, 30 months, and 36 months of age. During these visits, the children 

participated in a variety of assessments to determine their medical and developmental outcomes 

over time. Researchers also asked mothers and caretakers questions about the infants and the 

environment in which the children lived. 

Mother/child dyads have continued their involvement in the MLS through subsequent phases. 

Phase III assessed children at ages four years through seven years. Phase IV includes children 

between the ages of eight years and 11 years. Phase V (ages 12 years to 15 years) was recently 

funded by NIDA. The NICHD continues to support the Data Coordinating Center and the 

Neurobattery Center for this longitudinal study. 

MATERNAL-FETAL MEDICINE UNITS (MFMU) NETWORK

Like the NRN, the MFMU Network’s scientific partnership between the PPB, the 

funded maternal-fetal medicine divisions, and the data coordinating center has 

also become a strong force in the obstetric research community. Network 

members present regularly at national and international scientific meetings and 

have published more than 140 papers in peer-reviewed journals. The MFMU Network marked 

its 20th anniversary in 2006. The efforts of the committed individuals affiliated with the Network 

during the past two decades have yielded success in changing obstetrical practice by identifying 

new therapies and evaluating technologies used in maternal-fetal medicine, while also helping to 

abolish practices that are not useful (see Figure 10, Figure 11, and Table 2). 

39 Branch Activities: Cooperative Agreements 
Evaluations of Common Medical Practices 

Challenges remain related to investigating problems in clinical obstetrics, particularly those 

related to prevention of low birth weight, prematurity, and medical problems of pregnancy. The 

MFMU Network continues to rise to the challenge of designing programs and treatments for the 

prevention of preterm birth and for the improvement of maternal and infant outcomes using 

evidence-based medical practices. 

In October 2007, the ACOG Committee Opinion for subclinical hypothyroidism in pregnancy 

did not recommend routine screening for the condition. However, based on the potential for 

neurodevelopmental problems in the children whose mothers have thyroid deficiency during 

pregnancy, some national societies and public interest groups still recommend screening and 

treating women during pregnancy for subclinical hypothyroidism despite the lack of evidence to 

support this practice. To address these concerns, the MFMU Network designed a randomized, 

double-blind clinical trial to determine whether thyroxine treatment for women with subclinical 

hypothyroidism or hypothyroxinemia diagnosed during the first half of pregnancy is associated 

with intellectual improvements in their offspring at age five years, as measured by the Wechsler 

Preschool and Primary Scale of Intelligence. The researchers recruit women with singleton 

pregnancies between 8 weeks’ and 20 weeks’ gestation and conduct blood tests to determine 

whether subclinical hypothyroidism or hypothyroxinemia is present. Enrolled patients take 

levothyroxine supplements (thyroid replacement) or placebo daily until delivery. Blood draws 

are conducted during regularly scheduled study visits, and dosages are adjusted based on test 

results. The children born to enrolled patients will undergo developmental testing each year until 

age five years. Recruitment began in October 2006 and, to date, more than 40,000 women have 

been screened and 640 were enrolled. It is anticipated that data collection will continue until 

2014.

PRETERM DELIVERY AND 17 Α-HYDROXYPROGESTERONE CAPROATE (17-OHPC) 

As explained in the Branch’s previous report to the NACHHD Council, MFMU Network 

researchers made a groundbreaking finding related to preterm delivery and 17-OHPC—namely 

that weekly injections of the treatment reduced preterm birth rates by 34 percent among women 

who had a previous preterm singleton delivery compared to placebo. Further research confirmed 

that 17-OHPC successfully reduced the risk of recurrent preterm delivery in a subset of high-risk 

women and improved neonatal outcomes for infants born to these women. Since the initial 

finding was published, the MFMU Network has conducted these related studies: 

• The efficacious formulation of 17-OHPC is unknown, and 17-OHPC is currently not 

commercially available. The MFMU Network efforts resulted in a private company 

submitting a New Drug Application to the FDA to produce 17-OHPC. In response, the FDA 

requested that the MFMU Network followup on the children from the trial to ascertain the 

health and developmental outcomes for those exposed to 17-OHPC in utero versus those 

exposed to placebo. Of the offspring from the original trial, 80 percent (278) were available 

for followup, which consisted of a physical examination and developmental testing. The 

mean age at followup was four years. This followup indicated no significant differences in 

developmental and physical outcomes (including genital abnormalities) between the two 

groups. The private company continues to work with the FDA to bring this product to 

market. 

Branch Activities: Cooperative Agreements 40 
• The Network also studied omega-3 fatty-acid supplementation to prevent preterm birth in 

high-risk pregnancies. The aim of this double-masked randomized clinical trial was to 

determine whether omega-3 fatty acids, in conjunction with 17-OHPC injections, reduced the 

risk of preterm birth in women at high risk for spontaneous preterm delivery. 

o Eligible women with singleton pregnancies at 16 weeks’ to 21 6/7 weeks’ GA and who 

had a previous singleton spontaneous preterm delivery were randomized to either 250 mg 

17-OHPC weekly and 2,000 mg omega-3 daily or placebo plus 250 mg 17-OHPC weekly 

and 2,000 mg mineral oil daily. 

o Primary outcome was preterm delivery less than 37 weeks of gestation; secondary was a 

composite neonatal outcome. 

o Although designed as a three-year study, the trial ended more than one-and-a-half years 

earlier than expected. 

o Results, presented at the 2008 SMFM meeting, indicated that, among women with a prior 

spontaneous preterm birth, 17-OHPC/omega-3 supplementation did not reduce the rate of 

preterm birth. However, an association between dietary intake of fish and reduced 

preterm birth was observed. The manuscript has been submitted to a peer-reviewed 

journal. 

• The rate of multi-fetal pregnancies, with higher risk of preterm birth and associated 

morbidity and mortality, is increasing in the United States and is most likely the result of 

increases in assistive reproductive technologies. To date, no intervention exists to prevent 

preterm birth in this population. The Network conducted a randomized controlled trial to 

evaluate whether 17-OHPC reduced the rate of preterm birth in twin and triplet gestations. 

o More than 600 women were assigned to either 17-OHPC or placebo. 

o Results showed no significant differences between the groups within the twin cohort in 

terms of delivery or fetal death before 35 weeks’ gestation and serious adverse fetal or 

neonatal events. 

o Although the results of this part of trial were negative, the findings are important for the 

obstetric community because they indicate further studies are warranted to determine 

whether 17-OHPC is effective for reducing preterm birth for other pregnancies in which 

preterm birth is likely. This manuscript was published in The New England Journal of 

Medicine in 2007 (Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, & 

Spong CY, et al for the NICHD MFMU Network. [2007]. A trial of 17 alphahydroxyprogesterone caproate to prevent prematurity in twins. NEJM, 357, 454-461). 

• A previous Network study, conducted in the late 1990s, concluded that shortened cervical 

length at 16 weeks’ to 18 weeks’ gestation predicted spontaneous preterm delivery at less 

than 35 weeks’ gestation in women with a prior early spontaneous delivery (JAMA, 2001; 

286: 1340-1348). Utilizing the results of this study, the Network designed a trial to 

determine whether 17-OHPC, initiated after 16 weeks but before 23 weeks of gestation, 

reduced the risk of a preterm delivery (before 37 weeks’ gestation) in nulliparous women 

with short cervices (less than 30 mm). 

o Using transvaginal ultrasound, the researchers are screening women who are pregnant for 

the first time (or who have not had a pregnancy lasting more than 19 weeks’ gestation) to 

see if their cervices are short (less than 30 mm). 

41 Branch Activities: Cooperative Agreements 
o Those with shortened cervices will be randomized to weekly 17-OHPC or placebo. 

o The study began in March 2007 and has a sample size of 800. More than 5,000women 

have been screened and 150 enrolled to date. 

CESAREAN DELIVERIES AND VAGINAL BIRTH AFTER CESAREAN (VBAC) 

The rate of cesarean delivery has risen dramatically during the past two decades and currently 

ranks as the most commonly performed surgical procedure in the United States. A substantial 

portion of women who undergo a cesarean delivery have a history of a previous cesarean 

delivery, but some women who have had a previous cesarean deliver their infants by VBAC. 

Existing evidence about the risks and benefits of VBAC that could assist health care providers in 

counseling women with a history of a prior cesarean delivery is not current and is generally 

derived from small studies. The MFMU Network chose to use its large patient population, 

specifically in the MFMU Cesarean Registry, to study the outcomes of VBAC, including 

complications, fetal injury, and contributing factors. 

• The MFMU Cesarean Registry, completed in December 2002, includes observational data on 

more than 52,000 primary and repeat cesarean deliveries and more than 18,000 VBAC 

deliveries. 

• This Registry provides the largest resource of information on cesarean deliveries collected in 

a standardized, prospective fashion by trained study personnel. 

• The study found that women who attempted trial labor had significantly higher rates of 

maternal morbidity (i.e., uterine rupture, endometritis, and transfusion) and neonatal 

complications (i.e., HIE) compared with women who underwent an elective repeat cesarean 

delivery. Because serious maternal morbidity increases progressively with number of 

cesarean deliveries, the number of anticipated pregnancies should be considered when 

counseling women regarding elective repeat cesarean versus a trial of labor. These findings 

may be important when counseling patients regarding elective cesarean versus trial of labor 

after previous cesarean delivery. 

• These findings, in part, led to the 2006 release of the ACOG Committee on Obstetric Practice 

Committee Opinion Induction of Labor for Vaginal Birth After Cesarean Delivery, which 

states: 

o Induction of labor in women who have had cesarean deliveries may be necessary because 

of fetal or maternal indications. The potentially increased risk of uterine rupture should 

be discussed with the patient and documented in the patient record. Selecting women 

most likely to give birth vaginally and avoiding the sequential use of prostaglandins and 

oxytocin appear to offer the lowest risks (Number 342, August 2006). 

• In a study to evaluate the success rate and risks for women with twin pregnancies who 

attempted a trial of labor following at least one previous cesarean delivery, the Network 

ascertained data on 412 women pregnant with twins who had a prior cesarean delivery. 

o Of these, 226 had elective repeat cesarean delivery. Of the 186 women who attempted to 

deliver vaginally, 64.5 percent were successful. Almost half of the women who had a 

failed trial of labor had vaginal delivery for twin A and cesarean for twin B. There were 

no differences in maternal morbidity (i.e., transfusion, endometritis, NICU admission, 

uterine rupture) for those who attempted vaginal delivery versus those who elected for 

repeat cesarean delivery. 

Branch Activities: Cooperative Agreements 42 
o This study showed that, for women pregnant with twins who have a history of a prior 

cesarean, a trial of labor is a reasonable consideration for selected pregnancies at or near 

term and does not increase maternal morbidity. 

Because cesarean delivery is one of the most common operations performed in the United States, 

the Network evaluated anesthesia-related complications in cesarean deliveries. Regional 

anesthesia has become the anesthetic method of choice in obstetrics. Researchers assessed 

anesthetic use and complications in more than 37,000 women who underwent cesarean delivery 

and found that regional anesthetic was used in 93 percent of these deliveries; morbidity related to 

the procedure was rare. Increased maternal weight, higher preoperative risk, rapid decision-toincision interval, and placement later in labor were related to increased risk of failed regional 

procedure. Only one maternal death was directly implicated to anesthesia, due to a failed 

intubation. The results indicate that obstetric anesthesia for cesarean delivery is safe and rarely 

results in procedure-related complications. 

The Network also evaluated the decision-to-incision intervals and related them to maternal and 

neonatal outcomes using a cohort of women who underwent emergency cesarean deliveries. For 

most practitioners, the goal for emergency deliveries is for a cesarean to begin within 30 minutes 

of the decision to operate, even though the ACOG/AAP guideline on emergency cesarean 

delivery does not support the position that all cesareans must be performed within 30 minutes of 

the decision. Of the 11,481 primary cesarean deliveries, 2,808 were performed for an emergency 

indication; of those with emergency indication, 65 percent of deliveries began less than or equal 

to 30 minutes from the decision to operate and 35 percent began at more than 30 minutes from 

the decision to operate. Most of the deliveries occurring at more than 30 minutes after the 

decision to perform a cesarean were performed because of nonreassuring fetal heart rate tracings. 

Adverse neonatal outcomes were not increased in this group. Even though this large, multicenter study found that approximately one-third of emergency primary cesarean deliveries began 

more than 30 minutes after the decision to operate, more than 95 percent of these infants did not 

experience newborn compromise. Overall, in the setting of emergency delivery, the decision-toincision interval did not appear to impact maternal or neonatal complications, supporting the 

ACOG/AAP guidelines for emergency cesareans. 

OTHER MFMU NETWORK EFFORTS

As a result of an ACOG Practice Bulletin issued in 2001, universal screening and treatment of 

gestational diabetes mellitus (GDM) are widely practiced by the obstetrical community. To 

evaluate the true benefit of such screening and treatment, the MFMU Network conducted a 

randomized clinical trial to determine whether daily self blood-glucose monitoring and diet 

therapy reduced neonatal morbidity, including reducing the risk of problems for newborns, such 

as low blood sugar, jaundice, macrosomia, and other pregnancy outcomes, in women with mild 

GDM. The primary outcome composite included hypoglycemia, hyperinsulinemia, 

hyperbilirubinemia, birth trauma, death, or stillbirth. Eligible women between 24 weeks’ and 

31 weeks’ gestation diagnosed as having mild GDM were enrolled to either receive standard 

pregnancy care or diet therapy with self-administered blood sugar monitoring. Enrollment ended 

in November 2007, with 1,889 study subjects. Analyses of the data are ongoing. The knowledge 

gained from this study may help improve treatment and outcomes for women diagnosed with 

mild GDM. 

43 Branch Activities: Cooperative Agreements 
The MFMU Network also builds upon information obtained from its own studies. In 2000, the 

NIH panel for the consensus development conference Antenatal Corticosteroid Revisited: 

Repeat Courses concluded that the available data was inadequate to recommend the repeated use 

of antenatal corticosteroid therapy for women at risk of preterm birth (see 

http://consensus.nih.gov/cons/112/112_intro.htm). Follow-up studies indicated that repeated 

exposure to antenatal corticosteroids significantly reduced specific neonatal morbidities, but did 

not improve composite neonatal outcome, decreased birth weight, and increased the risk of SGA 

neonates. Therefore, routine weekly repetition of antenatal steroids for women at high risk for 

preterm birth could not be justified. As a result of these studies, efforts are underway to assess 

antenatal corticosteroids and the late preterm infant (34 weeks to 36 weeks of gestation). Recent 

data show that the late preterm infant suffers increased morbidity and mortality compared to term 

fetuses, a situation that increases NICU admissions. Although their risk of respiratory distress 

syndrome is minor, late preterm infants are at high risk for other respiratory morbidities related 

to clearing fetal lung fluid. There is biological plausibility as to why steroids may be useful in 

this group; however, there is no evidence on which to base such a practice. A randomized, 

double-blinded, placebo-controlled trial was recently approved within the Network to evaluate 

whether steroids are helpful to improving outcomes of late preterm infants. 

Technological Advances 

Sometimes, and not just within obstetrics, new technology is developed and adopted without 

rigorous studies to confirm its efficacy and safety. With its more than 140,000 deliveries per 

year, the MFMU Network provides a unique opportunity to rigorously test obstetrical 

technology. For instance, the FDA approved the OxiFirstTM Fetal Oxygen Saturation Monitoring 

System in May 2000. This technology, fetal pulse oximetry, measures fetal oxygenation 

throughout labor and was marketed as an adjunct to conventional electronic fetal heart rate 

monitoring. Results of a randomized clinical trial by the manufacturer, published in 2000, 

showed that this technology reduced the cesarean delivery rate for fetal distress by 50 percent, 

but the rate of cesarean for dystocia doubled. FDA approval was contingent upon additional 

studies to examine the system’s effectiveness and influence on cesarean delivery rates. An 

additional, larger study was also needed to assess infant outcomes in the event that an 

obstetrician withheld cesarean delivery in the presence of an abnormal heart rate pattern because 

fetal oxygenation was deemed normal. 

The 14 clinical centers in the MFMU Network developed a research protocol under an 

Investigational Device Exemption to more definitively measure how the additional knowledge of 

fetal oxygen saturation impacts labor management and infant outcomes. A total of more than 

5,300 nulliparous women were randomized at the time of delivery to either “open”—in which 

fetal oxygen saturation values were displayed to the clinician—or “masked”—in which the data 

was not available to the clinician. Results of the trial indicated no significant differences in 

cesarean delivery rates or infant outcomes between those deliveries for which obstetricians had 

fetal oximetry data versus those for which no oximetry data was available. This trial confirms 

the value of rigorous assessment of new technology. 

Branch Activities: Cooperative Agreements 44 
A Spirit of Trans-NIH and Trans-Agency Collaboration 

As the PPB-supported MFMU Network has grown and developed, additional expertise and 

funding for large studies has come from other NIH Institutes and federal agencies. For example: 

• The MFMU Network is collaborating with the NINDS on a randomized trial of the beneficial 

effects of antenatal exposure to magnesium sulfate for the prevention of cerebral palsy. This 

trial design was based on case-control studies that identified magnesium sulfate as protective 

against the development of cerebral palsy. This double-blind, randomized trial involved 

2,241 women at high risk of delivering very preterm (less than 32 weeks of gestation). 

Clinicians conducted more than 5,700 neurological exams and achieved 95.6 percent 

followup. The two-year follow-up period ended in 2007. The trial concluded that 

magnesium sulfate did not reduce the rate of the primary outcome of moderate to severe 

cerebral palsy or death, perhaps because death was the predominant component of the 

outcome. However, it did reduce the rate of moderate to severe cerebral palsy alone by 50 

percent. Results were presented at the SMFM meeting in 2008. The manuscript was 

published in the New England Journal of Medicine in August 2008. 

• The NHLBI provided funding to the MFMU Network to conduct the Combined Antioxidant 

and Preeclampsia Prediction Study (CAPPS) for the prediction and prevention of 

preeclampsia. This randomized, controlled trial is designed to determine if antioxidants 

(vitamins C and E) can prevent preeclampsia in low-risk women (n = 10,000). In addition, 

the observational component of the trial is designed to identify markers that may predict 

preeclampsia. Initiated in 2003, CAPPS recently completed enrollment, screening more than 

30,000 women and enrolling in 10,000 patients in the randomized controlled trial and more 

than 2,300 in the observational cohort. Efforts are underway to determine which markers 

should be evaluated. The last deliveries are anticipated in November 2008. The Network 

expects to present the results at the annual SMFM meeting in 2009. 

• In 2007, as the result of a congressional mandate requiring doctors to use quality measures to 

report on their performance, the MFMU Network collaborated with colleagues at the Agency 

for Healthcare Research and Quality to design a new study, An Observational Cohort Study 

to Evaluate Measures of Quality of Obstetric Care. The aim of this study is to identify 

several measures for assessing the safety of obstetrical care that can be incorporated into 

medical practice. The overall objective is to find tools for evaluating the quality of obstetric 

care by determining which process measures are associated with risk of poor outcomes. The 

five outcomes to be utilized are: uterine hemorrhage, maternal infection, thromboembolism, 

maternal third- and fourth-degree lacerations, and neonatal adverse outcomes. The study will 

include 25 hospitals from the Network. A recently completed pilot study of approximately 

2,500 patients prospectively collected data related to these measures; this pilot resulted in 

changes to the data-collection tool. Network researchers anticipate that the study will collect 

data from more than 120,000 patient charts that will be abstracted over 12 months. To date, 

more than 6,500 charts have been abstracted. 

The MFMU Network is working to release datasets from completed studies and trials in a format 

accessible to the public; that is, removing all identifiers. Two datasets have already been 

released and are available: Obstetrics Determinants of Neonatal Survival, and Preterm 

Prediction Study. Other datasets are also being prepared for release. 

45 Branch Activities: Cooperative Agreements 
The MFMU Network Data Coordinating Center was recompeted in 2008; the clinical sites will 

be recompeted in 2011; more information on the MFMU Network is available at 

http://www.bsc.gwu.edu/mfmu/. 

INFANT FEEDING PRACTICES STUDY (IFPS) II

The IFPS II, a longitudinal survey of a large cohort of 4,900 women enrolled prenatally, was 

conducted collaboratively by the FDA, CDC, and the NICHD. Investigators followed more than 

2,000 women through the first year of their infants’ lives to assess a wide range of topics related 

to infant feeding practices, including postpartum depression, consumption of herbal and 

alternative medicines, breast pump use, and infant sleeping arrangements. The first set of 13 

resulting papers includes results on several feeding issues: breastfeeding patterns, intensity, and 

duration; reasons for stopping breastfeeding; transitional and complementary feeding; provision 

of iron-rich foods and supplements to breastfed infants; the association between maternity care 

practices for the delivery location and the breastfeeding-related options associated with place of 

employment; infant formula handling practices; infant sleeping arrangements; food-related 

health problems, including food allergy; the effects of breastfeeding intensity, infant-initiated 

bottle emptying, and mothers’ encouragement of bottle emptying on excess weight during 

infancy. These papers were published in a supplement to Pediatrics (Vol. 122 [Suppl], 2008). 

Some of the major findings from the IFPS include the following: 

• Researchers found a large variation from common advice on breastfeeding practices, such as 

the length of feeds and feeding from both breasts, and a small percentage of breastfeeding 

mothers (about 6 percent) who never put the baby to the breast. 

• Nearly half of breastfed infants were supplemented with infant formula in the hospital, 

although this practice was not necessarily based on medical need. 

• Nearly half of infants were fed solid foods before the age of four months; more than half of 

infants consumed foods high in fat or sugar at one year of age. 

• About 58 percent of mothers who breastfeed their infants did not follow recommendations 

for adequate iron supplementation. 

• One-quarter of the three-month-old infants were not placed on their backs to sleep as 

recommended; bed sharing was also quite common, reported by 34 percent of mothers with 

three-month-old infants. 

• Among the various strategies mothers used to combine breastfeeding and employment, 

feeding the baby directly from the breast during the work day, either alone or in combination 

with pumping milk, was associated with longer breastfeeding duration after return to work. 

• More than 20 percent of infants were reported to have a food-related health problem, with 

about 6 percent having an apparent food allergy. The majority of affected infants developed 

food-related health problems by six months of age. 

The datasets from IFPS II will be available at http://www.cdc.gov/ifps/index toward the end of 

2008; the scientific community can use these data to pursue additional analyses and research. 

Branch Activities: Cooperative Agreements 46 
COLLABORATIVE HOME INFANT MONITORING AND EVALUATION (CHIME)

STUDY 

The CHIME Study, now complete, was a multi-center, cooperative study of home 

monitoring of high-risk infants. Almost 1,200 infants were enrolled in the 

following subject groups: healthy term infants, preterm infants weighing less than 

1,750 grams, and siblings of babies who died of SIDS or who experienced an 

idiopathic apparent life-threatening event. 

The PPB is now working to maintain the CHIME and NISP datasets (see the SIDS 

Research: Risk Reduction section of this report for more information on NISP) and to facilitate 

access to the data by the scientific community, thus ensuring that these important data are used to 

their fullest extent. To do so, the Branch funded the CHIME Data Coordinating and Analysis 

Center in fiscal year 2004 to complete the following tasks: 

• Determine the factors and physiological processes that predict extreme cardiorespiratory 

events, including early antecedents, developmental patterns, and immediate characteristics of 

onset and recovery. These analyses may include comparisons that distinguish “extreme” 

versus “conventional” events, when appropriate. 

• Continue the NISP Study and evaluate trends in infant sleep practices and dissemination of 

the Back to Sleep recommendations, and the factors that influence these trends. The Center 

will make efforts to increase the proportion of minorities in the completed calls, while using 

the current list sample. 

• Facilitate scientific community access to the data collected by the CHIME and NISP Studies. 

As explained earlier, NISP interviews were conducted annually from 2003 to 2007; the NICHD 

and AAP used the data to guide Back to Sleep campaign activities and to follow the impact of the 

2005 AAP recommendations on bed sharing and pacifier use. Overall, 5,549 respondents, 

including an enhanced sample of caretakers with lower education background, were interviewed 

by phone during the five-year study period (5,701 infants). Interviews were also conducted in 

Spanish. 

