Contributions of the NICHD Neonatal Research Network’s Generic Database to Documenting and Advancing the Outcomes of Extremely Preterm Infants

Abstract

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) maintains a database of extremely preterm infants known as the Generic Database (GDB). Begun in 1987, this database now includes more than 91,000 infants, most of whom are extremely preterm (<29 weeks gestation). The GDB has been a backbone of the NRN, providing high quality, prospectively collected data to study the changing epidemiology of extreme prematurity and its outcomes over time. In addition, GDB data have been used to generate hypotheses for prospective studies and to develop new clinical trials by providing information about the numbers and characteristics of available subjects and the expected event rates for conditions and complications to be studied. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, many of which have had a significant impact on the field of neonatology.

Introduction

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) was established in 1986 to conduct research to improve the health of preterm and critically ill newborn infants. The intent of the Network was to have centers work collaboratively on the design and implementation of clinical studies that would have an impact on the care and outcome of high-risk newborns. The NRN consists of a data coordinating center (DCC) and a group of academic medical centers (clinical centers), each with one or more neonatal intensive care units (NICUs). The DCC and the clinical centers are selected every 5 years through a competitive NIH peer-reviewed application process. The number of clinical centers has varied from 8–18 over the years (Table 1), with 1–7 NICUs in each center. The first data coordinating center was the George Washington University Biostatistics Center; RTI International has been the DCC since 1998.

Table 1.

Neonatal Research Network clinical centers by funding cycle

1986–1991 (8 centers) University of Alabama University of Vermont Case Western Reserve University University of Texas-Dallas Wayne State University Dartmouth University (Vermont subsite) University of Tennessee University of Miami	1991–1996 (12 centers) Case Western Reserve University University of Texas-Dallas Wayne State University University of Tennessee University of Miami Emory University