The CHIME/NISP Web site, http://dccwww.bumc.bu.edu/ChimeNisp/, was established in 2004 

as the primary portal to these datasets. During the project period, there have been more than 

20,000 visits on the site from more than 4,000 different Internet Provider addresses. The rate of 

visits has steadily increased, with number of visits in the current year approximately twice that of 

the prior year. The Data Coordinating Center has fielded 52 inquires from investigators 

regarding the datasets. 

Currently, two investigator-initiated grants are funded to analyze the CHIME dataset: 

• Grant Number: 1 R01 HD045653-01; PI: Robert A. Darnall, M.D., Project Title: 

Spontaneous Arousals in “CHIME” Infants at Risk for SIDS

• Grant Number: 1 R03 HD42479-01 (Revised); PI: Stephanie A. Schuckers, Ph.D., Project 

Title: Predicting Life-Threatening Events in CHIME Infant Data

47 Branch Activities: Cooperative Agreements 
The CHIME database, which includes all raw physiological records and study forms was also 

recently transferred to CD-ROM. 

MATERNAL-FETAL SURGERY NETWORK 

In 2001, the PPB created the Maternal-Fetal Surgery Network to evaluate, using a 

randomized clinical trial, in utero surgery as a treatment for antenatally diagnosed 

spina bifida. The Management of Myelomeningocele Study (MOMS) trial 

includes three sites: Children’s Hospital of Philadelphia, Vanderbilt University 

Medical Center, and the University of California, San Francisco. The PPB 

provides additional oversight and guidance, and the George Washington Biostatistics Center 

serves as the Data Coordinating Center for the Network. 

This collaborative, multi-center trial is comparing the safety and efficacy of fetal surgical repair 

to traditional postnatal repair of open neural tube defects. Of the 200 women planned for 

enrollment, 145 were randomized into the study as of July 2008. For more information on the 

MOMS trial or on the Maternal-Fetal Surgery Network, visit 

http://www.spinabifidamoms.com/english/index.html. 

VAGINAL ULTRASOUND CERCLAGE TRIAL

As explained in the earlier section about the MFMU Network, prior studies 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 of this situation. The 

Vaginal Ultrasound Cerclage Trial (1U01HD039939-01A1; PI: John Owen, M.D.) 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. Researchers at 11 centers studied women at significant risk for recurrent 

spontaneous preterm birth (e.g., those with a prior spontaneous birth at 17 weeks’ to 33 weeks’ 

gestation) and those at increased risk based on mid-trimester ultrasonographic findings of a 

cervical length less than 25 mm. This procedure is currently one of the most controversial issues 

in obstetrics and maternal-fetal medicine. Enrollment of the total sample size of 300 women is 

complete. Results from this trial, anticipated in early 2009, will provide significant evidence for 

the specialty, for women, and for their pregnancies. 

COMMUNITY CHILD HEALTH RESEARCH NETWORK (CCHN)

The CCHN is a community-linked research effort about maternal and child health that relies on 

cooperative agreements to plan and perform a multi-site, multi-level study examining how 

community, family, and individual influences interact with biological influences to result in 

health disparities in pregnancy outcomes and in infant and early childhood mortality and 

morbidity. One of the foci of the research enterprise is to improve family heath in the 

Branch Activities: Cooperative Agreements 48 
interconceptional period as a means of improving the outcomes of future pregnancies. The 

CCHN includes five collaborating sites, each one a partnership between an academic institution 

and community institutions; staff from the PPB, from the NICHD Demographic and Behavioral 

Sciences Branch, and from the NINR are also active in this effort. The CCHN has made 

progress toward its core hypotheses, methods development, and study design. 

The Phase I goal of the research program is to blend substantive theory, measurement regimes, 

and study designs currently found in the biomedical, social, and behavioral sciences into a study 

of infant mortality and child health. The current products of Phase I include a plan of action 

describing the hypotheses, design, and content the study, as well as preliminary work from each 

site that will provide a foundation upon which to build such a research network. Findings 

garnered from this study will improve understanding of the complicated interplay among 

environmental and genetic factors that produces biological outcomes in high-risk minority 

populations. 

PRENATAL ALCOHOL IN SIDS AND STILLBIRTH (PASS) NETWORK 

In 2003, the NICHD and NIAAA funded cooperative agreements to 

establish Phase I of the PASS Network, the primary hypothesis of which 

is that prenatal alcohol exposure increases the risk for SIDS and stillbirth. The conceptual 

framework that underlies the proposed studies is that the interaction among different 

environmental and genetic factors affects the risk for a spectrum of disorders, including SIDS, 

stillbirth, and the early manifestations of fetal alcohol syndrome and fetal alcohol spectrum 

disorders, related to prenatal alcohol exposure from mid-gestation through infancy. 

The Network is composed of two comprehensive clinical sites at the University of South Dakota 

and Stellenbosch University, South Africa; a developmental biology and pathology center at 

Children’s Hospital, Boston; a Data Coordinating and Analysis Center at DM-STAT; and a 

physiology assessment center at Columbia University. 

During Phase I, researchers conducted a pilot study to demonstrate the feasibility of collecting 

alcohol exposure, psychosocial, and physiological data from mothers, fetuses, and infants 

prospectively throughout the prenatal, perinatal, and postnatal periods. The target enrollment for 

the prospective study was 380 women, and 579 were enrolled. The Phase I data on drinking 

patterns during pregnancy in the catchment populations confirmed the expected high exposures 

and enabled researchers to develop samples sizes for Phase II. 

The Network also conducted retrospective studies of stillbirths and SIDS to determine feasibility 

of diagnostic procedures—those to collect and analyze brain tissue and other relevant specimens 

from stillbirths and post-discharge infant deaths, and those for interviewing the mothers. All 

targets for enrollment and specimen collection were met. 

In 2006, the PASS Network successfully competed for Phase II. Its study will be the first 

longitudinal effort, beginning in the prenatal period, to examine the effects of fetal alcohol 

exposure on fetal and infant morbidity and mortality. The PASS Network has the opportunity to 

49 Branch Activities: Cooperative Agreements 
gain new knowledge about genetic-environmental interactions that influence prenatal alcohol 

toxicity; the direct effects of prenatal alcohol exposure on the human brain and placenta, as well 

as on autonomic and neurological behaviors in early human life; the potential links between 

SIDS and unexplained stillbirth; and the effects of prenatal alcohol exposure on the risk for 

perinatal and infant mortality. The findings also have the potential to help develop innovative 

ways to predict and/or prevent the adverse effects of prenatal alcohol exposure before and at 

birth. 

STILLBIRTH COLLABORATIVE RESEARCH NETWORK (SCRN)

Stillbirth, defined as death at 20 weeks’ gestation or greater, accounts 

for a large proportion of perinatal mortality. According to annual 

national vital statistics, the number of fetal deaths at 20 weeks’ or more gestation, including 

stillbirths, is similar in magnitude to the total number of infant deaths in the United States. To 

begin to address gaps in knowledge about stillbirth, the PPB issued Research on the Scope and 

Causes of Stillbirth in the United States (RFA-HD-02-025) to create a Network of clinical 

research sites, with a central data collection and analysis resource, for developing and 

implementing common research protocols to study stillbirth. The awards for the SCRN were 

made in September 2003 to the following clinical investigators and research sites: 

• Dr. Marshall Carpenter, Women and Infants Hospital of Rhode Island, Providence; 

• Dr. Donald Dudley, University of Texas Health Sciences Center, San Antonio; 

• Dr. George Saade, University of Texas Medical Branch, Galveston; 

• Dr. Robert Silver, University of Utah, Salt Lake City; 

• Dr. Barbara Stoll, Emory University, Atlanta; and 

• Dr. Corette Parker, Statistical Center at RTI International, Raleigh. 

In the first year, the Network developed a multi-site, population-based, hypothesis-driven, casecontrol study with prospective enrollment of stillbirths as cases and live births as controls. 

Hypotheses were developed in surveillance and epidemiology, fetal and placental pathology, 

maternal disease mechanisms, immunology and infectious diseases, and genetics; these 

hypotheses have driven the design requirements of the study, including case ascertainment; 

selection, number, and type of controls; and timing and approach to data collection and 

management. Following the development of the study design, hypotheses, protocol and research 

instruments, and the piloting phase of the study, Network researchers began recruitment of cases 

and controls. 

To date, 58 hospitals are participating in the SCRN protocol. The final sample size for the study 

is 700 cases of stillbirth, 500 cases with complete information including autopsy, and 1,850 

controls. This sample size was selected to assure at least a 1:1 ratio of live births to stillbirths 

across ethnic categories and GA. Enrollment was completed in September 2008. The 

information derived from this five-year study will benefit families who have experienced a 

stillbirth, women who are pregnant or who are considering pregnancy, and their physicians. In 

Branch Activities: Cooperative Agreements 50 
addition, the knowledge will support future research aimed at improving preventive and 

therapeutic interventions and at understanding the pathological mechanisms that lead to stillbirth. 

GENOMIC AND PROTEOMIC NETWORK FOR PRETERM BIRTH RESEARCH (GPN/PBR)

The main objective of the GPN/PBR, established in 2005, is to use wide-scale, high-output 

genomic and proteomic strategies to accelerate knowledge of the mechanisms responsible for 

spontaneous preterm birth. Approaches, such as genome-wide scans and global serum protein 

profiling, are used to identify new biomarkers, which increase the risk or are predictive of a 

spontaneous preterm birth, and to use this information for understanding the molecular 

mechanisms involved. In addition, the Network acts as a resource for the scientific community 

by freely providing genomic and proteomic data generated by its research for secondary 

analyses. 

Network projects consist of three collaborative core components: the clinical core, comprising 

three clinical sites (University of Alabama at Birmingham, University of Texas at Galveston, and 

University of Utah), which is responsible for subject recruitment and specimen collection; the 

analytical core (University of Pennsylvania), which is responsible for genomic and proteomic 

analyses; and the data management, statistics, and informatics core (Yale University), which is 

responsible for central data collection, analysis, and management. Three study designs, 

explained below, were developed and recruitment for these studies began in late 2007. 

• The first study will follow 500 women at high risk for preterm birth (e.g., previous 

spontaneous preterm birth) throughout pregnancy, starting in the first trimester. The primary 

purpose of this study is to establish a simple test, using blood, urine, or saliva, to detect a 

biomarker for predicting whether a woman will have a spontaneous preterm delivery. If 

successful, this test would allow an intervention to be introduced early enough to possibly 

prevent the preterm delivery. 

• The second study will recruit 1,000 women who deliver spontaneously preterm and 1,000 

women who deliver spontaneously at term. Researchers will collect a DNA specimen from 

each woman to determine a DNA profile that increases the possibility for a spontaneous 

preterm birth. If successful, this study would enable physicians to determine women’s 

susceptibility to a preterm birth even before conception. This information would also allow 

physicians to closely monitor their patients and introduce the appropriate intervention based 

on a particular DNA profile. DNA from the newborn will also be obtained and may be used 

to develop a profile for predicting the outcomes of a preterm infant. 

• The third study will recruit 80 women, in labor and not in labor, for a medically indicated 

caesarean section resulting in either a spontaneous preterm or term delivery. This effort will 

include an ancillary study of an additional 40 women, in labor and not in labor, whose 

deliveries are complicated by the pPROM, and who undergo a medically indicated caesarean 

section. Numerous delivery specimens will be collected for analysis. This study is a very 

detailed global analysis of DNA, RNA, and protein expression. A comparison of the 

analyses between the various groups of women should allow important insight into the 

molecular mechanisms involved in spontaneous preterm birth and pPROM. 

51 Branch Activities: Cooperative Agreements 
Researchers anticipate that recruitment of subjects for these three studies will be complete by late 

2009, and that the final analyses will be completed by late 2010. Ultimately, this research may 

lead to relatively simple screening tests to identify pregnant women (or possibly even women 

contemplating pregnancy) who are at risk for a spontaneous preterm birth and provide them with 

interventions, which may enable them to carry a pregnancy to term. Furthermore, the selection 

of a particular intervention (therapy) may be informed by an individual’s genetic or proteomic 

profile. 

BRANCH ACTIVITIES: TRAINING AND CAREER DEVELOPMENT PROGRAMS 

The Branch supports research training and career development through various award 

mechanisms. For fiscal year 2004 through fiscal year 2007, the PPB funded the following 

training and career development awards: 

• Two new and five continuing National Research Service Award (NRSA) Predoctoral 

Fellowships for Minority Students and Students with Disabilities (F31); of a total of six 

applications, two were funded, resulting in a 33-percent success rate. 

• No new and two continuing NRSA for Individual Postdoctoral Fellowship (F32); of the 16 

applicants, none were funded, resulting in a 0-percent success rate. 

• Four new and 15 continuing Mentored Clinical Scientist Development Awards (K08); of the 

14 fourteen applicants, four were funded, resulting in a 29-percent success rate. 

• Five new and 12 continuing Mentored Patient-Oriented Research Career Development 

Awards (K23); of the 17 applicants, five were funded, resulting in a 29-percent success rate. 

• One new and four continuing Mid-Career Investigator Awards in Patient-Oriented Research 

(K24); of the three applications, one was funded, resulting in a 33-percent success rate. 

• Four new, seven renewals, and five continuing NRSA Institutional Research Training Grants 

(T32); six of these grants have been active for more than 20 years. Of the 20 applicants, 11 

were funded, resulting in a 55-percent success rate. 

It is noteworthy that neonatal/perinatal fellows and postdoctoral scientists funded through the 

Branch’s T32 mechanism have been presenting scientific papers in large numbers at regional and 

national professional society meetings. The Branch has tracked these data since 2005; each year 

these grantees present 45 to 50 research papers at the annual meetings of the Pediatric Academic 

Societies alone. 

OTHER BRANCH ACTIVITIES 

INSTITUTE OF MEDICINE (IOM) PREGNANCY WEIGHT GUIDELINES

Branch Activities: Training and Career Development Programs 52 
The PPB is co-sponsoring this IOM activity, which will review and update the 1990 IOM 

recommendations for weight gain during pregnancy. The new report will also suggest ways to 

encourage adoption of these recommendations through consumer education, strategies to assist 

practitioners, and public health outreach. The committee is sponsored by the Health Resources 

and Services Administration, NIH (NICHD, National Institute of Diabetes and Digestive and 

Kidney Diseases, Division of Nutrition Research Coordination), CDC, DHHS Office of 

Women’s Health, and the March of Dimes. The committee report is expected by summer 2009. 

BEST PHARMACEUTICALS FOR CHILDREN ACT (BPCA)

The congressional mandates of the BPCA provide an opportunity to address the challenges of 

conducting drug-related clinical trials in children for the purpose of labeling drugs for use in 

pediatric populations. Branch staff, especially Drs. Tonse Raju and Rosemary Higgins, are 

actively involved in this important initiative, in collaboration with other NICHD and NIH staff. 

Drs. Raju and Higgins helped to organize an NICHD/FDA Newborn Drug Development 

Initiative to foster the development of safe and effective drug therapies for term and preterm 

infants. Branch staff continue to be involved in BPCA activities in conjunction with the 

Obstetric and Pediatric Pharmacology Branch within the NICHD Center for Research for 

Mothers and Children. 

DHHS INTERAGENCY COORDINATING COUNCIL ON LOW BIRTH WEIGHT AND PRETERM 

BIRTH AND DISPARITIES SUBCOMMITTEE

The purpose of this Interagency Coordinating Council is to galvanize multidisciplinary research, 

scientific exchange, policy initiatives, and collaboration among DHHS agencies, including the 

NIH, and to assist the Department in focusing efforts to achieve the greatest advances toward the 

national goal of reducing infant mortality. The challenges faced by the Council include assuring 

adequacy of data, uncovering new knowledge through research, and promoting the best possible 

delivery and financing of relevant health care. In particular, the DHHS Secretary asked the 

Council to develop a Department-wide research agenda on combating low birth weight and its 

associated outcomes. 

This Council made recommendations related to DHHS research on preterm birth, low birth 

weight, and SIDS. In the area of preterm birth, opportunities for future research included 

mechanisms of initiation of labor and role of infection with respect to preterm delivery. For low 

birth weight, areas of research included smoking cessation, improvement of ultrasound dating to 

reduce unintentional preterm or low birth weight induction or delivery, investigation of ways to 

discourage assistive reproductive technology practices leading to multiple gestation, and 

investigation of partnerships for research. The Council also recommended assistance with 

approval of 17-OHPC to make it available for physicians to use in evidence-based practice. 

Suggestions for meetings, including Caesarean Section on Maternal Request and The Prevention 

of Preterm Birth, were recommended by the Council. In the area of SIDS, the Council 

recommended studies on the impact of prenatal alcohol use by American Indians/Alaska Natives 

53 Other Branch Activities 
on SIDS rates and possible interventions. Recommendations for continued research into the 

mechanisms involved in SIDS were made, as well as those for continued efforts of the Back to 

Sleep campaign to reduce the rates of SIDS. 

Other Branch Activities 54 
FUTURE DIRECTIONS FOR THE PPB 

On December 5-6, 2002, the Branch convened a two-day workshop to 

develop a research agenda that would help guide Branch activities and 

set priorities for the years 2005 through 2010. The findings from this 

two-day workshop were used to develop the Pregnancy and 

Perinatology Branch Strategic Plan: 2005-2010. The plan included 

ongoing areas of PPB-supported research and outlined some steps for 

expanding these initiatives. The plan also identified new areas of 

emphasis crucial to the PPB mission. New areas of emphasis included: 

• Prematurity 

• Fetal development, including maturation of individual organ 

systems and the impact of interventions on long-term function 

• Maternal morbidities 

• Neonatology, specifically intensive-care and long-term outcomes 

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

infant periods 

• Training of scientists and physician-scientists 

• Defining and improving the link between fetal, obstetric, and neonatal interventions and 

infant/child outcomes 

Since the development of the plan, the Branch has undertaken many activities to specifically 

address issues raised as high priorities. Branch staff have encouraged applications in the areas of 

emphasis. Although the time since development of the plan has been one of fiscal constraint, the 

PPB has initiated a number of initiatives to address the topics listed above. Future areas of 

research emphasis include many topics identified in the plan because many of the areas are broad 

and will require sustained efforts over decades to make inroads. 

On April 21, 2008, in accordance with the NICHD’s process for improving the transparency of 

and enhancing input toward strategic planning, the Branch convened an expert panel to review 

its activities and formulate future directions. The expert panel, comprising members of the 

NACHHD Council, professionals with backgrounds in neonatology, pediatrics, obstetrics, 

maternal-fetal medicine, and epidemiology, and representatives from interested public groups 

(see Appendix G for a list of panel members), identified the most important scientific 

opportunities that the Branch should consider pursuing during the next four years, including and 

emphasizing those areas that are making the most rapid advances, those that need special actions 

or stimulation by the Branch, and those that are not currently represented in the portfolio. An 

overarching theme of the panel’s discussion was that, for all areas, understanding the 

mechanism(s) of disease, including basic and translational research, is critical. 

55 Future Directions for the PPB 
PANEL DISCUSSION

The panel highlighted five critically important scientific opportunities. 

Obesity and nutrition and how these features affect the mother, the developing fetus, and the 

child were described as among the most important scientific opportunities for the Branch. Panel 

members suggested that such research include the pre-pregnant obese woman, weight gain 

during pregnancy, and the lifetime impact of post-pregnancy obesity. In addition, panel 

members noted the importance of understanding the effects of maternal obesity on the fetus; for 

instance, members cited a lack of knowledge about hypoglycemia in newborn, long-term impacts 

on the baby, and when intervention is required. 

The Branch indicated its desire to stimulate this area of research with a Request for Applications 

(RFA), which would include the treatment and management of obesity in pregnancy. In 

addition, the Branch plans to hold a workshop on optimizing nutrition in the NICU and would 

continue to support the IOM in updating its pregnancy weight gain guidelines report. The 

Branch also intends to capitalize on the findings from its researchers to stimulate new research in 

this area and to support trans-NIH conferences highlighting these issues. 

Preterm labor and preterm delivery remain a predominant scientific opportunity for the 

Branch and represent the primary cause of neonatal mortality with significant short- and longterm morbidities for those who survive. To date, the Branch’s focus has been on spontaneous 

preterm birth. The panel felt it was important to shift the focus to understand what is causing the 

increase in preterm birth rates and to evaluate other subgroups, such as late preterm births, and 

the care (medical and behavioral-based care) of the preterm infant. 

The Branch plans to stimulate this area by emphasizing the outcomes from a workshop held on 

this topic and from the recent Surgeon General’s Conference on the Prevention of Preterm Birth. 

The Branch will continue to support and encourage studies on the management of the preterm 

infant, especially through the NRN, and hopes to initiate a study on nulliparous women that will 

enhance understanding of preterm birth in another subgroup with a large and growing rate of 

preterm births. 

Long-term effects of pregnancy (fetal origins of adult disease) and the concept that what 

occurs during pregnancy may predict long-term maternal health was highlighted as another 

major opportunity for the Branch. This area would include pregnancy as a risk factor of later 

cardiovascular disease, as well as the fetal perspective; that is, understanding how the 

intrauterine environment impacts the long-term health for the child and its trans-generational 

effects. 

The Branch strongly believes that improving pregnancy and pregnancy outcomes will result in 

improved life-long health for the nation. The Branch will encourage investigators to research 

this area and will readily partner with other Institutes and agencies to stimulate the field. 

Future Directions for the PPB 56 
Development of non-invasive methods for evaluating the fetus and placenta in utero was also 

highlighted as an area of significant scientific opportunity for the Branch. The ability to better 

evaluate the fetus and placenta from early pregnancy, using non-invasive methods, is critically 

needed to facilitate understanding of growth and development. The panel also suggested pushing 

the technologies beyond ultrasound and Doppler, using such technologies as magnetic resonance 

spectroscopy, fetal DNA, and fetal RNA to create more accurate assessments of fetal growth. 

The Branch plans to work with other Institutes, such as the National Institute of Biomedical 

Imaging and Bioengineering, and agencies, such as the FDA, in order to move this area forward. 

Placental and fetal growth and development was also identified as a major opportunity for the 

Branch. Research needs highlighted included transplacental passage, physiology, pharmacology, 

environmental exposures, genomics, and epigenetics. Further understanding of the placenta, as 

well as its functions, and linking studies of the placenta to vascular biology and placental 

regulators would also be critical for the Branch to pursue. 

The Branch plans to issue a PA to stimulate research ideas in the field of epigenetics. In 

addition, the Branch will continue to work with the funded researchers who responded to the 

RFA on fetal growth restriction to encourage collaborative research in these fields. 

Other areas also highlighted as major opportunities for the Branch include: 

• Markers for adverse pregnancy outcome in the nulliparous patient—a woman without known 

risk factors; most work to date has focused on women with known risk factors; an RFA was 

recently published to address this issue 

• Short-term effects of pregnancy on physical and mental well-being of the mother; the Branch 

will continue to partner with NIMH on the PA related to women’s mental health in 

pregnancy 

• Effectiveness of prenatal care 

• Ongoing disparities in health outcomes 

• Evidence for intrapartum obstetrical care 

• Evidence for resuscitation of the newborn 

• Prenatal genetics/screening, including new technologies and deployment, such as disparities 

and health care utilization 

• Population-based environmental (e.g., chemicals, toxins, viruses) exposures and long-term 

effects (e.g., ASDs, cerebral palsy, etc.); perinatal factors beyond genetics that contribute to 

autism spectrum disorders, schizophrenia, etc. (the completion of the human microbiome 

project may be useful in this work) 

• Newly developed and developing technologies, including nanosystems therapy, for the tiny 

neonate and in regenerative medicine 

• Nutrition for both the mother and the neonate, including optimal nutrition for the developing 

brain, the ability to impact brain development using nutrition (especially in vulnerable 

neonates such as the preterm infant and those with fetal alcohol syndrome), and the role of 

both micro- and macronutrients 

57 Future Directions for the PPB 
• Management of substance abuse in pregnancy, including impact on pregnancy and neonatal 

outcomes and childhood, and the effects of other drugs, such as methamphetamines and 

selective serotonin reuptake inhibitors 

• Social determinants of adverse pregnancy outcome 

POSSIBLE BRANCH ACTIVITIES

The panel raised a number of concerns about ability to integrate training opportunities within the 

Branch priorities, including: 

• The difficulties newly trained investigators face, coming off a K or T grant, trying to get an R 

grant: With the fiscal constraints at the NIH and the mission-based budgets at academic 

institutions, these investigators are being lost. The panel noted that if a mechanism could be 

developed to facilitate this transition, it would be very beneficial. 

• The panel described a significant gender disparity in funded investigators, given that 

40 percent to 60 percent of obstetricians and gynecologists are women. 

• Members explained the importance of continuing support for an existing cohort of mentors. 

Given the burden on mentors to get their own grants funded and to mentor new investigators, 

the panel suggested a new grant mechanism for a joint mentor-mentee grant; the mechanism 

would be two linked grants (thus smaller than a program project) focused on single theme, 

but approaching it from different angles. Such a mechanism would help to ensure 

commitment of mentor, while also acknowledging mentors’ role, and assisting the mentee in 

getting an R grant. 

• In light of the five areas noted as scientific opportunities, the panel expressed a need for the 

Branch to support adequate training on bioinformatics and epigenetics. 

• Members added that T32 recipients need to demonstrate that they have training expertise in 

the areas of high priorities. 

• Grantees need to be able to train people in new techniques; however, the panel noted that no 

mechanism currently exists to allow for training in a new technique (e.g., short term, one to 

two months). 

• Metrics for and monitoring of training program success were also identified as critical but 

currently lacking. 

• The panel suggested that the field needed a national training program for perinatology, akin 

to the Physician-Scientist Development Program. Such a program could include training on 

how to do research and short-term training in specific techniques, mentoring, career advice, 

and professional development (possibly with nationwide mentors). 

• Members suggested incorporating perinatology into the Clinical and Translational Science 

Award program in a manner similar to pediatrics; they noted that it is critical for human 

development be incorporated into this program. 

Future Directions for the PPB 58 
59 Future Directions for the PPB 

The public health issues relevant to the Branch had a striking parallel to the important scientific 

opportunities. The public health issues most critical to address included: 

• Obesity and nutrition 

• Preterm labor and birth 

• Fetal origins of adult disease 

• Pandemic infections (including influenza) and the effects on pregnancy and pregnancy 

outcomes; although this work may affect a small segment of population, the impact on that 

population will be large 

• Nulliparous patient—namely that what a woman does in the first pregnancy has life-long 

impacts, including those on future reproductive health and the long-term health of the mother 

• Environmental exposures 

• Intrapartum care and events, such as the ability to identify true versus false labor both in the 

term and preterm settings; when cesarean delivery is appropriate; the ability to identify a 

women who will have an uncomplicated vaginal delivery (the safest delivery method) versus 

those who will have complications or a cesarean 

Other important public health issues included: 

• Following children with chronic diseases (e.g., BPD, preterm infants, congenital heart 

disease) as they become adults 

• Understanding pregnancy as a framework for future health 

• Elucidating the mechanisms and effects of complications of pregnancy, such as GDM, 

pregnancy-induced hypertension, preeclampsia, and postpartum health, such as failure to lose 

weight postpartum, recovery from cesarean delivery in first pregnancy, and mental health 

issues (i.e., anxiety/depression); also learning about the effects of fetal growth restriction and 

macrosomia on long-term health 

• Nutrition and availability of good nutrition, including the current food shortage due to gas 

prices 

• Disparities in outcomes along racial/ethnic lines 

• Social determinants of adverse pregnancy outcomes (the National Children’s Study’s 

household enrollment could provides a potential area for collaboration) 

• Effect of assistive reproductive technologies on pregnancy outcomes and beyond 

The panel also noted a need for the NICHD to motivate other Institutes to focus on pregnant 

women and neonates/children. One way to accomplish this task would be to highlight the public 

health issues and their implications on long-term health. The panel observed that the public 

health issues within the PPB portfolio are not considered to be general public health issues 

despite the work demonstrating how critical the pregnancy and perinatal timeframes are. 

Members also focused on communication needs during the meeting, including the need to have 

initiatives/mechanisms to allow the dissemination of information about PPB-related public health 

issues to grantees and the public. One suggestion was for the PPB to develop an electronic 

newsletter, which could be sent weekly or monthly to all NICHD-funded investigators. 

FIGURES AND TABLES 

Please Note: The numbers and amounts presented in these figures and tables represent 

unofficial figures prepared by the NICHD Referral and Program Analysis Branch. Some of the 

amounts may differ from those reported by the NIH Research, Condition, Disease, and 

Categorization Process, which provides the only offical amounts for the NIH. Please visit 

http://report.nih.gov/rcdc to view offical numbers and amounts for specific disease categories. 

TABLE 1: PPB PROJECTS BY PROGRAM AREA, FISCAL YEARS 2000, 2004, AND 2007

Fiscal Year 2000 Fiscal Year 2003 Fiscal Year 2007 

Projects Funds Projects Funds Projects Funds 

Maternal 

Basic 13 $2,866,387 7 $1,638,891 15 $3,921,172

Clinical 44 $17,069,455 33 $16,916,727 51 $21,523,533

Fetal 

Basic 33 $7,392,339 28 $7,414,627 35 $8,090,949

Clinical 4 $841,115 12 $4,592,060 16 $6,516,308

Placental 30 $5,833,037 38 $10,134,258 33 $8,272,131

Labor and Delivery 51 $13,264,197 53 $14,777,817 43 $12,757,772

Neonatal 

Basic 12 $1,921,424 11 $2,354,008 8 $2,375,736

Clinical 23 $9,927,268 40 $20,460,847 42 $16,207,690

SIDS 

Basic 16 $3,839,299 18 $4,325,465 18 $3,968,396

Clinical 15 $3,033,301 10 $3,300,173 14 $5,968,608

 Subtotal: 241 $65,987,822 250 $85,914,873 275 $89,602,295

Training 

F31 4 $111,119 2 $76,974

F32 3 $116,988 4 $198,150

T32 9 $1,254,514 11 $2,175,188 13 $3,152,451

Ks 

(01,02,08,12,23,24,25) 11 $2,615,354 26 $5,042,460 12 $1,504,979

 Subtotal: 23 $3,986,856 45 $7,526,917 27 $4,734,404

 Total: 264 $69,974,678 295 $93,441,790 302 $94,336,699

Figures and Tables-1 
FIGURE 1: PPB GRANTS AND CONTRACTS IN CURRENT AND CONSTANT DOLLARS, FISCAL 

YEAR 1992 TO FISCAL YEAR 2007

$94.3

$56.1 $56.2

$40

$50

$60

$70

$80

$90

$100

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Fiscal Year

Amount (In Millions of U.S. Dollars)

Current Dollars

Constant Dollars

(Note: Figures include total grant and contract extramural funding; numbers in parentheses 

represent the number of projects.)

(259)

(249) (229)

(226)

(227)

(222)

(225)

(218)

(224)

(241)

(251)

(239) (249) (249)

(242) (243)

Figures and Tables-2 
FIGURE 2: PPB FUNDS BY PROGRAM CATEGORY, SELECT FISCAL YEARS

$0 $5 $10 $15 $20 $25 $30 $35 $40

1995

1997

1999

2001

2003

2005

2007

Fiscal Year

Amount (In Millions of U.S. Dollars)

SIDS

Disorders of Newborn

Preterm Labor & Birth

Fetal Pathophysiology

High-Risk Pregnancy

Figures and Tables-3 
FIGURE 3: PPB-SUPPORTED RESEARCH BY DEPARTMENT, SELECT FISCAL YEARS

$0

$5

$10

$15

$20

$25

$30

$35

1999 2001 2003 2005 2007

Fiscal Year

Amount (In Millions of U.S. Dollars)

Ob/Gyn Pediatrics

Other Clinical Non-Clinical

Figures and Tables-4 
FIGURE 4: PPB-SUPPORTED RESEARCH BY INVESTIGATOR DEGREE, SELECT FISCAL YEARS

0

25

50

75

100

125

1999 2001 2003 2005 2007

Fiscal Year

Number of Investigators

M.D. Ph.D. M.D./Ph.D. Other

Figures and Tables-5 
FIGURE 5: PPB-SUPPORTED RESEARCH BY INVESTIGATOR GENDER, SELECT FISCAL YEARS

218

194 203 208

253 253

207

0

50

100

150

200

250

300

1995 1997 1999 2001 2003 2005 2007

Fiscal Year

Nu

m

b

er of Investigator

s

Male Female

FIGURE 6: FIRST-TIME R01 APPLICANTS AND SUCCESS RATES BY GENDER, FISCAL YEAR 2004

THROUGH FISCAL YEAR 2007

The number of first-time R01 applications (n = 308) is 40 percent for females and 60 percent for 

males, which is identical to their success rates, 40 percent and 60 percent, respectively (n = 47). 

60%

40%

Male

Female

Figures and Tables-6 
FIGURE 7: SUDDEN INFANT DEATH SYNDROME (SIDS) RATES AND SLEEP POSITION

1.411.411.37 1.4 1.39

1.3 1.3

1.2 1.17

1.03

0.87

0.740.77

0.72

0.67

0.62

0.560.570.530.550.54

70

74

78 81

85 85 87 88 86 85 86

54

39

28

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05

Year

Deaths per 1,000 Births

0

10

20

30

40

50

60

70

80

90

100

Percentage Non-Prone Sleeping

Pre-AAP 

Recommendation 

AAP 

Recommendation 

Back to Sleep/Post-AAP 

Recommendation 

Sleep Position Source: NICHD Household Survey; SIDS Rate Source: National Center for 

Health Statistics, Centers for Disease Control and Prevention 

Figures and Tables-7 
FIGURE 8: PAPERS PUBLISHED FOR THE NEONATAL RESEARCH NETWORK (NRN), FISCAL 

YEAR 1990 THROUGH FISCAL YEAR 2008

0

5

10

15

20

25

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Fiscal Year

Papers Accepted for Publication

Papers Published

Figures and Tables-8 
FIGURE 9: TIMELINE OF RECRUITMENT AND FOLLOWUP FOR NEONATAL RESEARCH 

NETWORK (NRN) STUDIES

Figures and Tables-9 
FIGURE 10: PAPERS PUBLISHED FOR THE MATERNAL-FETAL MEDICINE UNITS (MFMU)

NETWORK, 1993 THROUGH 2008

0

5

10

15

20

25

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

Number of Papers

Figures and Tables-10 
FIGURE 11: TIMELINE FOR RECRUITMENT AND FOLLOWUP OF MATERNAL-FETAL MEDICINE 

UNITS (MFMU) NETWORK STUDIES

 

Figures and Tables-11 
TABLE 2: MATERNAL-FETAL MEDICINE UNITS (MFMU) NETWORK TRIALS,

FISCAL YEAR 2004 THROUGH FISCAL YEAR 2008

Study Purpose/Description 

Type of Study/ 

Intervention 

Primary Outcome/ 

Sample Size Status 

FOX: Fetal Pulse OXimetry Trial 

Randomized controlled trial (RCT) to 

determine if fetal pulse oximetry affects 

overall cesarean delivery rate, 

cesarean delivery rate for fetal distress 

Two-arm Trial Cesarean Delivery/ 

10,000 Participants 

Enrollment complete; 

manuscript published in 

New England Journal of 

Medicine 

Progesterone Follow-up Study 

Determine whether there is a 

difference in achievement of 

developmental milestones and/or 

physical health between children 

exposed to progesterone and controls 

Observational 

Cohort Study 

Ages and Stages 

Questionnaire; 

Developmental 

Milestones/ 

348 Participants 

Enrollment complete 

(n = 278); manuscript 

published in Obstetrics 

& Gynecology. 

STTARS (17-α-OH caproate in Twins and Triplets: A Randomized Study) 

Double-masked placebo-controlled trial 

of whether 17-α hydroxyprogesterone 

prevents preterm birth in multi-fetal 

pregnancies 

Weekly 17-OHPC 

(1 ml IM with 

250mg) or 

Placebo 

Preterm Delivery at 

Less than 35 

Weeks of 

Gestation/ 

600 Twin 

Pregnancies and 

120 Triplet 

Pregnancies 

Enrollment complete 

(n = 661 twins; n = 134 

triplets); twin findings 

published in New 

England Journal of 

Medicine

RCTof Omega-3 Supplementation to Prevent Preterm Birth 

Double-masked placebo-controlled trial 

to determine whether Omega-3 in 

conjunction with 17-OHPC reduces the 

risk of preterm delivery in women at 

high risk for spontaneous preterm 

delivery 

Weekly 17-OHPC 

(1 ml IM with 

250mg) with 

Daily 2,000 mg 

Omega-3 or 

Placebo 

Preterm Delivery at 

Less than 37 

Weeks of 

Gestation/ 

800 Participants 

Enrollment complete 

(n = 852); plenary at 

Society for MaternalFetal Medicine 2008 

meeting 

BEAM Trial: Beneficial Effects of Antenatal Magnesium Sulfate in Prevention of Cerebral Palsy 

Double-masked, placebo-controlled 

trial to determine if antenatal 

Magnesium Sulfate can reduce the risk 

of cerebral palsy in offspring for women 

who deliver preterm at 24 to 31 weeks 

of gestation 

MgSO4 or 

Placebo 

Composite 

outcome of death 

before 1 year of 

age or cerebral 

palsy at 24 months 

of age/ 

2,220 Participants 

Enrollment complete; 

No. 1 plenary at Society 

for Maternal-Fetal 

Medicine 2008 meeting 

Gestational Diabetes Mellitus (GDM) Trial 

RCT with additional observational 

cohorts to test whether identification 

and dietary treatment of mild GDM 

reduces neonatal morbidity and 

mortality in women at 24 to 29 weeks 

of gestation, normal fasting blood 

sugar, abnormal three-hour glucose 

tolerance test 

Treatment versus 

Standard Care 

Fetal Composite/ 

700 (Trial 

Participants); 1,050 

(Cohorts) 

Enrollment complete 

(n = 1,889); analysis 

underway 

Figures and Tables-12 
Figures and Tables-13 

Study Purpose/Description 

Type of Study/ 

Intervention 

Primary Outcome/ 

Sample Size Status 

CAPPS (Combined Antioxidant & Preeclampsia Prediction Studies) 

Double-masked placebo-controlled trial 

to determine if antioxidants reduce 

serious maternal and infant 

complications associated with 

pregnancy-related hypertension in 

nulliparous women with a singleton 

gestation 

Vitamin C and E 

or Placebo 

Fetal Death at Less 

than 20 Weeks of 

Gestation or 

Composite/ 

10,000 (RCT); 

4,000 

(Observational) 

Enrollment: 

RCT = 9,844 (as of 

1/11/08), 

Observational = 2,321 

(as of 1/11/08) 

TSH Trial: A Randomized Trial of Thyroxine Therapy for Subclinical Hypothyroidism or 

Hypothyroxinemia Diagnosed During Pregnancy 

Double-masked placebo-controlled trial 

to determine whether thyroxine 

treatment for subclinical 

hypothyroidism or hypothyroxinemia 

diagnosed during the first half of 

pregnancy is associated with 

intellectual improvement in offspring 

Thyroxine or 

Placebo 

Intelligence 

Quotient (IQ) at 

Five Years of Age/ 

1,000 (500 per 

Strata) 

23,210 Screened; 

441 Enrolled (as of 

1/11/08) 

SCAN (Short Cervix And Nulliparity) 

Double-masked placebo-controlled trial 

to determine whether 17-α

hydroxyprogesterone prevents preterm 

birth in nulliparous women with short 

cervix 

Weekly 17-OHPC 

(1 ml IM with 

250mg) or 

Placebo 

Preterm Delivery at 

less than 37 Weeks 

of Gestation/ 

500 Women 

10 Randomized (as of 

07/31/07) 

APEX (Measurement of Obstetrical Patient Safety) 

Develop a set of valid quality measures 

for obstetric care; evaluate specific 

measures, processes, & outcomes 

Observational 

Study 

Protocol, data forms 

being finalized; pilot 

conducted November to 

December 2007; full 

study started April 2008 

APPENDIX A: BIOSKETCHES OF BRANCH PERSONNEL 

Stephanie Wilson Archer, M.A., joined the PPB in April 2007 as the program coordinator for 

the Neonatal Research Network (NRN). Ms. Archer has a master’s degree in sociology from 

George Mason University with interests in social networks and social and developmental 

neuroscience. She brings more than 12 years’ experience in project management/international 

development and more than seven years’ experience in academic/research libraries to the PPB. 

Rosemary D. Higgins, M.D., is a board-certified neonatologist who joined the Branch in 

January 2003. She is the program scientist for the NICHD NRN and Maternal Lifestyles Study. 

Prior to joining the Branch, she held faculty positions at New York University Medical Center 

and at Georgetown University. Dr. Higgins is a member of the Society for Pediatric Research 

and American Pediatric Society, is the NICHD liaison to the Vermont Oxford Network Database 

Advisory Committee, and is a fellow of the American Academy of Pediatrics (AAP). She is also 

the neonatology editor for the American Journal of Perinatology. Dr. Higgins’ area of expertise 

is retinopathy of prematurity. 

John V. Ilekis, Ph.D., joined the Branch in June 1999. He holds a Ph.D. in biology with 

specialization in molecular biology. Prior to joining the PPB, Dr. Ilekis was a research assistant 

professor in the Department of Obstetrics and Gynecology at the University of Illinois, Chicago. 

His main scientific responsibilities include managing basic research grants on the physiology, 

biochemistry, and molecular biology of the placenta, uterus, and cervix. He has particular 

research interests in the basic mechanisms underlying the diseases of spontaneous preterm birth 

and preeclampsia. Dr. Ilekis is also a program scientist for the Genomics and Proteomics 

Network for Preterm Birth Research (GPN/PBR). 

Susan Pagliaro joined the Branch in November 2001. She has more than 15 years’ experience 

in the areas of maternal-fetal medicine and adolescent health. Ms. Pagliaro earned her bachelor’s 

degree in public health with a focus on community health education from the University of 

Massachusetts. Her organizational skills and interest in clinical trials led her to the NIH, where 

she serves as a clinical trials specialist and the coordinator of both the Maternal-Fetal Medicine 

Units (MFMU) Network and the Maternal-Fetal Surgery Network. In 2006, Ms. Pagliaro 

received an NIH Merit Award for “Superior commitment, dedication, and accomplishment in 

achieving the designation of Best Practices for the NICHD’s MFMU Network.” 

Tonse Raju M.D., D.C.H., F.A.A.P., is a board-certified neonatologist who joined the PPB in 

June 2002. He is the program scientist/medical officer for the PPB portfolios of neonatal 

research grants, training grants, and Small Business Innovative Research/Small Business 

Technology Transfer programs; he is also the project officer for the Cochrane Neonatal Review 

Group contract. Dr. Raju is the NICHD liaison for the Vermont Oxford Network Neonatal 

Encephalopathy Registry, Cochrane Collaboration Child Health Advisory Board; the AAP 

Committee on Fetus and Newborn, the Executive Committee of the AAP Section on Perinatal 

Pediatrics. He is a fellow of the AAP and holds membership in the American Pediatric Society, 

the Society for Pediatric Research, and the American Osler Society. He has served as the 

associate editor for the Journal of Investigative Medicine, and AAP NeoReviews. 

Appendices-1 
Uma M. Reddy, M.D., M.P.H., joined the Branch in September 2003. Board certified in 

obstetrics and gynecology and maternal-fetal medicine, she was a Robert Wood Johnson Clinical 

Scholar and received her master’s in public health from Johns Hopkins University. Dr. Reddy 

completed her obstetrics and gynecology residency at the Johns Hopkins Hospital and her 

maternal-fetal medicine fellowship at Thomas Jefferson University Hospital. Dr. Reddy 

manages translational and clinical research grants in obstetrics and maternal-fetal medicine and 

serves as a program scientist for the Stillbirth Collaborative Research Network (SCRN) and the 

GPN/PBR. Dr. Reddy is a fellow of the American College of Obstetricians and Gynecologists 

(ACOG), a member of the Society for Maternal-Fetal Medicine, and a maternal-fetal medicine 

specialist at National Naval Medical Center. 

Caroline Signore, M.D., M.P.H., is a board-certified obstetrician/gynecologist who joined the 

Branch in October 2006. Dr. Signore is one of the Branch’s program officers managing the 

obstetric portfolio and is a program scientist for the Prenatal Alcohol in SIDS and Stillbirth 

(PASS) Network. She completed her obstetrics and gynecology residency at the University of 

Florida and received her master’s in public health from George Washington University. She 

came to the Branch from the NICHD’s Division of Epidemiology, Statistics, and Prevention 

Research. Dr. Signore is a fellow of ACOG and a member of the Society for Pediatric and 

Perinatal Epidemiology Research. 

Catherine Spong, M.D., joined the Branch in January 2000 and is board certified in maternalfetal medicine and obstetrics and gynecology. Dr. Spong is the program scientist for the MFMU 

Network and has been Branch chief since January 2001. She is an associate editor of Obstetrics 

& Gynecology and William’s Obstetrics, while also serving as a maternal-fetal medicine 

specialist at INOVA Alexandria hospital. Dr. Spong is the NICHD liaison for the ACOG 

Committee on Obstetric Practice, the Society for Maternal-Fetal Medicine Executive Board, and 

the Liaison Committee of Obstetrician/Gynecologists. She is a fellow of ACOG and a member 

of the Society for Maternal-Fetal Medicine, the Society for Gynecologic Investigation, the 

Society for Neuroscience, and the Perinatal Research Society. 

Marian Willinger, Ph.D., is the NICHD special assistant for SIDS, responsible for the direction 

of the Institute’s SIDS research program, including the development of the Institute’s third, fiveyear research plan Targeting SIDS: A Strategic Plan. She also serves as an expert on SIDS 

within the U.S. Public Health Service. Dr. Willinger is a program scientist for the Collaborative 

Home Infant Monitoring and Evaluation Study, the PASS Network, and the SCRN. She also 

recently completed contracts to support SIDS epidemiological studies. Dr. Willinger has been 

involved in the development, implementation, and evaluation of the Back to Sleep campaign and 

serves as a consultant to the AAP Task Force on Infant Positioning and SIDS. During the last 

five years, Dr. Willinger has participated in NIH- and government-wide activities, including the 

Advisory Board of the National Center on Sleep Disorders Research and the Interdisciplinary 

Research Workgroup of the NIH Roadmap. 

Appendices-2 
APPENDIX B: PPB-SUPPORTED STUDIES THAT 

HAVE IMPACTED CLINICAL PRACTICE 

Topic Impact on Clinical Practice 

NICHD Research Contributing to the 

Impact on Clinical Practice 

Antenatal 

corticosteroid therapy 

for fetal maturation 

ACOG Committee on Obstetric Practice. 

(2008). Antenatal corticosteroid therapy 

for fetal maturation (ACOG Committee 

Opinion No. 402). Obstet Gynecol, 

Mar;111(3), 805-807. 

MFMU Network trials: 

• Wapner, et al. (2006). Single versus weekly 

courses of antenatal corticosteroids: 

Evaluation of safety and efficacy. AJOG, 

Sep;195(3), 633-642. 

• Wapner, et al. (2007). Long-term outcomes 

after repeat doses of antenatal 

corticosteroids. NEJM, Sep20;357(12), 

1190-1198. 

NIH Consensus Development Conferences: 

• Antenatal corticosteroids revisited: Repeat 

courses. (2000). NIH Consens Statement. 

Aug 17-18; 17(2), 1-10. 

• The effect of antenatal steroids for fetal 

maturation on perinatal outcomes. (1994). 

NIH Consens Statement. Feb 28-Mar 

2;12(2), 1-24. 

Breast milk and 

extremely low birth 

weight infants: 

neurodevelopmental 

outcome 

improvement 

Promotion of breastfeeding NRN studies: 

• Vohr, et al. (2007). Persistent beneficial 

effects of breast milk ingested in the NICU 

on outcomes of extremely low birth weight 

infants at 30 months of age. Pediatrics, 

Oct;120(4), e953-e959. 

• Vohr, et al. (2006). Beneficial effects of 

breast milk in the neonatal intensive care 

unit on the developmental outcome of 

extremely low birth weight infants at 18 

months of age. Pediatrics, Jul;118(1), e115-

e123. 

Cesarean delivery on 

maternal request 

ACOG Committee on Obstetric Practice. 

(2007). Cesarean delivery on maternal 

request (ACOG Committee Opinion No. 

394). Obstet Gyncol, Dec;110(6), 1501. 

• National Institutes of Health State-of-theScience Conference Statement: Cesarean 

delivery on maternal request. Obstet 

Gynecol. 2006;107, 1386-1397. 

• MFMU Network study on VBAC; Silver, et al. 

(2006). Maternal morbidity associated with 

multiple repeat cesarean deliveries. Obstet 

Gynecol, Jun;107(6), 1226-1232. 

Induction of labor for 

vaginal birth after 

cesarean (VBAC) 

delivery 

ACOG Committee on Obstetric Practice. 

(2006). Induction of labor for vaginal birth 

after cesarean delivery (ACOG 

Committee Opinion No. 342). Obstet 

Gyncol, Aug;108(2), 465-468. 

• MFMU Network study; Landon, et al. (2004). 

Maternal and perinatal outcomes associated 

with a trial of labor after prior cesarean 

delivery. NEJM, Dec 16;351(25), 2581-2589. 

• R01-HD039441; Macones, et al. (2005). 

Maternal complications with vaginal birth 

after cesarean delivery: A multi-center study. 

AJOG, Nov;193(5), 1656-1662. 

Infection and 

neurodevelopmental 

impairment 

Increased vigilance for followup for 

extremely low birth weight infants 

NRN study; Stoll, et al. (2004). 

Neurodevelopmental and growth 

impairment among extremely low birthweight infants with neonatal infection. 

JAMA, Nov 17;292(19), 2357-2365. 

Appendices-3 
Topic Impact on Clinical Practice 

NICHD Research Contributing to the 

Impact on Clinical Practice 

Inhaled Nitric Oxide 

(NO) 

Limitation of use of inhaled NO in preterm 

infants; followup shows no difference in 

outcomes. 

NRN studies: 

• Van Meurs, et al. (2005). Inhaled nitric oxide 

for premature infants with severe respiratory 

failure. N Engl J Med, Jul 7;353(1), 13-22. 

• Hintz, et al. (2007). Neurodevelopmental 

outcomes of premature infants with severe 

respiratory failure enrolled in a randomized 

controlled trial of inhaled nitric oxide. J 

Pediatr, Jul;151(1), 16-22, 22, e1-e3. 

Late-preterm infants • Engle, Tomashek, Wallman, & the AAP 

Committee on the Fetus and Newborn. 

(2007). “Late preterm” infants: A 

population at Risk. Pediatrics, Dec;120(6), 

1390-1401. 

• ACOG Committee on Obstetric Practice. 

(2008). Late preterm infants (ACOG 

Committee Opinion No. 404). Obstet 

Gyncol, Apr;111(4), 1029-1032. 

NICHD Workshop on Late-Preterm Infant 

Neonatal pain 

management and 

morphine therapy 

Most centers have reduced or stopped 

using continuous intravenous (IV) 

morphine for very low birth weight infants. 

Even intermittent IV morphine use has 

declined, with increasing use of fentanyl. 

Anand, et al. (2004). Effects of morphine 

analgesia in ventilated preterm neonates: 

Primary outcomes from the NEOPAIN 

randomised trial. Lancet, 363, 1673-1682. 

Perinatal risks 

associated with 

assisted reproductive 

technology 

ACOG Committee on Obstetric Practice. 

(2005). Perinatal risks associated with 

assisted reproductive technology (ACOG 

Committee Opinion No. 324). Obstet 

Gyncol, Nov;106(5 Pt 1), 1143-1146. 

NRN study; Stevenson, et al. (1998). Very 

low birth weight outcomes of the NICHD 

Neonatal Research Network, January 1993 

through December 1994. AJOG, Dec;179(6 

Pt 1), 1632-1639. 

Periviable calculator Source of information for threatened 

preterm birth at 22 weeks’ to 25 weeks’ 

gestation 

NRN study; Tyson, et al. (2008). Intensive 

care for extremely premature newborns:

Moving beyond gestational age thresholds. 

NEJM, 358(16), 1672-1681. 

Screening for fetal 

chromosomal 

abnormalities 

ACOG Committee on Practice Bulletins. 

(2007). Screening for fetal chromosomal 

abnormalities (ACOG practice bulletin 

77). Obstet Gyncol, Jan;109(1), 217-227. 

• NICHD Workshop: Incorporating FirstTrimester Down Syndrome Studies Into 

Prenatal Screening 

• Prenatal screening: Incorporating the first 

trimester screening. Seminars in 

Perinatology, 2005;29(4). 

• Reddy & Mennuti. (2006). Incorporating firsttrimester Down syndrome studies into 

prenatal screening: Executive summary of 

the NICHD workshop. Obstet Gyncol, 107, 

167-173. 

Subclinical 

hypothyroidism in 

pregnancy 

ACOG Committee on Patient Safety and 

Quality Improvement. (2007). Subclinical 

hypothyroidism in pregnancy (ACOG 

Committee Opinion No. 381). Obstet 

Gyncol, Oct;110(4), 959-960. 

Casey, et al. (2007). Perinatal significance 

of isolated maternal hypothyroxinemia 

identified in the first half of pregnancy. 

Obstet Gynecol, May;109(5), 1129-1135. 

Appendices-4 
Topic Impact on Clinical Practice 

NICHD Research Contributing to the 

Impact on Clinical Practice 

Sudden Infant Death 

Syndrome (SIDS) 

AAP Medical Home Initiatives for Children 

with Special Needs Project Advisory 

Committee. (2004). Policy Statement: 

Organizational principles to guide and 

define the child health care system and/or 

improve the health of all children. 

Pediatrics, 113, 1545-1547. 

AAP Task force on SIDS. (2005). The 

Changing Concept of SIDS: Diagnostic 

coding shifts, controversies regarding the 

sleeping environment, and new variables 

to consider in reducing risk. Pediatrics, 

116, 1245-1255. 

• National Infant Sleep Position (NISP) Study 

Public Access Web site: 

http://dccwww.bumc.bu.edu/ChimeNisp/ 

Main_Nisp.asp 

• Hauck, et al. (2002). The contribution of 

prone sleeping position to the racial disparity 

in SIDS: The Chicago Infant Mortality Study. 

Pediatrics, 110, 772-780. 

• Li, et al. (2003). Infant sleep position and 

SIDS risk in California, 1997-2000. Am J 

Epidemiol, 157, 446-455. 

• Willinger, et al. (1998). Factors associated 

with the transition to nonprone sleep 

positions of infants in the United States: The 

NISP Study. JAMA, 280, 329. 

• Mitchell, et al. (1999). Changing infants' 

sleep position increases risk of SIDS. Arch 

Pediatr Adoles Med, 153, 1136-1141. 

• Hauck, et al. (2003). Sleep environment and 

the risk of SIDS in an urban population: The 

Chicago Infant Mortality Study. Pediatrics, 

111, 1207-1214. 

• Kemp, et al. (1998). Softness and potential 

to cause rebreathing: Differences in bedding 

used by infants at high and low risk for 

SIDS. J Pediatrics, 132, 234-239. 

• Flick, et al. (2001). Sleep position and the 

use of soft bedding during bed sharing 

among African American infants at 

increased risk for SIDS. J Pediatrics, 138, 

338-343. 

• Mosko, et al. (1997) Infant arousals during 

mother-infant bed sharing: implications for 

infant sleep and SIDS research. Pediatrics, 

100, 841-849. 

• McKenna, et al. (1997). Bed sharing 

promotes breastfeeding. Pediatrics, 100, 

214-219. 

• Unger, et al. (2003). Racial disparity and 

modifiable risk factors among infants dying 

suddenly and unexpectedly. Pediatrics, 

111(2), E127. 

• Kemp, et al. (2000). Unsafe sleep practices 

among infants dying suddenly and 

unexpectedly: Results of a four year, 

population-based, death-scene investigation 

study of SIDS and related death. Pediatrics, 

106(3). 

• Ramanathan, et al. (2001). 

Cardiorespiratory events recorded on home 

monitors: comparison of healthy infants with 

those at increased risk for SIDS. JAMA, 285, 

2199-2207. 

• Vernacchio, et al. (2003). Sleep position of 

low birth weight infants. Pediatrics, 111, 

633-640. 

Appendices-5 
Topic Impact on Clinical Practice 

NICHD Research Contributing to the 

Impact on Clinical Practice 

• Willinger, et al. (2000). Factors associated 

with caregivers’ choice of infant sleep 

position, 1994-1998: The NISP Study. 

JAMA, 283, 2135-2142. 

Use of progesterone 

to reduce preterm 

birth 

ACOG Committee on Obstetric Practice. 

(2003). Use of progesterone to reduce 

preterm birth (ACOG committee opinion 

291). Obstet Gyncol, Nov;102(5 Pt 1), 

1115-1116. (In revision for publication in 

2008) 

• MFMU Network trial; Meis, et al. (2003). 

Prevention of recurrent preterm delivery by 

17 alpha-hydroxyprogesterone caproate. 

NEJM, 348, 2379-2385. 

• MFMU Network study; Northen, et al. 

(2007). Followup of children exposed in 

utero to 17 alpha-hydroxyprogesterone 

caproate compared with placebo. Obstet 

Gynecol, Oct;110(4), 865-872. 

Whole-body cooling Blackmon, Stark, & the AAP Committee 

on the Fetus and Newborn. (2006). 

Hypothermia: A neuroprotective therapy 

for neonatal hypoxic-ischemic 

encephalopathy. Pediatrics, Mar;117(3), 

942-948. 

NRN Network study; Shankaran, et al. 

(2005). Whole-body hypothermia for 

neonates with hypoxic-ischemic 

encephalopathy. NEJM, Oct13;353(15), 

1574-1584. 

Appendices-6 
APPENDIX C: PPB-SUPPORTED CONFERENCES AND WORKSHOPS, 

FISCAL YEAR 2004 THROUGH FISCAL YEAR 2007 

American Academy of Pediatrics (AAP)-NICHD Workshop on Research in Neonatology 

was held on January 15-16, 2004, in collaboration with the Section on Perinatal Pediatrics of the 

AAP in Rockville, Maryland. The focus of the workshop was to: address the basic and 

translational research issues in neonatal-perinatal medicine; identify knowledge gaps; and review 

the role of promising methods, such as genomics, proteomics, imaging, and molecular biology, 

in neonatal-perinatal research fields. Other issues addressed included: training needs for 

physician-scientists in neonatal-perinatal medicine; board-certification issues; and strategies to 

overcome the dwindling pool of physician-scientists, especially of women and underrepresented 

minorities in academic medicine. For the agenda and a list of conference participants, visit 

http://www.nichd.nih.gov/about/meetings/2004/ppb_aapneonate.cfm. 

Workshop of the Border of Viability, held March 4-5, 2004, addressed one of the most 

complex areas in perinatal-neonatal medicine—care of the mother who delivers an infant at the 

border of viability—referred to as “periviable” gestation in the resulting paper. Output from this 

conference includes the following: Higgins RD, Delivoria-Papadopoulos M, & Raju T. (2005). 

Executive summary on the workshop on viability. Pediatrics, 115, 1392-1396. 

Fetal Treatment: Needs Assessment and Future Directions Workshop was held on 

August 16-17, 2004, in collaboration with the NIH Office of Rare Diseases (ORD) and the 

National Heart, Lung, and Blood Institute (NHLBI). The purpose of the workshop was to 

develop a plan for the surgical, maternal-fetal, and neonatal evaluation and treatment of 

pregnancies which might benefit from in utero therapy and assess the need and appropriate 

mechanisms for dissemination of innovations in maternal-fetal treatment. Participants included 

experts in maternal-fetal therapy, representatives from involved specialty societies and 

organizations, and others interested in the area. Experts presented specific topics emphasizing 

areas of controversy or knowledge gaps when applicable. Output from the meeting includes: 

Chescheir NC, & Socol M. (2005). The NIH Workshop on Fetal Treatment: Needs assessment 

and future directions. Obstetrics & Gynecology, 106(4), 828-833. 

Incorporating First-Trimester Down Syndrome Studies into Prenatal Screening Workshop, 

held December 16-17, 2004, was a collaborative effort between the NICHD, the Society for 

Maternal-Fetal Medicine (SMFM), the American College of Obstetricians and Gynecologists 

(ACOG), and the March of Dimes (MOD). The field of prenatal screening is rapidly developing, 

with the emergence of alternative testing approaches earlier in pregnancy making decisions about 

prenatal screening increasingly complex. The purpose of this workshop was to summarize 

available research on first trimester and second trimester screening for aneuploidy and the effect 

of incorporation of first trimester screening as part of prenatal screening. The workshop 

determined that sufficient evidence supported the incorporation of first-trimester testing into 

prenatal practice in the United States, and that providers should focus on the most effective 

implementation of various screening schema based on patient counseling and available 

resources. The output of this workshop includes the following: 

Appendices-7 
• Reddy UM, & Mennuti MT. (2006). Incorporating first-trimester Down syndrome studies 

into prenatal screening: Executive summary of the NICHD Workshop. Obstetrics & 

Gynecology, 107(1), 167-173. 

• Prenatal screening: Incorporating the first-trimester studies; proceedings of an NICHD 

Workshop, December 16-17, 2004. (2005). Semin Perinatol, 29(4), 189-279. 

Improving Maternal Nutrition to Optimize Pregnancy Outcome: Development of a 

Research Plan, held November 8-9, 2004, in Bethesda, Maryland, was co-sponsored by the 

International Society for the Development of Origins of Health and Disease and the U.S. Agency 

for International Development. The goal was to develop a coherent research strategy for 

improving maternal and infant nutrition, focusing on periconception, and optimizing fetal 

development, antenatal factors and adaptation/transition. National and international experts met 

and identified research gaps and strategies addressing both basic and clinical research needs, as 

well as issues unique to the developing world that may impact on development and 

implementation of evidence-based programs. Specific topics included: factors operative in the 

periconceptual period, including adequacy of diet; determinants of optimal fetal development; 

mechanisms and reversibility; and adaptations and transition, including how the baby is managed 

after birth. An executive summary of the meeting is being prepared. 

Hypothermia for Perinatal Asphyxia Workshop, co-sponsored by the NIH ORD, occurred on 

May 18-19, 2005. The goal of the meeting was to discuss the current state of knowledge about 

the benefits of hypothermia for perinatal asphyxia and to identify knowledge gaps. This 

information will help professional organizations to make evidence-based practice 

recommendations related to this critical topic. Output from this conference includes: Higgins 

RD, Raju TNK, Perlman J, Azzopardi DV, Blackmon LR, Clark RH, & Edwards, et al. (2006). 

Hypothermia and perinatal asphyxia: Executive summary of the NICHD Workshop. J Pediatr, 

148, 170-175. 

Care of Near-Term Fetus and the Near-Term Neonate Workshop, co-sponsored by the NIH 

ORD and the MOD, was held July 18-19, 2006. Obstetric and neonatal care at 35 weeks’ to 

37 (“near-term”) weeks’ gestation presents a unique set of challenges and dilemma. At these 

gestations, women are often assumed to be at low risk, and their newborn infants considered 

normal. Yet, near-term newborn infants need close monitoring, and some require intensive care. 

Such infants are at high risk for complications related to preterm birth, such as respiratory 

distress syndrome, transient tachypnea of the newborn, patent ductus arteriosus, hypothermia, 

apnea, infection, feeding difficulty, necrotizing enterocolitis, and hyperbilirubinemia. Compared 

to their term counterparts, re-hospitalization rates are more common in near-term infants due to 

higher incidence of apnea, meningitis, seizures, intracranial hemorrhage, and bilirubin-induced 

brain injury and Kernicterus. The purpose of the workshop was to invite a multidisciplinary 

team of experts to discuss management of these infants. The executive summary from the 

meeting was published in Pediatrics in October 2006, and manuscripts from presentations 

delivered at the conference were published in Seminars in Perinatology in 2006. 

Oxygen in Neonatal Therapies: Controversies and Opportunities for Research, a meeting 

held August 8-9, 2006, examined the use of oxygen in newborn care. Evidence for its use has 

large gaps including appropriate oxygenation in normal infants, use of oxygen in newborn 

Appendices-8 
resuscitation, and appropriate use of oxygen in preterm and extremely preterm infants. Shortterm and long-term benefits and risks have been described; however, optimal use of oxygen in 

newborns is not well defined. The goals of this meeting were to review the current evidence for 

care practices and define gaps for which knowledge regarding care is lacking. It is hoped that 

information (or lack thereof) presented at this meeting will lead to new initiatives and 

advancement of knowledge and care in the field. The executive summary from this meeting, 

which was co-sponsored by the NIH ORD, was published as: Higgins RD, Bancalari E, 

Willinger M, & Raju TNK. (2007). Executive summary of the Workshop on Oxygen in Neonatal 

Therapies: Controversies and opportunities for research. Pediatrics, 119(4), 790-796. 

Infertility Treatment and Adverse Pregnancy Outcomes Workshop was held September 

12-13, 2005, and was co-sponsored by the PPB and the Reproductive Sciences Branch at the 

NICHD, the NIH ORD, and the NIH Office of Research on Women’s Health (ORWH). 

Increased use of assisted reproductive technology (ART) over the past two decades has allowed 

thousands of infertile couples to have children; ART births currently accounting for 1 out of 100 

births in the United States. ART is a significant contributor to preterm delivery and associated 

risks of preterm birth through an increased rate of multiple gestations. However, recent evidence 

of higher rates of adverse pregnancy outcomes even in singleton pregnancies associated with 

ART, including increased preterm and term low birthweight, very low birthweight, preterm 

delivery, fetal growth restriction, genetic disorders, and congenital anomalies, is cause for 

concern. Children who are born as a result of intracytoplasmic sperm injection (ICSI) also have 

an increased risk of a major congenital malformation compared to those born as a result of 

spontaneous conception. The role of underlying infertility, the direct effects of the ART/ICSI 

treatments and other maternal-fetal exposures in producing the increased risk of adverse 

pregnancy outcomes remain poorly understood. The goals of this meeting were to review the 

current research in this area, identify gaps, stimulate research to better define the range of 

adverse fetal outcomes, and understand the mechanisms underlying adverse pregnancy outcomes 

associated with infertility treatments. The executive summary is available at: Reddy UM, 

Wapner RJ, Rebar R, & Tasca R. (2007). Infertility, assisted reproductive technology, and 

adverse pregnancy outcomes: Executive summary of an NICHD Workshop. Obstet Gynecol, 

109, 967-977. 

NIH State-of-the-Science Conference Cesarean Delivery on Maternal Request, held March 

27-29, 2006, followed a planning process that began in January-February 2005 and was cosponsored by the NIH Office of Medical Applications of Research, the National Institute of 

Diabetes and Digestive and Kidney Diseases, the ORWH, and the National Institute on Nursing 

Research. Despite the Healthy People 2010 goal of reducing cesarean section rates to 

15 percent, rates have continued to increase, with a 25-percent increase since 1995 to the 2002 

rate of 26.1 percent (National Center for Health Statistics/Centers for Disease Control and 

Prevention [CDC]). In part, this increase is due to elective cesarean deliveries (patient choice) 

and is compounded by hospitals refusing to allow vaginal births after cesarean (VBAC), given 

the rigorous requirements and potential liability. It is estimated that elective cesareans account 

for 4 percent to 18 percent of all cesarean deliveries. Thus, the acceptance of elective cesarean 

sections by the medical community will likely result in further dramatic increases in cesarean 

delivery rates. Elective cesareans may also have gained popularity due a link to fewer problems 

with pelvic floor disorders and flexibility for the medical community. However, this procedure 

Appendices-9 
is being adopted without evaluation of the evidence, both of the potential benefits 

(urogynecologic) and risks (maternal and fetal). This conference allowed for a rigorous 

evaluation of the evidence and for raising public health awareness of the findings to design 

research goals and guide practitioners in discussing the options and assessing risks and benefits. 

Visit http://consensus.nih.gov/2006/2006CesareanSOS027main.htm for more information on the 

conference. Output from the conference included: 

• NIH State-of-the-Science Conference Statement (Eds. C. Spong & U. Reddy). (2006). 

Cesarean section on maternal request. Obstet Gynecol, 107, 1386-1397. 

• Cesarean delivery on maternal request: Manuscripts from the experts. (Oct;2006). Seminars 

in Perinatology. 

Perinatal stroke is a poorly understood neurological entity affecting the fetus and the newborn 

that has potential for significant neurological morbidity. The Perinatal Stroke Workshop, held 

August 21-22, 2006, and co-sponsored by the National Institute of Neurological Disorder and 

Stroke (NINDS), the NIH ORD, and United Cerebral Palsy, invited a team of experts from 

multidisciplinary fields to discuss the current state of knowledge, identify knowledge gaps, and 

develop and prioritize a research agenda related to perinatal stroke. Because the topic is of 

interest to specialists from diverse fields, invitations to participate in the meeting were extended 

to specialists from fetal and perinatal medicine, hematology, general pediatrics, neonatology, 

pediatric neurology, neuropathology, neuro-radiology, hematology, genetics, pediatric/perinatal 

pathology, and epidemiology. Output from this meeting includes: Raju TN, Nelson KB, 

Ferriero D, Lynch JK, & the NICHD-NINDS Perinatal Stroke Workshop Participants. (2007). 

Ischemic perinatal stroke: Summary of a workshop sponsored by the NICHD and the NINDS. 

Pediatrics, 120, 609-616. 

The Prenatal Imaging: Sonography and MRI Workshop, held September 18-19, 2006, was 

co-sponsored by the NIH ORD, National Institute on Biomedical Imaging and Bioengineering, 

the Department of Defense, the Telemedicine & Advanced Technology Research Center of the 

U.S. Army Medical Research and Material Command, and the Gottesfeld-Hoeler-Carlson 

Foundation. Since its introduction in 1983, magnetic resonance imaging (MRI) has 

revolutionized imaging. Dramatic reduction in image acquisition time has allowed introduction 

of this technology for fetal evaluation and currently, high-quality fetal images are routinely 

achievable without the need for fetal sedation. As currently used, MRI has been compared to 

sonography in some settings, or as an adjunct for further evaluation of an anomaly detected by 

sonography. Fetal MRI improves diagnostic accuracy for major central nervous system 

anomalies, mid-brain anomalies, cortical destruction and hemorrhage. In addition, MRI is 

suggested to improve diagnostic accuracy for posterior cleft palate, neck and thoracic anomalies, 

urinary tract anomalies in the setting of oligohydramnios, and fetal spinal cord anomalies. The 

role of prenatal MRI remains undefined and the potential for MRI to evaluate fetal metabolic 

functions (e.g., brain, placenta, other) is looming on the horizon and may revolutionize fetal 

diagnosis and evaluation. The goals of this workshop were to identify the research knowledge 

and gaps for fetal MRI and ultrasound and to define a research agenda for this area. Output from 

this meeting includes: Reddy UM, Filly RA, & Copel JA. (2008). Executive summary—Prenatal 

imaging: Ultrasonography and MRI. Obstet Gynecol, 112, 145-157. 

Appendices-10 
Preeclampsia is one of the most common complications of pregnancy and remains a major cause 

of fetal and maternal morbidity and mortality. Preeclampsia: A Pressing Problem, a meeting 

held September 22-23, 2006, with support from the PPB and the NIH ORD, the NIH Office of 

Disease Supplements, and the MOD, sought to address several promising areas of research on 

this topic, including the inappropriate remodeling of uterine vasculature, increased oxidative 

stress level, immune response to paternal antigens, production of autoantibodies, and abnormal 

placental production of endothelial growth factors and their antagonists. The purpose of this 

workshop was to bring together lead researchers in the field to discuss their particular area of 

research, identify scientific gaps, and stimulate collaborative research. Output from this meeting 

includes: Ilekis JV, Reddy UM, & Roberts JM. (2007). Preeclampsia—a pressing problem: An 

Executive Summary of an NICHD Workshop. Reprod Sci, 14, 508-523. 

The PPB hosted the Antenatal Testing: A Reevaluation meeting on August 27-28, 2007, with 

support from the NIH ORD, ACOG, and AAP. Fetal death occurs in 6.4 out of 1,000 

pregnancies in the United States, although experts believe this figure is an underestimate. In half 

of these deaths, antepartum risk factors are present and, of those with risk factors, 25 percent to 

75 percent may be amenable to prenatal modification. In addition, cerebral palsy affects 2 out of 

1,000 live born infants, while neonatal encephalopathy occurs in 1.9 to 3.8 out of 1,000 births 

and may result in permanent neurologic disability, similar to cerebral palsy. In the vast majority 

of cases, the neurologic insults resulting in neonatal encephalopathy seem to arise in the 

antepartum period, before the onset of labor. Multiple techniques for antepartum assessment of 

fetal well-being have been developed in attempts to identify at-risk fetuses and enable prevention 

of adverse outcomes, such as stillbirth and central nervous system injury resulting in neonatal 

encephalopathy and/or cerebral palsy. However, the evidence base supporting the use of these 

techniques and the recommendation of one modality over another is limited. It is not clear which 

antenatal testing strategy best reduces perinatal mortality and morbidity. The goals of this 

meeting were to review the current evidence for antepartum assessments and define gaps for 

which knowledge regarding care is lacking. By identifying and highlighting research needs, 

participants aimed to stimulate research to fill those gaps and advance knowledge and care in the 

field. Output from this meeting includes an issue of Seminars in Perinatology devoted to 

manuscripts based on the workshop presentations (Signore C, Spong CY, guest editors. [2008]. 

Antenatal testing: A reevaluation. Semin Perinatol, 32, 231-332). An executive summary is 

currently in progress. 

The Stillbirth Definition and Classification System: Developing an International 

Consensus for Research, held October 22-24, 2007, sought to address issues related to stillbirth. 

According to official international reports, approximately 3.3 million stillbirths occur each year. 

Such deaths in less developed countries, which account for 97 percent of reported stillbirths, are 

not always registered and, therefore, the true burden is likely underestimated. As more research 

into the causes of stillbirth is being conducted internationally, including the PPB-led Stillbirth 

Collaborative Research Network, an internationally agreed upon classification system is urgently 

required for the comparison of results of these various research studies and to devise prevention 

strategies for stillbirth. The workshop, co-sponsored by the SMFM, First Candle, and the NIH 

ORD, gathered international experts and researchers to address the definition of stillbirth, define 

goals of a stillbirth classification system, and the identify necessary criteria for assigning cause 

Appendices-11 
of death. International researchers presented their research studies and evidence for various 

classification systems. An executive summary is currently in progress. 

Preconception Care Research: Improving Birth Outcomes and Reproductive Health, held 

April 14-15, 2008, in Bethesda, Maryland, was co-sponsored by a number of agencies and 

organizations, including: NIH ORD, ORWH, CDC, MOD, SMFM, and ACOG. Preconception 

care is important to women’s health across the reproductive lifespan and is a proven strategy to 

improve reproductive outcomes. It is increasingly clear that factors, such as nutrition, exercise 

and drug use, can influence the quality of male and female gametes, perhaps many years prior to 

conception. Investigators now believe that peri- and post-conception insults to eggs, embryos, 

and fetuses can lead to childhood, adolescent, and adult health disorders and diseases. The goal 

of preconception care is to promote healthy families and facilitate optimal prenatal, intrapartum, 

and postpartum maternal and fetal health. Because many events before and around the time of 

fertility may affect pregnancy outcomes, such care focuses on women’s health long before 

pregnancy begins. This workshop brought together a broad spectrum of experts, including 

clinicians and basic science and translational investigators, to define a multidisciplinary 

framework for developing an agenda in preconception care research by addressing the current 

state of knowledge, identifying emerging issues or continuing gaps in knowledge, and exploring 

future opportunities for research. Output from the meeting will be a research agenda on 

preconception care. 

Electronic Fetal Heart Rate Monitoring: A Re-evaluation, held April 27-28, 2008, was cosponsored by ACOG and the SMFM. From May 1995 to November 1996, the NICHD held a 

succession of workshops to develop standardized and unambiguous definitions for fetal heart rate 

tracings; the series culminated in recommendations for interpreting fetal heart rate patterns 

(AJOG, 1997;177, 1385-1390). The definitions from the workshops allowed the predictive value 

of monitoring to be assessed more meaningfully and allowed more evidence-based clinical 

management of intrapartum fetal compromise. In the ensuing decade, these definitions have 

been utilized and taught throughout the country, and new interpretations and definitions have 

been proposed, including three-tier and five-tier systems. The Society of Obstetricians and 

Gynaecologists of Canada Consensus Guidelines for Fetal Health Surveillance presents the 

three-tiers (e.g., normal, atypical, and abnormal) versus the two-tiered (e.g., 

reassuring/nonreassuring) classification; other research (Parer, AJOG, 2007;197, 26.e1-26.e6) 

presents a five-tiered management grading system based on Homeland Security Risk categories. 

The objective of this workshop was to convene experts in the field to clarify the terminology 

used in electronic fetal heart rate monitoring, based on the ACOG Practice Committee Bulletin 

(December 2005), the executive summary from the NICHD workshop (AJOG, 1997;177: 1385-

1390), and subsequent expert articles. Participants reviewed the evidence and provided a current 

source document for the practicing clinician on the terminology to be used in electronic fetal 

monitoring. 

Surgeon General’s Conference on the Prevention of Preterm Birth, held June 16-17, 2008, 

was co-sponsored by the Office of the Surgeon General, the NICHD’s Division of 

Epidemiology, Statistics, and Prevention Research, the PPB, the ORWH, the NIH Office of 

Women’s Health, the MOD, AAP, ACOG, and the Association of Women’s Health, Obstetric, 

and Neonatal Nurses. The purpose of the conference, which was outlined in the Prematurity 

Appendices-12 
Research Expansion and Education for Mothers who Deliver Infants Early (PREEMIE) Act (P.L. 

109-450), included the following tasks: 

• Increase awareness of preterm birth as a serious, common and costly public health problem; 

• Review the findings and reports issued by the Interagency Coordinating Council on Low 

Birth Weight and Preterm Birth (a group convened in response to recommendations of the 

Secretary’s Advisory Committee on Infant Mortality and headed by the Health Resources 

and Services Administration and the NICHD at the behest of the DHHS Secretary), key 

stakeholders, and other relevant entities; and 

• Establish an agenda for activities in both the public and private sectors that will speed the 

identification of and treatments for the causes of and risk factors for preterm labor and 

delivery. 

More information about the conference, including the final presentations to the Surgeon General, 

is available at http://www.nichd.nih.gov/about/meetings/2008/SG_pretermbirth.cfm. 

The PPB is working with the NIH Office of Medical Applications of Research and other partners 

to convene Consensus Development Conference: Vaginal Birth after Cesarean (VBAC), 

which is anticipated in 2009. Despite the Healthy People 2010 goal of decreasing cesarean 

births, the cesarean delivery rate in the United States has been steadily rising since 1996, 

reaching an all-time high (more than 30 percent) in 2005. A major driving force behind the 

increase in cesarean births is the declining rate of VBAC. In 1996, delivery by VBAC peaked at 

28.3 percent; by 2004, VBAC rates had dropped to 9.2 percent. The coupling of this trend with a 

concomitant increase in the primary cesarean rate portends a continued escalation in the overall 

national cesarean delivery rate. Numerous studies have examined the outcomes of repeat 

cesarean delivery and VBAC, which is associated with risks of uterine rupture, need for 

hysterectomy or transfusion, and endometritis. Repeat cesarean, especially multiple repeat 

cesarean deliveries, also carries risk of hemorrhage and hysterectomy due to placental 

implantation problems, as well as maternal infectious morbidity and neonatal respiratory 

morbidity. The goal of this conference is to raise awareness of this complicated issue, allow for 

a rigorous evaluation of existing evidence, and develop a statement that advances understanding 

of VBAC that will be useful to health professionals and the public. Such a consensus statement 

will be of immediate use to practitioners and pregnant patients as they discuss risks and benefits 

associated with planned mode of delivery. An organizational meeting of NICHD, OMAR, other 

institutes, and federal partners was held in October 2007. Dr. F. Gary Cunningham accepted the 

committee’s invitation to chair the future consensus panel. The next stage in preparation, a 

planning committee meeting of federal partners and other experts and organizational 

representatives (e.g., ACOG, AAP, SMFM, American College of Nurse Midwives), was held in 

August 2008. 

Other PPB-sponsored meetings include the following: 

• Long-Term Followup of Prenatal Drug Exposure: Challenges and Opportunities; cosponsored by the National Institute on Drug Abuse; March 2004 

http://www.drugabuse.gov/NIDA_notes/NNvol19N3/Conference.html 

• Obesity meeting; June 12-13, 2006 

Appendices-13 
• Necrotizing Enterocolitis (NEC) meeting; July 10-11, 2006; output from the conference 

includes: Grave GD, Nelson SA, Walker WA, Moss RL, Dvorak B, Hamilton FA, Higgins 

R, & Raju TN. (2007). New therapies and preventive approaches for NEC: Report of a 

research planning workshop. Pediatr Res, Oct;62(4), 510-514. 

• Neonatal Hyperbilirubinemia in Egypt: Shedding Light on Improving Outcomes (Cairo, 

Egypt); March 12, 2007; co-sponsored by the National Research Center Egypt and Fogarty 

International Center; output from this conference includes: Severe Neonatal 

Hyperbilirubinemia and Bilirubin-induced Brain Damage in Egypt, White Paper for Action 

Plan Based on the Workshop, submitted to the NACHHD Council in May 2007, and to the 

Egyptian Ministry of Health in June 2007 (through U.S. Department of Health and Human 

Services). 

• Improving the Treatment of Neonatal Seizures; sponsored by NINDS; May 31-June 1, 2007 

Appendices-14 
APPENDIX D: BRANCH SOLICITATIONS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2007 

REQUESTS FOR APPLICATIONS (RFAS)

• HD-02-103: Maternal Lifestyle Study Phase IV 

• HD-02-104: The Collaborative Home Infant Monitoring Study (CHIME)

• HD-02-105: Data Coordinating Center for the Cooperative Multi-center Maternal-Fetal 

Medicine Units (MFMU) Network

• HD-02-106: Data Center for the Cooperative Neonatal Research Network (NRN) 

• HD-03-004: Prenatal Alcohol Exposure among High-Risk Populations: Relationship to SIDS

• HD-03-018: Research into Mechanisms of Fetal Growth Restriction

• HD-03-104: Mentored Specialized Clinical Investigator Development Awards in the NRN

• HD-03-106: NIH-DC Initiative to Reduce Infant Mortality in Minority Populations

• HD-03-112: Data Coordinating Center for the NIH-DC Initiative to Reduce Infant Mortality 

in Minority Populations

• HD-04-002: Genomic and Proteomic Network for Premature Birth Research (GPN/PBR)

• HD-04-010: NICHD Cooperative Multi-center NRN

• HD-04-023: NICHD MFMU Network

• HD-05-108: PHASE II of the Community Child Health Network (CCHN)

• HD-05-111: Prenatal Alcohol in SIDS and Stillbirth Network

• HD-06-001: Data Coordination and Analyses Center for the CCHN 

• HD-06-104: MSCIDA for the MFMU Network and the NRN

• HD-07-002: Data Coordinating Center for the NICHD Cooperative Multi-center NRN

• HD-07-004: Data Coordinating Center for the NICHD Cooperative Multi-center MFMU 

Network

• HD-07-102: Limited Competition: Study of Attitudes and Factors Affecting Infant Care

PROGRAM ANNOUNCEMENTS (PAS)

• PA-02-102: The Role of Gene-Environmental Interactions Underlying the Health Disparity 

of Premature Birth (sponsored by the NICHD, National Institute on Environmental Health 

Sciences, and the National Institute on Nursing Research) 

• PA-03-135: Women’s Mental Health in Pregnancy and the Postpartum Period (sponsored 

by the National Institute of Mental Health, the National Institute on Drug Abuse, and the 

NICHD) 

• PA-04-027: Reducing Preterm and Low Birth Weight in Minority Families 

• PA-080103: Adverse Outcomes of Assisted Reproductive Technologies (P01) 

Appendices-15 
Appendices-16 

• PA-080104: Adverse Outcomes of Assisted Reproductive Technologies (R01) 
APPENDIX E: PUBLICATIONS FROM PPB STAFF AND 

PPB-SUPPORTED NETWORKS, 2004 THROUGH 2008 

(PPB staff names appear in bold. * Denotes staff peer-reviewed publications) 

SELECTED PPB PORTFOLIO PUBLICATIONS

Arechavaleta-Velasco F, Ma Y, Zhang J, McGrath CM, & Parry S. (2006). Adeno-associated 

virus-2 (AAV-2) causes trophoblast dysfunction, and placental AAV-2 infection is associated 

with preeclampsia. Am J Pathol, 168, 1951-1959. 

Bergmann A, Zygmunt M, & Clapp JF, III. (2004). Running throughout pregnancy: Effect on 

placental villous vascular volume and cell proliferation. Placenta, Sep-Oct;25(8-9), 694-698. 

Colson ER, Levenson S, Rybine D, Calianos C, Margolis A, Colton T, Lister G, & Corwin MJ. 

(2006). Barriers to following the supine sleep recommendations among mothers at four WIC 

centers. Pediatrics, 118, e243-e250. 

Condon JC, Jeyasuria P, Faust JM, & Mendelson CR. (2004). Surfactant protein secreted by the 

maturing mouse fetal lung acts as a hormone that signals the initiation of parturition. PNAS, 

101, 4978-4983. 

Cox LA, Nijland MJ, Gilbert JS, Schlabritz-Loutsevitch NE, Hubbard GB, McDonald TJ, Shade 

RE, & Nathanielsz PW. (2006). Effect of 30 percent maternal nutrient restriction from 0.16 

to 0.5 gestation on fetal baboon kidney gene expression. J Physiol, 572, 67-85. 

Cronk LB, Ye B, Toshihiko K, Tester DJ, Vatta M, Makielski JC, & Ackerman MJ. (2007). 

Novel mechanism for SIDS: Persistent late sodium current secondary to mutations in 

caveolin-3. Heart Rhythm, 4, 161-166. 

Gravett MG, Adams KM, Sadowsky DW, Grosvenor AR, Witkin SS, Axthelm MK, & Novy MJ. 

(2007). Immunomodulators plus antibiotics delay preterm delivery after experimental 

intraamniotic infection in a nonhuman primate model. Am J Obstet Gynecol, 197, 518.e1-

518e8. 

Grieve PG, Myers MM, Stark RI, Housman S, & Fifer WP. (2005). Topographic localization of 

electrocortical activation in newborn and two- to four-month-old infants in response to head 

up tilting. Acta Paediatr, 94, 1756-1763. 

Hardy DB, Janowski BA, Corey DR, & Mendelson CR. (2006). Progesterone receptor plays a 

major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kB 

activation of cyclooxygenase 2 expression. Mol Endocrinol, 20, 2724-2733. 

Huang ST, Vo KC, Lyell DJ, Faessen GH, Tulac S, Tibshirani R, Giaccia AJ, & Giudice LC. 

(2004). Developmental response to hypoxia. FASEB J, Sep;18(12), 1348-1365. 

Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, Roberts JM, Markovic N, Thadhani R, 

Luft FC, & Dechend R. (2007). Agonistic angiotensin II type 1 receptor autoantibodies in 

postpartum women with a history of preeclampsia. Hypertension, Mar;49(3), 612-617. 

Jeffreys RM, Stepanchak W, Lopez B, Hardis J, & Clapp JF, III. (2006). Uterine blood flow 

during supine rest and exercise after 28 weeks of gestation. BJOG, Nov;113(11), 1239-1247. 

Appendices-17 
Kahraman L, & Tach BT. (2004). Inhibitory effects of hyperthermia on mechanisms involved in 

autoresuscitation from hypoxic apnea in mice: A model for thermal stress causing SIDS. J 

Appl Physiol, 97, 669-674. 

Kanaan A, Farahani R, Douglas RM, LaManna JC, & Haddad GG. (2006). Effect of chronic 

continuous or intermittent hypoxia and reoxygenation on cerebral capillary density and 

myelination. Am J Physiol Regul Integr Comp Physiol, 290, R1105-R1114. 

Khosrotehrani K, Reyes RR, Johnson KL, Freeman RB, Salomon RN, Peter I, Stroh H, Guégan 

S, & Bianchi DW. (2007). Fetal cells participate over time in the response to specific types of 

murine maternal hepatic injury. Hum Reprod, Mar;22(3), 654-661. 

Kinney HC, Myers MM, Belliveau RA, Randall LL, Trachtenberg FL, Ten Fingers S, 

Youngman M, Habbe D, & Fifer WP. (2005). Subtle autonomic and respiratory dysfunction 

in SIDS associated with serotonergic brainstem abnormalities: A case report. J Neuropathol 

Exp Neurol, 64, 689-694. 

Kinney HC, Rava LA, Belliveau RA, Filiano JJ, & Paterson DS. (2007). The development of the 

medullary serotonergic system in early human life. Auton Neurosci, 132, 98-102. 

LaCoursiere DY, Baksh L, Bloebaum L, & Varner MW. (2006). Maternal body mass index and 

self-reported postpartum depressive symptoms. Matern Child Health J, Jul;10(4), 385-390. 

*Li DK, Willinger M, Pettiti, DB, Odouli R, Liu L; Vu H, & Hoffman HJ. (2006). Use of a 

dummy and the risk of SIDS: Population-based case-control study. BMJ, 332, 18-22. 

Li M, Yee D, Magnuson TR, Smithies O, & Caron KM. (2006). Reduced maternal expression of 

adrenomedullin disrupts fertility, placentation, and fetal growth in mice. J Clin Invest, 116, 

2653-2662. 

Louey S, Jonker SS, Giraud GD, & Thornburg KL. (2007). Placental insufficiency decreases cell 

cycle activity and terminal maturation in fetal sheep cardiomyocytes. J Physiol, 580(Pt. 2), 

639-648. 

Macones GA, Cahill AG, Stamilio DM, Odibo A, Peipert J, & Stevens EJ. (2006). Can uterine 

rupture in patients attempting vaginal birth after cesarean delivery be predicted? Am J Obstet 

Gynecol, Oct;195(4), 1148-1152. 

Macones GA, Peipert J, Nelson DB, Odibo A, Stevens EJ, Stamilio DM, Pare E, Elovitz M, 

Sciscione A, Sammel MD, & Ratcliffe SJ. (2005). Maternal complications with vaginal birth 

after cesarean delivery: A multi-center study. Am J Obstet Gynecol, Nov;193(5), 1656-1662. 

Macy PM, Woo MA, Macey E, Keens TG, Saeed MM, Alger JR, & Harper RM. (2005). 

Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital 

central hypoventilation syndrome. J Applied Physiol, 98, 958-969. 

Maner WL, & Garfield RE. (2007). Identification of human term and preterm labor using 

artificial neural networks on uterine electromyography data. Ann Biomed Eng, 35, 465-473. 

Massmann GA, Zhang J, Rose JC, & Figueroa JP. (2006). Acute and long-term effects of clinical 

doses of antenatal glucocorticoids in the developing fetal sheep kidney. J Soc Gynecol 

Investig, 13, 174-180. 

Appendices-18 
*McCoy RC, Hunt CE, Lesko SM, Vezina R, Corwin MJ, Willinger M, & Hoffman HJ. (2004). 

Frequency of bed sharing and its relationship to breastfeeding. J Dev Behav Pediatr, 25, 141-

149. 

Myers MM, Gomez-Gribben E, Smith KS, Tseng A, & Fifer WP. (2006). Developmental 

changes in infant heart-rate responses to head-up tilting. Acta Paediatr, 95, 77-81. 

Paluszynska DA, Harris KA, & Thach BT. (2004). Influence of sleep position experience on 

ability of prone-sleeping infants to escape from asphyxiating microenvironments by changing 

head position. Pediatrics, 114, 1634-1639. 

Paterson DS, Thompson EG, Belliveau RA, Trachtenberg FL, Darnall RA, Chadwick AE, Krous 

HF, & Kinney HC. (2006). Multiple abnormalities in the brainstem serotonergic system in 

SIDS. JAMA, 296(17), 2124-2132. 

Peranteau WH, Endo M, Adibe OO, Merchant A, Zoltick PW, & Flake AW. (2006). CD26 

inhibition enhances allogeneic donor-cell homing and engraftment after in utero

hematopoietic-cell transplantation. Blood, Dec 15;108(13), 4268-4274. 

Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA, Karumanchi SA, Thadhani R, 

Wolf M, Harger G, & Markovic N. (2005). Extra-placental expression of vascular endothelial 

growth factor receptor-1 (Flt-1) and soluble Flt-1 (sFlt-1) by peripheral blood mononuclear 

cells (PBMCs) in normotensive and preeclamptic pregnant women. Placenta, 26, 563-573. 

Roberts JM, Bodnar LM, Lain KY, Hubel CA, Markovic N, Ness RB, & Powers RW. (2005). 

Uric acid is as important as proteinuria in identifying fetal risk in women with gestational 

hypertension. Hypertension, 46, 1263-1269. 

Sahni R, Schulzs KF, Kashyap S, Ohira-kist K, Fifer WP, & Myers MM. (2005). Sleeping 

position and electrocortical activity in low birth weight infants. Arch Dis Child Fetal 

Neonatal Ed, F311-F315. 

Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, & Mintz J. (2007). Effects of antenatal 

depression and antidepressant treatment on gestational age at birth and risk of preterm birth. 

Am J Psychiatry, Aug;164(8), 1206-1213. 

Taylor NC, Aihua L, & Nattie EE. (2005). Medullary serotonergic neurons modulate the 

ventilatory response to hypercapnia, but not hypoxia in conscious rats. J Physiol, London, 

566, 543-557. 

Taylor NC, Li A, Green A, Kinney HC, & Nattie EE. (2004). Chronic fluoxetine microdialysis 

into the medullary raphe nuclei of the rat but not systemic administration, increases the 

ventilatory response to CO2. J Appl Physiol, 97, 1763-1773. 

Tester DJ, Dura M, Carturan E, Reiken S, Wronska A, Marks AR, & Ackerman MJ. (2007). A 

mechanism for SIDS: Stress-induced leak via ryanodine receptors. Hearth Rhythm, 4, 733-

739. 

Van Nostrand DW, Valdivia CR, Tester DJ, Ueda K, London B, Malielski JC, & Ackerman MJ. 

(2007). Molecular and functional characterization of novel glycerol-3-phosphate 

dehydrogenase 1-like gene (GPD1-L) mutations in SIDS. Circulation, 116, 2253-2259. 

Wang H, Parry S, Macones G, Sammel MD, Kuivaniemi H, Tromp G, Argyropoulos G, Halder 

I, Shriver MD, Romero R, & Strauss JF, III. (2006). A functional SNP in the promoter of the 

Appendices-19 
SERPINH1 gene increases risk of preterm premature rupture of membranes in African 

Americans. Proc Natl Acad Sci USA, 103, 13463-13467. 

Weier JF, Weier HU, Jung CJ, Gormley M, Zhou Y, Chu LW, Genbacev O, Wright AA, & 

Fisher SJ. (2005). Human cytotrophoblasts acquire aneuploidies as they differentiate to an 

invasive phenotype. Dev Biol, 279, 420-432. 

Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, Sun C, Ahmed A, Kellems RE, & Xia 

Y. (2007). Angiotensin II induces soluble fms-like tyrosine kinase-1 release via calcineurin 

signaling pathway in pregnancy. Circ Res, 100, 88-95. 

COLLABORATIVE HOME INFANT MONITORING AND EVALUATION (CHIME), NATIONAL 

INFANT SLEEP POSITION (NISP), AND SPECIAL SUPPLEMENTAL NUTRITION PROGRAM FOR 

WOMEN, INFANTS, AND CHILDREN (WIC) STUDY PUBLICATIONS

Colson ER, Levenson S, Rybine D, Calianos C, Margolis A, Colton T, Lister G, & Corwin MJ. 

(2006). Barriers to following the supine sleep recommendations among mothers at four WIC 

centers. Pediatrics, 118, e243-e250. 

Colson ER, McCabe LK, Fox K, Levenson S, Colton T, Lister G, & Corwin MJ. (2005). Barriers 

to following the Back to Sleep recommendations: Insights from focus groups with inner-city 

caregivers. Ambulatory Pediatrics, 5, 349-354. 

*Crowell DH, Brooks LJ, Corwin MJ, Davidson-Ward S, Hunt CE, Kapuniai LE, Neuman MR, 

Silvestri J, Tinsley L, Weese-Mayer DE, Di Fiore J, Peucker M, Grove JS, Pearce JW, & the 

CHIME Study Group. (2004). Ontogeny of arousal. J Clin Neurophysiol, 21, 290-300. 

Hoppenbouers T, Hodgman JE, Rybine D, Fabrikant G, Corwin MJ, Crowell D, Weese-Mayer 

DE, & the CHIME Study Group. (2005). Sleep architecture in term and preterm infants 

beyond the neonatal period: The influence of gestational age (GA), steroids, and ventilatory 

support. Sleep, 28, 1428-1436. 

*Hunt CE, Corwin MJ, Baird T, Tinsley LR, Palmer P, Rangasamy R, Crowell DH, Schafer S, 

Martin RJ, Hufford D, Peucker M, Weese-Mayer DE, Silvestri JM, Neuman MR, CanteyKiser J, & the CHIME Study Group. (2004). Cardiorespiratory events detected by home 

memory monitoring and one year neurodevelopmental outcome. Journal of Pediatrics, 145, 

465-471. 

*Hunt CE, Corwin MJ, Lister G, Weese-Mayer DE, Davidson-Ward S, Tinsely LR, Neuman 

MR, Willinger M, Ramanathan R, Rybin D, & the CHIME Study Group. (2008). Precursors 

of cardiorespiratory events in infants detected by home memory monitor. Pediatric 

Pulmonology, 43, 87-98. 

Lewicke A, Sazonov E, Corwin M, Neuman M, Shuckers S, & the CHIME Study Group. (2008). 

Sleep-state classification from heart rate variability using computational intelligence: 

Consideration of rejection in classification models. IEEE Transactions on Biomedical 

Engineering, 55, 108-118. 

Appendices-20 
Lewicke AT, Sazonov ES, Schuckers SA, & the CHIME Study Group. (2004). Sleep-wake 

identification in infants: Heart rate variability compared to actigraphy. Conf Proc IEEE Eng 

Med Biol Soc, 1, 442-445. 

*Sazonov E, Sazonova N, Schuckers S, Neuman M, & the CHIME Study Group. (2004). 

Activity-based sleep-wake identification in infants. Physiol Meas, 25, 1291-1304. 

Sazonova NA, Sazonov EE, Tan B, & Schuckers SA. (2006). Sleep-state scoring in infants from 

respiratory and activity measurements. Conf Proc IEEE Eng Med Biol Soc, 1, 2462-2465. 

*Silvestri JM, Lister G, Corwin MJ, Smok-Pearsall SM, Baird TM, Crowell DH, Cantey-Kiser J, 

Hunt CE, Tinsely L, Palmer PH, Mendenhall RS, Hoppenbrouwers TT, Neuman MR, 

Weese-Mayer DE, Willinger M, & the CHIME Study Group. (2005). The CHIME Study: 

Factors influencing use of a home cardiorespiratory monitor for infants. Archives of 

Pediatrics & Adolescent Medicine, 159, 18-24. 

MATERNAL-FETAL MEDICINE UNITS (MFMU) NETWORK PUBLICATIONS

*Aagaard-Tillery K, Sibai B, Spong CY, Momirova V, Wendel G, Wenstrom K, Samuels P, 

Moawad A, Caritis SN, Sorokin Y, Meis P, Miodovnik M, O’Sullivan MJ, Conway D, 

Wapner RJ, & Gabbe SG for the NICHD MFMU Network. (2006). Sample bias among 

women with retained DNA samples for future genetic studies. Obstetrics and Gynecology, 

108, 1115-1120. 

*Alexander JM, Leveno KJ, Hauth JC, Landon MB, Thom E, Leindecker S, Spong CY, Varner 

MW, Moawad AH, Johnson F, McCampbell J, & Gabbe SG for the NICHD MFMU 

Network. (2006). Fetal injury associated with cesarean delivery. Obstetrics and Gynecology, 

108, 885-890. 

*Alexander JM, Leveno KJ, Rouse DJ, Landon MB, Gilbert S, Spong CY, Varner MW, 

Moawad AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, 

Sibai BM, Langer O, & Gabbe SG for the NICHD MFMU Network. (2007). Comparison of 

maternal and infant outcomes from primary cesarean delivery during the second compared 

with first stage of labor. Obstetrics and Gynecology, 109, 917-921. 

*Andrews WW, Klebanoff MA, Thom EA, Hauth JC, Carey JC, Meis PJ, Caritis SN, Leveno 

KJ, Wapner RJ, Varner MW, Iams JD, Moawad A, Miodovnik M, Sibai B, Dombrowski M, 

Langer O, & O’Sullivan MJ for the NICHD MFMU Network. (2006). Mid-pregnancy 

genitourinary tract infection with Chlamydia Trachomatis: Association with subsequent 

preterm delivery in women with bacterial vaginosis and Trichomonas Vaginalis. American 

Journal of Obstetrics and Gynecology, 194, 493-500. 

Bailit JL, Landon MB, Lai Y, Rouse DJ, Spong CY, Varner MW, Moawad AH, Simhan HN, 

Harper, Wapner RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, Sibai BM, & Langer O for the 

NICHD MFMU Network. (2008). MFMU Cesarean Registry: Impact of shift change on 

cesarean complications. American Journal of Obstetrics and Gynecology, 198, 173.e1-

173.e5. 

*Bailit JL, Landon MB, Thom E, Rouse DJ, Spong CY, Varner MW, Moawad AH, Caritis SN, 

Harper M, Wapner, RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, Sibai BM, & Langer O for 

Appendices-21 
the NICHD MFMU Network. (2006). The MFMU Network Cesarean Registry: Impact of 

time of day on cesarean complications. American Journal of Obstetrics and Gynecology, 

195, 1132-1137. 

Berghella V, Iams JD, Newman, RB, MacPherson C, Goldenberg RL, Mueller-Heubach E, 

Caritis SN, & Dombrowski MP for the NICHD MFMU Network. (2004). Frequency of 

uterine contractions in asymptomatic pregnant women with or without a short cervix on 

transvaginal ultrasound. American Journal of Obstetrics & Gynecology, 191, 1253-1256. 

Berghella V, Owen J, MacPherson C, Yost N, Swain M, Dildy GA, Miodovnik M, Langer O, & 

Sibai B for the NICHD MFMU Network. (2007). Natural history of cervical funneling in 

women at high risk for spontaneous preterm birth. Obstetrics and Gynecology, 109, 863-869. 

*Bloom SL, Leveno KJ, Spong CY, Gilbert S, Hauth JC, Landon MB, Varner MW, Moawad 

AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, Sibai BM, 

Langer O, & Gabbe SG for the NICHD MFMU Network. (2006). Decision-to-incision times 

and maternal and infant outcomes. Obstetrics and Gynecology, 108, 6-11. 

*Bloom SL, Spong CY, Thom E, Varner MW, Rouse DJ, Weininger S, Ramin SM, Caritis SN, 

Peaceman A, Sorokin Y, Sciscione A, Carpenter M, Mercer B, Thorp J, Malone F, Harper M, 

Iams J, & Anderson G for the NICHD MFMU Network. (2006). Fetal pulse oximetry and 

cesarean delivery. New England Journal of Medicine, 355, 2195-2202. 

*Bloom SL, Spong CY, Weiner SJ, Landon MB, Rouse DJ, Varner MW, Moawad AH, Caritis 

SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, Sibai B, Langer O, & 

Gabbe SG for the NICHD MFMU Network. (2005). Complications of anesthesia for 

cesarean delivery. Obstetrics and Gynecology, 106, 281-287. 

*Dizon-Townson D, Miller C, Sibai B, Spong CY, Thom E, Wendel G, Wenstrom K, Samuels 

P, Cotroneo M, Moawad A, Sorokin Y, Meis P, Miodovnik M, O’Sullivan MJ, Conway D, 

Wapner RJ, & Gabbe SG for the NICHD MFMU Network. (2005). The relationship of the 

Factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstetrics and 

Gynecology, 106, 517-524. 

Dombrowski M, Schatz M, Wise R, Thom E, Landon M, Mabie W, Newman R, McNellis D, 

Hauth J, Lindheimer M, Caritis S, Leveno K, Meis P, Miodovnik M, Wapner R, Varner M, 

O’Sullivan MJ, & Conway D for the NICHD MFMU Network and the National Heart, Lung, 

and Blood Institute. (2004). Randomized trial of inhaled beclomethasone dipropionate versus 

theophylline for moderate asthma during pregnancy. American Journal of Obstetrics & 

Gynecology, 190, 737-744. 

Dombrowski MP, Schatz M, Wise R, Momirova V, Landon M, Mabie W, Newman R, McNellis 

D, Hauth J, Lindheimer M, Caritis S, Leveno K, Meis P, Miodovnik M, Wapner R, Paul R, 

Varner M, O’Sullivan MJ, Thurnau G, & Conway D for the NICHD MFMU Network and 

the National Heart, Lung, and Blood Institute. (2004). Asthma during pregnancy. Obstetrics 

& Gynecology, 103, 5-12. 

*Durnwald CP, Hauth JC, Leveno KJ, Spong CY, MacPherson C, Varner MW, Moawad AH, 

Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai B, Langer O, Thorp JM, Ramin SM, Mercer BM, & Gabbe SG for the 

NICHD MFMU Network. (2006). The MFMU Cesarean Registry: Safety and efficacy of a 

Appendices-22 
trial of labor in preterm pregnancy after a prior cesarean delivery. American Journal of 

Obstetrics and Gynecology, 195, 1119-1126. 

Goepfert AR, Varner M, Ward K, MacPherson C, Klebanoff M, Mercer B, Meis P, Iams J, 

Moawad A, Carey JC, Leveno K, Wapner R, Caritis SN, Miodovnik M, Sorokin Y, 

O’Sullivan MJ, Van Dorsten JP, & Langer O for the NICHD MFMU Network. (2005). 

Differences in inflammatory cytokine and toll-like receptor genes and bacterial vaginosis in 

pregnancy. American Journal of Obstetrics and Gynecology, 193, 1478-1485. 

*Grobman WA, Gersnoviez R, Landon MB, Spong CY, Leveno KJ, Rouse DJ, Varner MW, 

Moawad AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2007). Pregnancy outcomes for women with placenta previa in relation to 

the number of prior cesareans. Obstetrics and Gynecology, 110, 1249-1255. 

*Grobman WA, Gilbert S, Landon MB, Spong CY, Leveno KJ, Rouse DJ, Varner MW, 

Moawad AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM. (2007). 

Outcomes of induction of labor after one prior cesarean. Obstetrics and Gynecology, 109, 

262-269. 

*Grobman WA, Lai Y, Landon MB, Spong CY, Leveno KJ, Rouse DJ, Varner MW, Moawad 

AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, O’Sullivan 

MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD MFMU 

Network. (2007). Development of a nomogram for prediction of vaginal birth after cesarean 

delivery. Obstetrics and Gynecology, 109, 806-812. 

Hendler I, Andrews WW, Carey CJ, Klebanoff MA, Noble WD, Sibai BM, Hillier SL, Dudley 

D, Ernest JM, Leveno KL, Wapner R, Iams J, Varner M, Moawad A, Miodovnik M, 

O’Sullivan MJ, & Van Dorsten PJ. (2007). The relationship between resolution of 

asymptomatic bacterial vaginosis and spontaneous preterm birth in fetal fibronectin-positive 

women. American Journal of Obstetrics and Gynecology, 197, 488-490. 

Hendler I, Goldenberg RL, Mercer BM, Iams JD, Meis PJ, Moawad AH, MacPherson CA, 

Caritis SN, Miodovnik M, Menard MK, Thurnau GR, & Sorokin Y for the NICHD MFMU 

Network. (2005). The Preterm Prediction Study: Association between maternal body mass 

index (BMI) and spontaneous and indicated preterm birth. American Journal of Obstetrics 

and Gynecology, 192, 882-886. 

*Hendler I, Schatz M, Momirova V, Wise R, Landon M, Mabie W, Newman RB, Kiley J, Hauth 

JC, Moawad A, Caritis SN, Spong CY, Leveno KJ, Miodovnik M, Meis P, Wapner RJ, Paul 

RH, Varner MW, O’Sullivan MJ, Thurnau GR, & Conway DL for the NICHD MFMU 

Network. (2006). Association of obesity with pulmonary and non-pulmonary complications 

of pregnancy in asthmatic women. Obstetrics and Gynecology, 108, 77-82. 

*Hibbard JU, Gilbert S, Landon MB, Hauth JC, Leveno KJ, Spong CY, Varner MW, Caritis SN, 

Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O’Sullivan 

MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM, & Gabbe SG for the NICHD 

MFMU Network. (2006). Trial of labor or repeat cesarean delivery in women with morbid 

obesity and previous cesarean delivery. Obstetrics and Gynecology, 108, 124-133. 

Appendices-23 
Hnat MD, Mercer BM, Miodovnik M, Thurnau G, Goldenberg R, Thom E, Meis P, Moawad A, 

Iams JD, Van Dorsten JP, & Paul RH for the NICHD MFMU Network. (2005). Perinatal 

outcomes in women with preterm rupture of membranes between 24-32 weeks and a history 

of vaginal bleeding. American Journal of Obstetrics & Gynecology, 193, 164-168. 

How H, Sibai B, Lindheimer M, Caritis S, Hauth J, Klebanoff M, MacPherson C, Van Dorsten P, 

Miodovnik M, Landon M, Paul R, Meis P, Thurnau G, Dombrowski M, & Roberts J for the 

NICHD MFMU Network. (2004). Is early-pregnancy proteinuria associated with an 

increased rate of preeclampsia in women with pregestational diabetes mellitus? American 

Journal of Obstetrics & Gynecology, 190, 775-778. 

Klebanoff M, Hauth JC, MacPherson C, Carey JC, Heine P, Wapner R, Iams J, Moawad A, 

Miodovnik M, Sibai B, Van Dorsten JP, & Dombrowski MP for the NICHD MFMU 

Network. (2004). Time course of regression of asymptomatic bacterial vaginosis in 

pregnancy with and without treatment. American Journal of Obstetrics & Gynecology, 190, 

363-370. 

Klebanoff MA, Hillier SL, Nugent RP, MacPherson CA, Hauth JC, Carey JC, Ernest JM, 

Wapner RJ, Trout W, Moawad A, Leveno KJ, Miodovnik M, & the NICHD MFMU 

Network. (2005). Is bacterial vaginosis a stronger risk factor for preterm birth when it is 

diagnosed earlier in gestation? American Journal of Obstetrics & Gynecology, 192, 470-477. 

Knudtson EJ, Smith K, Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Meis PJ, 

Moawad AH, Van Dorsten JP, Paul RH, Sorokin Y, Roberts JM, & Das A for the NICHD 

MFMU Network. (2004). Serum homocysteine levels after preterm premature rupture of the 

membranes. American Journal of Obstetrics & Gynecology, 191, 537-541. 

*Landon MB, Hauth JC, Leveno JK, Spong CY, Leindecker MS, Varner MW, Moawad AH, 

Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai B, Conway D, Thorp JM, Ramin SM, Mercer BM, & Gabbe SG for the 

NICHD MFMU Network. (2004). The MFMU Cesarean Registry: Maternal and perinatal 

outcome in women undergoing trial of labor after cesarean delivery. New England Journal of 

Medicine, 351, 2581-2589. 

*Landon MB, Leindecker S, Spong CY, Hauth JC, Bloom S, Varner MW, Moawad AH, Caritis 

SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM, & Gabbe SG for 

the NICHD MFMU Network. (2005). The MFMU Cesarean Registry: Factors affecting the 

success of trial of labor following prior cesarean delivery. American Journal of Obstetrics 

and Gynecology, 193, 1016-1023. 

*Landon MB, Spong CY, Thom E, Hauth JC, Bloom SL, Varner MW, Moawad AH, Caritis SN, 

Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O’Sullivan 

MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM, & Gabbe SG for the NICHD 

MFMU Network. (2006). Risk of uterine rupture with a trial of labor in women with multiple 

and single prior cesarean delivery. Obstetrics and Gynecology, 108, 12-20. 

*Landon MB, Thom E, Spong CY, Carpenter M, Mele L, Johnson F, Tillinghast J, & Anderson 

G for the NICHD MFMU Network. (2007). The NICHD MFMU Network randomized 

clinical trial in progress: Standard therapy versus no therapy for mild gestational diabetes 

mellitus. Diabetes Care, 30, S194-S199. 

Appendices-24 
*Louis J, Landon MB, Gersnoviez RJ, Leveno KJ, Spong CY, Hauth JC, Moawad AH, Varner 

MW, Caritis SN, Harper M, Wapner RJ, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2007). The MFMU Cesarean Registry: Perioperative morbidity among 

HIV-infected women undergoing cesarean delivery. Obstetrics and Gynecology. 110, 385-

390. 

Meis PJ, Klebanoff M, Dombrowski MP, Sibai BM, Leindecker S, Moawad AH, Northen A, 

Iams JD, Varner MW, Caritis SN, O’Sullivan MJ, Miodovnik M, Leveno KJ, Conway D, 

Wapner RJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, & Gabbe S for 

the NICHD MFMU Network. (2005). Does progesterone treatment influence risk factors for 

recurrent preterm delivery? Obstetrics and Gynecology, 106, 557-561. 

Mercer BM, Gilbert S, Landon MB, Spong CY, Leveno KJ, Rouse DJ, Varner MW, Moawad 

AH, Simhan HN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman 

A, O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, & Ramin SM for the NICHD MFMU 

Network. (2008). Labor outcomes with increasing number of prior vaginal births after 

cesarean delivery. Obstetrics and Gynecology, 111, 285-291. 

Mercer BM, MacPherson C, Goldenberg RL, Goepfert AR, Haugel-de Mouzon S, Varner MW, 

Iams JD, Meis PJ, Moawad AH, Miodovnik M, Caritis SN, Van Dorsten JP, Sorokin Y, 

Thurnau GR, & Spong CY for the NICHD MFMU Network. (2006). Are women with 

recurrent spontaneous preterm births different from those without such history? American 

Journal of Obstetrics and Gynecology, 194, 1176-1185. 

Mercer BM, Rabello YA, Thurnau GR, Miodovnik M, Goldenberg RL, Das AF, Meis PJ, 

Moawad AH, Iams JD, Van Dorsten JP, Dombrowski MP, Roberts JM, & McNellis D for the 

NICHD MFMU Network. (2006). The NICHD-MFMU antibiotic treatment of pPROM 

study: Impact of initial amniotic fluid volume on pregnancy outcome. American Journal of 

Obstetrics and Gynecology, 194, 438-445. 

Newman RB, Iams JD, Das A, Goldenberg RL, Meis P, Moawad A, Sibai BM, Caritis SN, 

Miodovnik M, Paul RH, Dombrowski MP, & Fischer M for the NICHD MFMU Network. 

(2006). A prospective masked observational study of uterine contraction frequency in twins. 

American Journal of Obstetrics and Gynecology, 195, 1564-1570. 

Newman RB, Johnson F, Das A, Goldenberg RL, Swain M, Moawad A, Sibai BM, Caritis SN, 

Miodovnik M, Paul RH, Dombrowski MP, Collins-Sharp BA, & Fischer M for the NICHD 

MFMU Network. (2003). Uterine contraction frequency before and after successful tocolytic 

therapy for preterm uterine contractions. The Journal of Reproductive Medicine, 48, 843-849. 

Northen AT, Norman GS, Anderson K, Moseley L, DiVito M, Cotroneo M, Swain M, 

Bousleiman S, Johnson F, Dorman K, Milluzzi C, Tillinghast J, Kerr M, Mallett G, Thom E, 

Pagliaro S, & Anderson G for the NICHD MFMU Network. (2007). Followup of children 

exposed in utero to 17-alpha hydroxyprogesterone caproate versus placebo. Obstetrics and 

Gynecology, 110, 865-872. 

Owen J, Yost N, Berghella V, MacPherson, C, Swain M, Dildy GA, Miodovnik M, Langer O, & 

Sibai B for the NICHD MFMU Network. (2004). Can shortened mid-trimester cervical 

length predict very early spontaneous preterm birth? American Journal of Obstetrics & 

Gynecology, 191, 298-303. 

Appendices-25 
*Peaceman AM, Gersnoviez R, Landon MB, Spong CY, Leveno KJ, Varner MW, Rouse DJ, 

Moawad AH, Caritis SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2006). The MFMU Cesarean Registry: Impact of fetal size on trial of 

labor success for patients with prior cesarean for dystocia. American Journal of Obstetrics 

and Gynecology, 195, 1127-1131. 

*Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, Spong CY, Varner M, Malone 

F, Iams JD, Mercer BM, Thorp J, Sorokin Y, Carpenter M, Lo J, Ramin S, Harper M, & 

Anderson G for the NICHD MFMU Network. (2007). A trial of 17 alphahydroxyprogesterone caproate to prevent prematurity in twins. New England Journal of 

Medicine, 357, 454-461. 

*Rouse DJ, Landon M, Leveno KJ, Leindecker S, Varner MW, Caritis SN, O’Sullivan MJ, 

Wapner RJ, Meis PJ, Miodovnik M, Sorokin Y, Moawad AH, Mabie W, Conway D, Gabbe 

S, & Spong CY for the NICHD MFMU Network. (2004). The MFMU Network Cesarean 

Registry: Chorioamnionitis at term and its duration—relationship to outcomes. American 

Journal of Obstetrics & Gynecology, 191, 211-216. 

*Rouse DJ, Leindecker S, Landon M, Bloom SL, Varner MW, Moawad AH, Spong CY, Caritis 

SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, O’Sullivan MJ, Sibai BM, & Langer O 

for the NICHD MFMU Network. (2005). The MFMU Cesarean Registry: Predictability of 

uterine atony after primary cesarean delivery. American Journal of Obstetrics and 

Gynecology, 193, 1127-1131. 

*Rouse DJ, MacPherson C, Landon M, Varner MW, Leveno KJ, Moawad AH, Spong CY, 

Caritis SN, Meis PJ, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2006). Blood transfusion and cesarean delivery. Obstetrics and 

Gynecology, 108, 891-897. 

*Sawady J, Mercer B, Wapner RJ, Zhao Y, Sorokin Y, Johnson F, Dudley DJ, Spong CY, 

Peaceman AM, Leveno KJ, Harper M, Caritis SN, Miodovnik M, Thorp JM, Ramin S, 

Carpenter MW, & Rouse DJ for the NICHD MFMU Network. (2007). Beneficial Effects of 

Antenatal Repeated Steroids Study: Impact of repeated doses of antenatal corticosteroids on 

placental growth and histologic findings. American Journal of Obstetrics and Gynecology, 

197, 281.e1-281.e8. 

Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Hauth 

JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, 

Varner MW, O’Sullivan MJ, Thurnau GR, & Conway DL for the NICHD MFMU Network. 

(2004). The relationship of asthma medication use to perinatal outcomes. Journal of Allergy 

and Clinical Immunology, 113, 1040-1045. 

Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Hauth 

JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, 

Varner MW, O’Sullivan MJ, Thurnau GR, & Conway DL for the NICHD MFMU Network. 

(2006). Spirometry is related to perinatal outcomes in pregnant women with asthma. 

American Journal of Obstetrics & Gynecology, 194, 120-126. 

Appendices-26 
Sciscione A, Landon MB, Leveno KJ, Spong CY, MacPherson C, Varner MW, Rouse DJ, 

Moawad AH, Caritis SN, Harper M, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp J, Ramin SM, & and Mercer BM for the NICHD 

MFMU Network. (2008). Previous preterm cesarean delivery and risk of subsequent uterine 

rupture. Obstetrics and Gynecology, 111, 648-653. 

Sheffield JS, Andrews WW, Klebanoff MA, MacPherson C, Carey J, Ernest JM, Wapner RJ, 

Trout W, Moawad A, Miodovnik M, Sibai B, Varner MW, Caritis SN, Dombrowski M, 

Langer O, & O’Sullivan MJ for the NICHD MFMU Network. (2005). Spontaneous 

resolution of asymptomatic Chlamydia Trachomatis in pregnancy. Obstetrics and 

Gynecology, 105, 557-562. 

Sibai B, Meis PJ, Klebanoff M, Dombrowski MP, Weiner SJ, Moawad AH, Northen A, Iams JD, 

Varner MW, Caritis SN, O’Sullivan MJ, Miodovnik M, Leveno KJ, Conway D, Wapner RJ, 

Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, & Gabbe S for the NICHD 

MFMU Network. (2005). Plasma CRH measurement at 16-20 weeks’ gestation does not 

predict preterm delivery in women at high-risk for preterm delivery. American Journal of 

Obstetrics and Gynecology, 193, 1181-1186. 

*Silver RM, Landon MB, Rouse DJ, Leveno KJ, Spong CY, Thom EA, Moawad AH, Caritis 

SN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai B, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2006). Maternal morbidity associated with multiple repeat cesarean 

deliveries. Obstetrics and Gynecology, 107, 1226-1232. 

*Spong CY, Landon MB, Gilbert S, Rouse DJ, Leveno KJ, Varner MW, Moawad AH, Simhan 

HN, Harper M, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2007). Risk of uterine rupture and adverse perinatal outcome at term after 

cesarean delivery. Obstetrics and Gynecology, 110, 801-807. 

*Spong CY, Meis PJ, Thom EA, Sibai B, Dombrowski MP, Moawad AH, Hauth JC, Iams JD, 

Varner MW, Caritis SN, O’Sullivan MJ, Miodovnik M, Leveno KJ, Conway D, Wapner RJ, 

Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, & Gabbe S for the NICHD 

MFMU Network. (2005). Progesterone for prevention of recurrent preterm birth: Impact of 

gestational age at previous delivery. American Journal of Obstetrics and Gynecology, 193, 

1056-1060. 

Thom EA, & Klebanoff MA. (2005). Issues in clinical trial design: Stopping a trial early and the 

large and simple trial. American Journal of Obstetrics and Gynecology, 193, 619-625. 

*Varner MW, Leindecker S, Hibbard JU, Hauth JC, Landon M, Leveno K, Sorokin Y, Harper 

M, Caritis SN, Wapner R, Modovnik M, Sibai B, Carpenter M, Conway D, Mercer B, Thorp 

J, Peaceman A, O’Sullivan MJ, Ramin S, Malone F, & Gabbe S for the NICHD MFMU 

Network. (2005). The MFMU Cesarean Registry: Trial of labor with a twin gestation. 

American Journal of Obstetrics and Gynecology, 193, 135-140. 

Varner MW, Noble WD, Dombrowski M, Sibai B, Rouse DJ, Paul R, Caritis SN, Miodovnik M, 

Moawad A, Iams, JD, Witter F, Romero R, Leveno K, Meis P, Wapner R, Rosen M, Thurnau 

G, Van Dorsten P, O’Sullivan MJ, & Conway D for the NICHD MFMU Network. (2005). Is 

Appendices-27 
there a seasonal variation in the diagnosis of oligohydramnios? The Journal of MaternalFetal and Neonatal Medicine, 17, 173-177. 

*Varner MW, Thom E, Spong CY, Landon MB, Leveno KJ, Rouse DJ, Moawad AH, Caritis 

SN, Harper M, Wapner RJ, Sorokin RJ, Miodovnik M, Carpenter M, Peaceman A, 

O’Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, & Mercer BM for the NICHD 

MFMU Network. (2007). Trial of labor after one previous cesarean delivery for multifetal 

gestation. Obstetrics & Gynecology, 110, 814-819. 

*Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY, Peaceman A, Leveno KJ, 

Malone F, Caritis S, Mercer B, Harper M, Rouse DJ, Thorp JM, Ramin S, Carpenter MW, & 

Gabbe SG for the NICHD MFMU Network. (2007). Long-term outcomes of a randomized 

trial of repeat antenatal corticosteroids. New England Journal of Medicine, 357, 1190-1198. 

*Wapner RJ, Sorokin Y, Thom EA, Johnson F, Dudley D, Spong CY, Peaceman AM, Leveno 

KJ, Harper M, Caritis SN, Miodovnik M, Mercer BM, Thorp JM, Moawad A, O’Sullivan 

MJ, Ramin S, Carpenter MW, Rouse DJ, Sibai B, & Gabbe SG for the NICHD MFMU 

Network. (2006). Single versus weekly courses of antenatal corticosteroids: Evaluation of 

safety and efficacy. American Journal of Obstetrics & Gynecology, 195, 633-642. 

Yost NP, Owen J, Berghella V, MacPherson C, Swain M, Dildy GA, Miodovnik M, Langer O, & 

Sibai B for the NICHD MFMU Network. (2004). Second-trimester cervical sonography: 

Features other than cervical length for the prediction of spontaneous preterm birth. Obstetrics 

and Gynecology, 103, 457-462. 

Yost NP, Owen J, Berghella V, MacPherson C, Swain M, Dildy GA, Miodovnik M, Langer O, & 

Sibai B for the NICHD MFMU Network. (2004). Number and gestational age of prior 

preterm births does not modify the predictive value of a short cervix. American Journal of 

Obstetrics & Gynecology, 191, 241-246. 

Yost NP, Owen J, Berghella V, Thom E, Swain M, Dildy GA, Miodovnik M, Langer O, & Sibai 

B for the NICHD MFMU Network. (2006). The effect of coitus on recurrent preterm birth. 

Obstetrics and Gynecology, 107, 793-797. 

NEONATAL RESEARCH NETWORK (NRN) PUBLICATIONS 

*Adams-Chapman I, Hansen N, Stoll B, & Higgins R for the NICHD NRN. (2008). 

Neurodevelopmental outcome of ELBW infants with posthemorrhagic hydrocephalus 

requiring shunt insertion. Pediatrics, May;121(5), e1167-e1177. 

Ahlfors CE, Vreman HJ, Wong RJ, Bender GJ, Oh W, Morris BH, et al. (2007). Effects of 

sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound 

bilirubin in premature newborns. Clin Biochem, Feb;40(3-4), 261-267. 

*Ambalavanan N, Baibergenova A, Carlo WA, Saigal S, Schmidt B, Thorpe KE, & the Trial of 

Indomethacin Prophylaxis in Preterms (TIPP) Investigators. (2006). Early prediction of poor 

outcome in extremely low birth weight infants by classification tree analysis. J Pediatr, 

Apr;148(4), 438-444. 

Appendices-28 
Ambalavanan N, Carlo WA, Bobashev G, Mathias E, Liu B, & Poole K. (2005). Prediction of 

death for extremely low birth weight neonates. Pediatrics, Dec;116(6), 1367-1373. 

*Ambalavanan N, Carlo WA, Shankaran S, Bann CM, Emrich SL, Higgins RD, Tyson JE, 

O’Shea TM, Laptook AR, Ehrenkranz RA, Donovan EF, Walsh MC, Goldberg RN, Das A, 

& the NICHD NRN. (2006). Predicting outcomes of neonates diagnosed with hypoxemicischemic encephalopathy. Pediatrics, Nov;118(5), 2084-2093. 

Ambalavanan N, Tyson JE, Kennedy KA, Hansen N, Vohr BR, Wright LL, & Carlo WA. 

(2005). Vitamin A supplementation for extremely low birth weight infants: Outcome at 18 to 

22 months. Pediatrics, Mar;115(3), e249-e254. 

Bender GJ, Cashore WJ, & Oh W. (2007). Ontogeny of bilirubin-binding capacity and the effect 

of clinical status in premature infants born at less than 1,300 grams. Pediatrics, Nov;120(5), 

1067-1073. 

*Benjamin DK Jr., Stoll BJ, Fanaroff AA, McDonald SA, Oh W, Higgins R, Duara S, Poole K, 

Laptook A, & Goldberg R. (2006). Neonatal Candidiasis among extremely low birth weight 

infants: Risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. 

Pediatrics, Jan;117(1), 84-92. 

Blakely ML, Lally KP, McDonald S, Brown RL, Barnhart DC, Ricketts RR, Thompson WR, 

Scherer LR, Klein MD, Letton RW, Chwals WJ, Touloukian RJ, Kurkchubasche AG, 

Skinner MA, Moss RL, Hilfiker ML, & the Necrotizing Enterocolitis (NEC) Subcommittee 

of the NICHD NRN. (2005). Postoperative outcomes of extremely low birth-weight infants 

with necrotizing enterocolitis or isolated intestinal perforation: A prospective cohort study by 

the NICHD NRN. Ann Surg, Jun;241(6), 984-989; discussion 989-994. 

*Blakely ML, Tyson JE, Lally KP, McDonald S, Stoll BJ, Stevenson DK, Poole WK, Jobe AH, 

Wright LL, Higgins RD, & the NICHD NRN. (2006). Laparotomy versus peritoneal 

drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth 

weight infants: Outcomes through 18 months adjusted age. Pediatrics, Apr;117(4), e680-

e687. 

*Broitman E, Ambalavanan N, Higgins RD, Vohr BR, Das A, Bhaskar B, Murray K, Hintz SR, 

& Carlo WA for the NICHD NRN. (2007). Clinical data predict neurodevelopmental 

outcome better than head ultrasound in extremely low birth weight infants. J Pediatr, 

Nov;151(5), 500-505. 

Castro L, Yolton K, Haberman B, Roberto N, Hansen NS, Ambalavanan N, Vohr BR, & 

Donovan EF. (2004). Bias in reported neurodevelopmental outcomes among extremely low 

birth weight survivors. Pediatrics, Aug;114(2), 404-410. 

Clyman RI, Saha S, Jobe A, & Oh W. (2007). Indomethacin prophylaxis for preterm infants: The 

impact of 2 multi-center randomized controlled trials on clinical practice. J Pediatr, 

Jan;150(1), 46-50. 

Cotten CM, McDonald SA, Stoll BJ, Goldberg RN, Poole WK, & Benjamin DK for the NICHD 

NRN. (2006). The association of third-generation cephalosporin use and invasive candidiasis 

in extremely low birth-weight infants. Pediatrics, Aug;118(2), 717-722. 

Cotten CM, Oh W, McDonald S, Fanaroff AA, Carlo WA, Duara S, Stoll BJ, Laptook AR, Poole 

WK, Wright LL, & Goldberg RN. (2005). Prolonged hospital stay for extremely premature 

Appendices-29 
infants: Risk factors, center differences, and the impact of mortality on selecting a bestperforming center. J Perinatol, Oct;25(10), 650-655. 

Doyle NM, Gardner MO, Wells L, Qualls C, & Papile LA. (2005). Outcome of very low birth 

weight infants exposed to antenatal indomethacin for tocolysis. J Perinatol, May;25(5), 336-

340. 

Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage L, & Poole WK. (2006). Growth in 

the NICU influences neurodevelopmental and growth outcomes of extremely low birth 

weight infants. Pediatrics, Apr;117(4), 1253-1261. 

Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, Wrage LA, Poole K, 

& the NICHD NRN. (2005). Validation of the NIH consensus definition of 

bronchopulmonary dysplasia. Pediatrics, Dec;116(6), 1353-1360. 

Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, Bauer CR, Donovan 

EF, Korones SB, Laptook AR, Lemons JA, Oh W, Papile LA, Shankaran S, Stevenson DK, 

Tyson JE, Poole WK, & the NICHD NRN. (2007). Trends in neonatal morbidity and 

mortality for very low birthweight infants. Am J Obstet Gynecol, Feb;196(2), 147, e1-e8. 

Finer NN, Carlo WA, Duara S, Fanaroff AA, Donovan EF, Wright LL, Kandefer S, Poole WK, 

& the NICHD NRN. (2004). Delivery room continuous positive airway pressure/positive 

end-expiratory pressure in extremely low birth weight infants: A feasibility trial. Pediatrics, 

Sep;114(3), 651-657. 

Guillet R, Stoll BJ, Cotten CM, Gantz M, McDonald S, Poole WK, et al. (2006). Association of 

H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight 

infants. Pediatrics, Feb;117(2), e137-e142. 

Heller CD, O’Shea M, Yao Q, Langer J, Ehrenkranz RA, Phelps DL, Poole WK, Stoll B, Duara 

S, Oh W, Lemons J, Poindexter B, & the NICHD NRN. (2007). Human milk intake and 

retinopathy of prematurity in extremely low birth weight infants. Pediatrics, Jul;120(1), 1-9. 

*Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, Poole WK, Blakely 

ML, Wright L, Higgins R, & the NICHD NRN. (2005). Neurodevelopmental and growth 

outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics, 

Mar;115(3), 696-703. 

*Hintz SR, Kendrick DE, Vohr BR, Poole WK, & Higgins RD for the NICHD NRN. (2005). 

Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants 

of less than 25 weeks’ gestational age born in 1993-1999. Pediatrics, Jun;115(6), 1645-1651. 

*Hintz SR, Kendrick DE, Vohr BR, Poole WK, & Higgins RD for the NICHD NRN. (2006). 

Gender differences in neurodevelopmental outcomes among extremely preterm, extremely 

low birthweight infants. Acta Paediatr, Oct;95(10), 1239-1248. 

Hintz SR, Poole WK, Wright LL, Fanaroff AA, Kendrick DE, Laptook AR, Goldberg R, Duara 

S, Stoll BJ, Oh W, & the NICHD NRN. (2005). Changes in mortality and morbidities among 

infants born at less than 25 weeks during the post-surfactant era. Arch Dis Child Fetal 

Neonatal Ed, Mar;90(2), F128-F133. 

*Hintz SR, Van Meurs KP, Perritt R, Poole WK, Das A, Stevenson DK, Ehrenkranz RA, 

Lemons JA, Vohr BR, Heyne R, Childers DO, Peralta-Carcelen M, Dusick A, Johnson YR, 

Appendices-30 
Morris B, Dillard R, Vaucher Y, Steichen J, Adams-Chapman I, Konduri G, Myers GJ, de 

Ungria M, Tyson JE, Higgins RD, & the NICHD NRN. (2007). Neurodevelopmental 

outcomes of premature infants with severe respiratory failure enrolled in a randomized 

controlled trial of inhaled nitric oxide. J Pediatr, Jul;151(1), 16-22, 22, e1-e3. 

Konduri G, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singhal N, Wright LL, Van 

Meurs K, Stork E, Kirpalani H, & Peliowski A for the NRN Neonatal Inhaled Nitric Oxide 

Study Group. (2004). A randomized trial of early versus standard inhaled nitric oxide therapy 

in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics, 

Mar;113(3 Pt 1), 559-564. 

Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, Ehrenkranz RA, Singhal 

N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A, & Johnson Y for the NRN 

Neonatal Inhaled Nitric Oxide Study Group. (2007). Early inhaled nitric oxide therapy for 

term and near-term newborn infants with hypoxic respiratory failure: Neurodevelopmental 

followup. J Pediatr, Mar;150(3), 235-240, 240, e1. 

Lainwala S, Perritt R, Poole K, & Vohr B. (2007). Neurodevelopmental and growth outcomes of 

extremely low birth weight infants who are transferred from neonatal intensive care units to 

level I or II nurseries. Pediatrics, May;119(5), e1079-e1087. 

Laptook AR, O’Shea TM, Shankaran S, & Bhaskar B for the NICHD NRN. (2005). Adverse 

developmental outcomes among extremely low birth weight infants with a normal head 

ultrasound: Prevalence and antecedents. Pediatrics, Mar;115(3), 673-680. 

Laptook AR, Salhab W, & Bhaskar B. (2007). Admission temperature of low birth weight 

infants: Predictors and associated morbidities. Pediatrics, Mar;119(3), e643-e649. 

Laptook AR, Salhab W, Allen J, Saha S, & Walsh M. (2006). Pulse oximetry in very low birth 

weight infants: Can oxygen saturation be maintained in the desired range? J Perinatol, 

Jun;26(6), 337-341. 

Lee BH, Stoll BJ, McDonald SA, & Higgins RD for the NICHD NRN. (2006). Adverse neonatal 

outcomes associated with antenatal dexamethasone versus antenatal betamethasone. 

Pediatrics, May;117(5), 1503-1510. 

*Lee BH, Stoll BJ, McDonald SA, & Higgins RD for the NICHD NRN. (2008). 

Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to 

dexamethasone versus betamethasone. Pediatrics, Feb;121(2), 289-296. 

Lowe J, Woodward B, & Papile LA. (2005). Emotional regulation and its impact on 

development in extremely low birth weight infants. J Dev Behav Pediatr, Jun;26(3), 209-

213. 

Malcolm WF, Gantz M, Martin RJ, Goldstein RF, Goldberg RN, & Cotten CM for the NICHD 

NRN. (2008). Use of medications for gastroesophageal reflux in extremely low birth weight 

infants at discharge. Pediatrics, Jan;121(1), 22-27. 

Morris BH, Gard CC, & Kennedy K. (2005). Rehospitalization of extremely low birth weight 

(ELBW) infants: Are there racial/ethnic disparities? J Perinatol, Oct;25(10), 656-663. 

Oh W, Poindexter BB, Perrits R, Lemons JA, Bauer CR, Ehrenkranz RA, Papile LA, Stoll BJ, 

Poole WK, & Wright LL. (2005). Association between fluid intake and weight loss during 

Appendices-31 
the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth 

weight infants. J Pediatr, Dec;147(6), 786-790. 

Ohls R, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Sherwonit E, Delaney-Black V, Papile 

A, Simon NP, Steichen JL, & Gronsman Lee K. (2004). Neurodevelopmental outcome and 

growth at 18 to 22 months’ corrected age in extremely low birth weight infants treated with 

early erythropoietin and iron. Pediatrics, Nov;114(5), 1287-1291. 

Poindexter BB, Ehrenkranz RA, Stoll BJ, Wright LL, Poole WK, Oh W, Bauer CR, Papile L, 

Tyson JE, Carlo WA, Laptook AR, Narendran V, Stevenson DK, Fanaroff AA, Korones SB, 

Shankaran S, Finer NN, & Lemons JA. (2004). Parenteral glutamine supplementation does 

not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. 

Pediatrics, May;113(5), 1209-1215. 

Poindexter BB, Langer JC, Dusick AM, & Ehrenkranz RA. (2006). Early provision of parenteral 

amino acids in extremely low birth weight infants: Relation to growth and 

neurodevelopmental outcome. J Pediatr, Mar;148(3), 300-305. 

Shankaran S, Johnson Y, Langer JC, Vohr BR, Fanaraff AA, Wright LL, & Poole WK. (2004). 

Outcome of extremely low birth weight infants at highest risk: Gestational age ≤ 24 weeks, 

birth weight ≤ 750g and 1 minute Apgar ≤ 3. Am J Obstet Gynecol, Oct;191(4), 1084-1091. 

Shankaran S, Langer JC, Kazzi SN, Laptook AR, & Walsh M. (2006). Cumulative index of 

exposure to hypocarbia and hyperoxia as risk factors for periventricular leukomalacia in low 

birth weight infants. Pediatrics, Oct;118(4), 1654-1659. 

*Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff 

AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, 

Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH, & the NICHD NRN. (2005). 

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J 

Med, Oct 13;353(15), 1574-1584. 

Stoll BJ, Hansen N, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr BR, & Higgins RD. 

(2004). Neurodevelopmental and growth impairment among extremely low birth-weight 

infants with neonatal infection. JAMA, Nov 17;292(19), 2357-2365. 

Stoll BJ, Hansen N, Fanaroff AA, & Lemons JA. (2004). Enterobacter Sakazakii is a rare cause 

of neonatal sepsis/meningitis in VLBW infants. J Pediatr, Jun;144(6), 821-823. 

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, Lemons JA, Donovan 

EF, Stark AR, Tyson JE, Oh W, Bauer CR, Korones SB, Shankaran S, Laptook AR, 

Stevenson DK, Papile L, & Poole WK. (2004). To tap or not to tap: High likelihood of 

meningitis without sepsis among very low birth weight infants. Pediatrics, May;113(5), 

1181-1186. 

*Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. (2004). 

Neurodevelopmental and growth impairment among extremely low-birth-weight infants with 

neonatal infection. JAMA, Nov17;292(19), 2357-2365. 

*Stoll BJ, Hansen NI, Higgins RD, Fanaroff AA, Duara S, Goldberg R, Laptook A, Walsh M, 

Oh W, Hale E, & the NICHD NRN. (2005). Very low birth weight preterm infants with early 

onset neonatal sepsis: The predominance of gram-negative infections continues in the 

NICHD Neonatal Research Network, 2002-2003. Pediatr Infect Dis J, Jul;24(7), 635-639. 

Appendices-32 
*Tyson JE, Parikh N, Langer J, Green C, & Higgins RD. (2008). Intensive care for extremely 

premature newborns: Moving beyond gestational age thresholds. NEJM, 358(16), 1672-1681. 

*Van Meurs KP, Hintz SR, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, Perritt R, Das A, 

Higgins RD, & Stevenson DK. (2005). Inhaled nitric oxide in infants > 1500 g and < 34 

weeks gestation with severe respiratory failure. J Perinatol, Jun;27(6), 347-352. 

*Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, Perritt R, 

Higgins RD, Oh W, Hudak ML, Laptook AR, Shankaran S, Finer NN, Carlo WA, Kennedy 

KA, Fridriksson JH, Steinhorn RH, Sokol GM, Konduri GG, Aschner JL, Stoll BJ, D’Angio 

CT, & Stevenson DK. (2005). Inhaled nitric oxide for premature infants with severe 

respiratory failure. N Engl J Med, Jul 7;353(1), 13-22. 

Vohr BR, Msall ME, Wilson D, Wright LL, McDonald S, & Poole WK. (2005). Spectrum of 

gross motor function in extremely low birth weight children with cerebral palsy at 18 months 

of age. Pediatrics, Jul;116(1), 123-129. 

*Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC, Poole WK, & 

the NICHD NRN. (2007). Effects of human milk in the NICU on the developmental outcome 

and growth of ELBW infants at 30 months of age. Pediatrics, Oct;120(4), e953-e959. 

Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Wright LL, Langer JC, & Poole WK. 

(2006). Beneficial effects of breast milk in the NICU on the developmental outcome of 

extremely low birth weight infants at 18 months of age. Pediatrics, Jul;118(1), e115-e123. 

Vohr BR, Wright LL, Dusick AM, Perritt R, Poole WK, Delaney–Black V, Yolton K, Broyles S, 

Tyson JE, Steichen JJ, Bauer CR, Fleisher BE, Papile LA, Wilson DC, Simon NP, & Kaplan 

MD for the NICHD NRN. (2004). Center differences and outcomes of extremely low birth 

weight infants. Pediatrics, Apr;113(4), 781-789. 

Vohr BR, Wright LL, Poole WK, & McDonald S. (2005). Neurodevelopmental outcomes of 

extremely low birth weight infants < 32 weeks gestation between 1993-1998. Pediatrics, 

Sep;116(3), 635-643. 

Wadhawan R, Oh W, Perritt R, Laptook AR, Poole K, Wright LL, Fanaroff AA, Duara S, Stoll 

BJ, & Goldberg R. (2007). Association between early postnatal weight loss and death or 

BPD in small and appropriate for gestational age extremely low-birth-weight infants. J 

Perinatol, Jun;27(6), 359-364. 

Walden RV, Taylor SC, Hansen NI, Poole WK, Stoll BJ, Abuelo D, & Vohr BR for the NICHD 

NRN. (2007). Major congenital anomalies place extremely low birth weight infants at higher 

risk for poor growth and developmental outcomes. Pediatrics, Dec;120(6), e1512-e1519. 

*Walsh M, Laptook A, Kazzi SN, Engle WA, Yao Q, Rasmussen M, Buchter S, Heldt G, Rhine 

W, Higgins R, Poole K, & the NICHD NRN. (2007). A cluster-randomized trial of 

benchmarking and multimodal quality improvement to improve rates of survival free of 

bronchopulmonary dysplasia for infants with birth weights of less than 1,250 grams. 

Pediatrics, May;119(5), 876-890. 

Walsh MC, Engle W, Laptook A, Kazzi SNJ, Buchter S, Rasmussen M, et al. (2005). Oxygen 

delivery through nasal cannulae to preterm infants: Can practice be improved? Pediatrics, 

Oct;116(4), 857-861. 

Appendices-33 
Walsh MC, Morris BH, Wrage L, Vohr BR, Poole WK, Tyson JE, Wright LL, Ehrenkranz RA, 

Stoll BJ, & Fanaroff AA. (2005). Extremely low birthweight neonates with protracted 

ventilation: Mortality and 18-month neurodevelopmental outcomes. J Pediatr, Jun;146(6), 

798-804. 

Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A, Everett R, Peters N, Miller N, 

Muran G, Auten K, Newman N, Rowan G, Grisby C, Arnell K, Miller L, Ball B, & McDavid 

G. (2004). Impact of a physiologic definition on bronchopulmonary dysplasia rates. 

Pediatrics, Nov;114(5), 1305-1311. 

Walsh MC, Yao Q, Horbar JD, Carpenter JH, Lee S, Ohlsson A, the NICHD NRN, the Vermont 

Oxford Network, & the Canadian Neonatal Network. (2006). Changes in the use of postnatal 

steroids for bronchopulmonary dysplasia in three large neonatal networks. Pediatrics, 

Nov;118(5), e1328-e1335. 

MATERNAL LIFESTYLE STUDY PUBLICATIONS

*Bada H, Das A, Bauer CR, Shankaran S, Lester B, LaGasse L, Hammond J, Wright L, & 

Higgins R. (2007). Impact of prenatal cocaine exposure on child behavior problems through 

school age. Pediatrics, Feb;119(2), e348-e359. 

*Bada HS, Das A, Bauer CR, Shankaran S, Lester BM, Gard C, Wright LL, Smeriglio V, & 

LaGasse L. (2005). Low birth weight and preterm births: Etiologic fraction attributable to 

prenatal drug exposure. J Perinatol, Oct;25(10), 631-637. 

Bauer CR, Langer JC, Shankaran S, Bada HS, Lester B, Wright LL, et al. (2005). Acute neonatal 

effects of cocaine exposure during pregnancy. Archives of Pediatrics & Adolescent Medicine, 

159(9), 824-834. 

Boukydis CF, Bigsby R, & Lester BM. (2004). Clinical use of the NICU network 

neurobehavioral scale. Pediatrics, Mar;113(3 Pt 2), 679-689. 

Brunner SM, Messinger DS, & Bauer CR. (2005). Cocaine exposure and mother-toddler social 

play. Infant and Behavior, 28, 62-73. 

Das A, Gard C, Bada H, & Poole WK. (2005). Simultaneous modeling of multiple outcomes 

over time: A hierarchical modeling approach. Proceedings of the American Statistical 

Association, Section on Statistics in Epidemiology [CD-ROM], Alexandria, VA: American 

Statistical Association, pp. 3035-3044. 

Das A, Poole WK, & Bada HS. (2004). A repeated measures approach for simultaneous 

modeling of multiple neurobehavioral outcomes in newborns exposed to cocaine in utero. 

Am J Epidemiology, May 1;159(9), 891-899. 

Gard CC, Das A, Poole WK, & Bada H. (2004). Sequential estimation of adjusted attributable 

risk in a cross-sectional study: A bootstrap approach. 2004 Proceedings of the American 

Statistical Association, Biometrics Section [CD-ROM], Alexandria, VA: American Statistical 

Association. 

LaGasse LL, Neal AR, & Lester BM. (2005). Assessment of infant cry: Acoustic cry analysis 

and parental perception. Ment Retard Dev Disabil Res Rev, 11(1), 83-93. 

Appendices-34 
*LaGasse LL, Hammond J, Liu J, Lester BM, Shankaran S, Bada H, Bauer C, Higgins R, & Das 

A. (2006). Violence and delinquency, early onset drug use, and psychopathology in drug 

exposed youth at 11 years. Annals of the New York Academy of Sciences, Dec;1094, 313-318. 

Lester BM, & Tronick EZ. (2004). History and description of the NICU Network 

Neurobehavioral Scale. Pediatrics, Mar;113(3 Pt 2), 634-640. 

Lester BM, Tronick EZ, & Brazelton TB. (2004). The NICU Network Neurobehavioral Scale 

procedures. Pediatrics, Mar;113(3 Pt 2), 641-667. 

Lester BM, Tronick EZ, LaGasse L, Seifer R, Bauer CR, Shankaran S, Bada HS, Wright LL, 

Smeriglio VL, & Lu J. (2004). Summary statistics of NICU Network Neurobehavioral Scale 

scores from the Maternal Lifestyle Study: A quasi-informative sample. Pediatrics, 

Mar;113(3 Pt 2), 668-675. 

Messinger DS, Bauer CR, Das A, Seifer R, Lester BM, LaGasse LL, Wright LL, Shankaran S, 

Bada HS, Smeriglio VL, Langer JC, & Poole WK. (2004). The Maternal Lifestyles Study 

(MLS): Cognitive, motor, and behavioral outcomes of cocaine exposed and opiate exposed 

infants through three years of age. Pediatrics, Jun;113(6), 1677-1685. 

Miller-Loncar C, Lester BM, Seifer R, LaGasse LL, Bauer CR, Shankaran S, Bada HS, Wright 

LL, Smeriglio VL, Bigsby R, & Liu J. (2005). Predictors of motor development in children 

prenatally exposed to cocaine. Neurotoxicol Teratol, Mar-Apr;27(2), 213-220. 

Salisbury AL, Fallone MD, & Lester B. (2005). Neurobehavioral assessment from fetus to 

infant: The NICU Network Neurobehavioral Scale and the Fetal Neurobehavior Coding 

Scale. Ment Retard Dev Disabil Res Rev, 11(1), 14-20. 

Salisbury AL, Lester BM, Seifer R, LaGasse L, Bauer C, Shankaran S, Bada H, Wright L, Liu J, 

& Poole K. (2007). Prenatal cocaine use and maternal depression: Effects on infant 

neurobehavior. Neurotoxicol Teratol, May-Jun;29(3), 331-340. 

Seifer R, LaGasse LL, Lester B, Bauer CR, Shankaran S, Bada HS, Wright LL, Smeriglio VL, & 

Liu J. (2004). Attachment status in children prenatally exposed to cocaine and other 

substances. Child Dev, 75(3), 850-868. 

*Shankaran S, Das A, Bauer CR, Bada H, Lester B, Wright L, Higgins R, & Poole K. (2006). 

Fetal origin of childhood disease: Intrauterine growth restriction in term infants and risk for 

hypertension at 6 years of age. Arch Pediatr Adolesc Med, Sep;160(9), 977-981. 

Shankaran S, Das A, Bauer CR, Bada HS, Lester B, Wright LL, & Smeriglio V. (2004). 

Association between patterns of maternal substance use and infant birth weight, length, and 

head circumference. Pediatrics, Aug;114(2), e226-e234. 

*Shankaran S, Lester B, Das A, Bauer CR, Bada H, LaGasse L, & Higgins RD. (2007). Impact 

of maternal substance use during pregnancy on childhood outcome. Semin Fetal Neonatal 

Med, Apr;12(2), 143-150. 

*Sheinkopf SJ, LaGasse LL, Lester BM, Liu J, Seifer R, Bauer C, Shankaran S, Bada H, Higgins 

R, & Das A. (2006). Prenatal cocaine exposure, cardiorespiratory function, and resilience. 

Annals of the New York Academy of Sciences, 1094, 354-358. 

Appendices-35 
Sheinkopf SJ, LaGasse LL, Lester BM, Liu J, Seifer R, Bauer CR, Shankaran S, Bada H, & Das 

A. (2007). Vagal tone as a resilience factor in children with prenatal cocaine exposure. 

Development and Psychopathology, 19, 649-673. 

Sheinkopf SJ, Lester BM, LaGasse LL, Seifer R, Bauer CR, Shankaran S, Bada HS, Poole WK, 

& Wright LL. (2005). Interactions between maternal characteristics and neonatal behavior in 

the prediction of parenting stress and perception of infant temperament. J Pediatr Psychol, 

Jan-Feb;31(1), 27-40. 

Tronick EZ, Messinger DS, Weinberg MK, Lester BM, LaGasse LL, Seifer R, Bauer CR, 

Shankaran S, Bada H, Wright LL, Smeriglio VL, Poole WK, & Liu J. (2005). Cocaine 

exposure is associated with subtle compromises of infants’ and mothers’ social-emotional 

behavior and dyadic features of their interaction in the face-to-face still-face paradigm. Dev 

Psychol, Sep;41(5), 711-722. 

Tronick EZ, Olson K, Rosenberg R, Bohne L, Lu J, & Lester BM. (2004). Normative 

neurobehavioral performance of healthy infants on the NICU Network Neurobehavioral 

Scale. Pediatrics, Mar;113(3 Pt 2), 676-678. 

STAFF PUBLICATIONS

Bettes BA, Coleman VH, Zinberg S, Spong CY, Portnoy B, DeVoto E, & Schulkin J. (2007). 

Cesarean delivery on maternal request: Obstetrician/gynecologists’ knowledge, perception, 

and practice patterns. Obstet Gynecol, Jan;109(1), 57-66. 

Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, & Cunningham GF. (2007). 

Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of 

pregnancy. Obstet. Gynecol, May;109, 1129-1135. 

Deering SH, Patel N, Spong CY, Pezzullo JC, & Ghidini A. (2007). Fetal growth after preterm 

premature rupture of membranes (pPROM): Is it related to amniotic fluid volume? J Matern 

Fetal Neonatal Med, May;20(5), 397-400. 

Deering SH, Staff AR, Spong CY, Kabir AB, Pezzullo JC, & Ghidini A. (2005). Antenatal 

magnesium treatment and neonatal illness severity as measured by the Score for Neonatal 

Acute Physiology (SNAP). The Journal of Maternal-Fetal and Neonatal Medicine, 

Feb;17(2), 151-155. 

Endres M, Toso L, Roberson R, Park J, Abebe D, Poggi S, & Spong CY. (2005). Prevention of 

alcohol-induced developmental delays and learning abnormalities in a model of fetal alcohol 

syndrome. Am J Obstet Gynecol, 193, 1028-1034. 

Finer NN, Higgins R, Kattwinkel J, & Martin RJ. (2006). Summary proceedings from the apneaof-prematurity group. Pediatrics, Mar;117(3 Pt 2), S47-S51. 

Higgins RD. (2006). 50 years ago in The Journal of Pediatrics—Incidence of retrolental 

fibroplasias: Past and present. J Pediatr, Jun;148(6), 778. 

Higgins RD. (2005). Hypoxic ischemic encephalopathy and hypothermia: A critical look. 

Obstetrics & Gynecology, Dec;106(6), 1385-1387. 

Appendices-36 
Higgins RD. (2005). Ocular neovascularization: Genomic implications. Current Genomics, 6, 

315-318. 

Higgins RD. (2007). The vascular contribution to necrotizing enterocolitis. J Pediatr, 

Jan;150(1), 5-6. 

Hintz SR, Slovis T, Bulas D, VanMeurs KP, Perritt R, Stevenson DK, Poole WK, Das A, 

Higgins RD, & the NICHD NRN. (2007). Interobserver reliability and accuracy of cranial 

ultrasound scanning interpretation in premature infants. J Pediatr, Jun;150(6), 592-596, 

596.e1-596.e5. 

Hodor JG, Poggi SH, Spong CY, Goodwin KM, Vink JS, Pezzullo JC, & Ghidini A. (2006). 

Risk of third-trimester amniocentesis: A case-control study. Am J Perinatol, Apr;23(3), 177-

180. 

Hollowell JG, LaFranchi S, Smallridge RC, Spong CY, Haddow JE, & Boyle CA. (2005). 

Where do we go from here? Summary of working group discussions on thyroid function and 

gestational outcomes. Thyroid, 15, 72-76. 

Mercer BM, MacPherson C, Goepfert AR, Haugel-de Mouzon S, Varner MW, Iams JD, Meis PJ, 

Moawad AH, Miodovnik M, Caritis SN, VanDorsten JP, Dombrowski M, Thurnau GR, & 

Spong CY for the NICHD MFMU Network. (2006). Clinical, biologic, and genetic 

characteristics of recurrent spontaneous preterm birth. American Journal of Obstetrics and 

Gynecology, 194, 438-445. 

Poggi SH, Allen RH, Patel C, Deering SH, Pezzullo JC, Shin Y, & Spong CY. (2004). Effect of 

epidural anaesthesia on clinician-applied force during vaginal delivery. Am J Obstet Gynecol, 

191, 903-906. 

Poggi SH, Allen RH, Patel CR, Ghidini A, Pezzullo JC, & Spong CY. (2004). Randomized trial 

of McRoberts versus lithotomy positioning to decrease the force that is applied to the fetus 

during delivery. Am J Obstet Gynecol, 191, 874-878. 

Poggi SH, Park J, Toso L, Abebe D, Roberson R, Woodard JE, & Spong CY. (2005). No 

phenotype associated with established lipopolysaccharide model for cerebral palsy. Am J 

Obstet Gynecol, 192, 727-733. 

Reddy U, & Spong CY. (2006). Cesarean delivery on maternal request: Introduction. Seminars 

in Perinatology, Oct; 30(5), 233-234. 

Reddy UM, Baschat AA, Zlatnik MG, Towbin JA, Harman CR, & Weiner CP. (2005). 

Detection of viral deoxyribonucleic acid in amniotic fluid: Association with fetal 

malformation and pregnancy abnormalities. Fetal Diagn Ther, 20(3), 203-207. 

Reddy UM, Branum AM, & Klebanoff MA. (2005). Relationship of maternal body mass index 

and height to twinning. Obstetrics & Gynecology, 105(3), 593-597.

Reddy UM, Ko C-W, & Willinger M. (2006). Maternal age and risk of stillbirth throughout 

pregnancy in the United States. Am J Obstet Gynecol, 195, 764-770. 

Roberson R, Woodard JE, Toso L, Abebe D, Poggi SH, & Spong CY. (2006). Postnatal 

inflammatory rat model for cerebral palsy: Too different from humans. Am J Obstet Gynecol, 

195(4), 1038-1040. 

Appendices-37 
Signore C, Ueland PM, Troendle J, Mills JL. (2008). Choline concentrations in human maternal 

and cord blood and intelligence at 5 years of age. Am J Clin Nutr, 87, 896-902.

Spong CY, Meis PJ, Thom EA, Sibai B, Dombrowski MP, Moawad AW, Hauth JC, Iams JD, 

Varner MW, Caritis SN, O’Sullivan MJ, Miodovnik M, Leveno KJ, Conway D, Wapner RJ, 

Carpenter M, Mercer B, Ramin SM, Thorp MM, Peaceman AM, & Gabbe S. (2005). 

Progesterone for prevention of recurrent preterm birth: Impact of gestational age at prior 

delivery. Am J Obstet Gynecol, 193, 1127-1131. 

Spong CY. (2007). Prediction and prevention of recurrent spontaneous preterm birth. Obstet 

Gynecol, Aug;110(2 Pt 1), 405-415. 

Spong CY. (2006). Protection against prenatal alcohol-induced damage. PLOS Medicine, 

Apr;3(4), 474-475. 

Toso L, Endres M, Vink J, Abebe DT, Brenneman DE, & Spong CY. (2006). Learning 

enhancement with neuropeptides. American Journal of Obstetrics and Gynecology, 

Apr;194(4), 1153-1158. 

Toso L, Johnson A, Bissell S, Roberson R, Abebe D, & Spong CY. (2007). Understanding the 

mechanism of learning enhancement: NMDA and GABA receptor expression. Am J Obstet 

Gynecol, Sep;197(3), 267.e1-267.e4. 

Toso L, Poggi S, Park J, Einat H, Roberson R, Woodard J, Abebe D, & Spong CY. (2005). 

Inflammatory-mediated model of cerebral palsy with developmental sequelae. Am J Obstet 

Gynecol, 193, 933-941. 

Toso L, Poggi S, Park J, & Spong CY. (2005). NMDA subunit expression during mouse 

development altered by in utero alcohol exposure. Am J Obstet Gynecol, 193, 1534-1539. 

Toso L, Poggi SH, Roberson R, Woodard J, Park J, Abebe D, & Spong CY. (2006). Prevention 

of alcohol-induced learning deficits in fetal alcohol syndrome mediated through NMDA and 

GABA receptors. Am J Obstet Gynecol, 194, 681-686. 

Toso L, Roberson R, Abebe D, & Spong CY. (2007). Neuroprotective peptides prevent some 

alcohol-induced alteration in gamma-aminobutyric acid A-beta3, which plays a role in cleft 

lip and palate and learning in fetal alcohol syndrome. Am J Obstet Gynecol, Mar;196(3), 

259.e1-259.e5. 

Toso L, Roberson R, Woodard J, Abebe D, & Spong CY. (2006). Prenatal alcohol exposure 

alters GABA(A)alpha(5) expression: A mechanism of alcohol-induced learning dysfunction 

Am J Obstet Gynecol, Aug;195(2), 522-527. 

Vink J, Auth J, Abebe DT, Brenneman DE, & Spong CY. (2005). Novel peptides prevent 

alcohol-induced spatial learning deficits and proinflammatory cytokine release in a mouse 

model of fetal alcohol syndrome, Am J Obstet Gynecol, 193(3), 825-829. 

Vink JY, Poggi SH, Ghidini A, & Spong CY. (2006). Amniotic fluid index and birth weight: Is 

there a relationship in diabetics with poor glycemic control? Am J Obstet Gynecol, 

Sep;195(3), 848-850. 

Zhou FC, Sari Y, Powrozek TA, & Spong CY. (2004). A neuroprotective peptide antagonizes 

fetal alcohol exposure-compromised brain growth. Journal of Molecular Neuroscience, 24, 

189-199. 

Appendices-38 
AAP Task Force on SIDS. (2005). The changing concept of SIDS: Diagnostic coding shifts, 

controversies regarding the sleeping environment, and new variables to consider in reducing 

risk. Pediatrics, 116, 1245-1255. 

Ariagno RL, Van Marter LJ, Higgins R, & Raju TN. (2005). Neonatology research for the 21st

century: Executive summary of the NICHD-AAP workshop, Part II: Training Issues. 

Pediatrics, 115, 475-479. 

Facchinetti F, Reddy U, Stray-Pedersen B, Baronciani D, Requejo JH; Stillbirth International 

Group. (2008). International issues in stillbirth. J Matern Fetal Neonatal Med, 21, 425-428. 

Higgins RD, Bancalari E, Willinger M, & Raju T. (2007). Executive summary of the workshop 

on oxygen in neonatal therapies: Controversies and opportunities for research. Pediatrics, 

119, 790-796. 

Higgins RD, Delivoria-Papadopoulos M, & Raju T. (2005). Executive summary of the 

workshop on viability. Pediatrics, 115, 1392-1396. 

Higgins RD, Raju TNK, Perlman J, Azzopardi DV, Blackmon LR, Clark RH, Edwards AD, 

Ferriero DM, Gluckman PD, Gunn AJ, Jacobs SE, Eicher DJ, Jobe AH, Laptook AR, 

LeBlanc MH, Palmer C, Shankaran S, Soll RF, Stark AR, Thoresen M, & Wyatt J for the 

NICHD Hypothermia Workshop Speakers and Discussants. (2006). Hypothermia and 

perinatal asphyxia: Executive summary of the National Institute of Child Health and Human 

Development workshop. J Pediatr, 148, 170-175. 

Ilekis JV, Reddy UM, & Roberts JM. (2007). Preeclampsia—a pressing problem: An executive 

summary of an NICHD workshop. Reprod Sci, 14, 508-523. 

Raju TN, Ariagno RL, Higgins R, & VanMarter LJ. (2005). Research in neonatology for the 

21st century: Executive summary of the NICHD-AAP workshop, Part I: Academic Issues. 

Pediatrics, 115, 468-474. 

Raju TN, Higgins RD, Stark AR, & Leveno KJ. (2006). Optimizing care and outcome for latepreterm (near-term) infants: A summary of the workshop sponsored by the NICHD. 

Pediatrics, Sep;118(3), 1207-1214. 

Reddy UM, & Mennuti MT. (2006). Incorporating first-trimester Down syndrome studies into 

prenatal screening: Executive summary of the NICHD workshop. Obstet Gynecol, 107(1), 

167-173. 

Reddy UM, & and Wapner RJ. (2007). Comparison of first and second trimester aneuploidy risk 

assessment. Clin Obstet Gynecol, 50(2), 442-453. 

Reddy UM, Wapner RJ, Rebar R, & Tasca R. (2007). Infertility, assisted reproductive 

technology, and adverse pregnancy outcomes: Executive summary of a NICHD workshop. 

Obstet Gynecol, 109, 967-977. 

Reddy UM. (2007). Prediction and prevention of recurrent stillbirth. Obstet Gynecol, 

Nov;110(5), 1151-1164. 

Reddy UM. (2007). The evolving prenatal screening scene. Obstet Gynecol, 110(1), 2-4. 

Reddy UM, Filly RA, & Copel JA. (2008). Prenatal imaging: Ultrasonography and magnetic 

resonance imaging. Obstet Gynecol, 112, 145-157. 

Appendices-39 
Silver RM, Varner MW, Reddy U, Goldenberg R, Pinar H, Conway D, Bukowski R, Carpenter 

M, Hogue C, Willinger M, Dudley D, Saade G, & Stoll B. (2007). Work-up of stillbirth: 

Review of the evidence. Obstet Gynecol, 196, 433-444. 

Signore C, Klebanoff M. (2008). Neonatal morbidity and mortality after elective cesarean 

delivery. Clin Perinatol, 35, 361-371. 

Willinger M. (2004). Broadening our concept of the potential harm from maternal alcohol 

exposure. Addiction Biology, 9, 187. 

Appendices-40 
APPENDIX F: PPB STAFF AWARDS, FISCAL YEAR 2004 

THROUGH FISCAL YEAR 2008 

• Plain Language Award, NIH, 2004, Willinger 

• Director’s Award, NIH, 2004, Spong 

• Society of Maternal Fetal Medicine Research Award, 2004, Spong 

• NIH Award of Merit, 2005, Ilekis 

• Director’s Award, NIH, 2005, Willinger 

• Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease 

Registry, Honor Award for Silo Busters: Collaborative Success, 2005, Spong 

• Donald Eitzman Lecturer, University of Florida, 2005, Raju 

• NIH Award of Merit, 2005, Reddy 

• NIH Award of Merit, 2005, Higgins 

• NIH Award of Merit, 2005, Raju 

• Most Distinguished Physician Award, American Association of Physicians of Indian Origin, 

2006, Raju 

• NIH Award of Merit, 2006, Willinger 

• NIH Award of Merit, 2006, Raju 

• NIH Award of Merit, 2006, Reddy 

• NIH Award of Merit, 2006, Higgins 

• NIH Award of Merit, 2006, Pagliaro 

• Best Practices Network from the NIH Roadmap: Initiative Inventory and Evaluation of 

Clinical Research Networks, 2006, MFMU Network Award, Pagliaro 

• Thomas Cone Jr. Lecturer, AAP National Convention, 2007, Raju 

• Society for Maternal Fetal Medicine Achievement Award, 2008, Spong 

Appendices-41 
Appendices-42 

APPENDIX G: EXPERT PANEL MEMBERS 

Michele Walsh, M.D. 

Medical Director, Neonatal Intensive Care 

Unit (NICU) 

Rainbow Babies & Children’s Hospital, 

Case Medical Center 

Professor, Department of Pediatrics, 

Case Western Reserve University 

Cleveland, Ohio 

Yoel Sadovsky, M.D. 

Scientific Director 

Magee-Women’s Research Institute 

Pittsburgh, Pennsylvania 

Mark Phillippe, M.D.* 

Professor & Chairman 

Department of Obstetrics & Gynecology 

University of Vermont College of Medicine 

Burlington, Vermont 

George R. Saade, M.D. 

University of Texas Medical Branch 

Department of Obstetrics & Gynecology 

Galveston, Texas 

Sherin Devaskar, M.D.* 

Professor 

Department of Pediatrics 

David Geffen School of Medicine 

University of California, Los Angeles 

Los Angeles, California 

Michael Myers 

Columbia University 

Co-Principal Investigator 

New York, New York 

Hal Lawrence, M.D. 

Vice President, Practice Activities 

American College of Obstetricians and 

Gynecologists 

Washington, D.C. 

Alan Fleishman, M.D. 

Senior Vice President and Medical Director 

March of Dimes 

White Plains, New York 

Diana W. Bianchi, M.D. 

Natalie V. Zucker Professor of Pediatrics, 

Obstetrics & Gynecology 

Tufts University School of Medicine 

Vice-Chair for Research 

Department of Pediatrics 

Floating Hospital for Children and 

Tufts-New England Medical Center 

Boston, Massachusetts 

Kjersti Aagard Tillery, M.D. 

Assistant Professor 

Maternal-Fetal Medicine 

Obstetrics & Gynecology, 

Baylor College of Medicine 

Baylor Obstetrics and Gynecology 

Houston, Texas 

* Denotes NACHHD Council Member 
Appendices-43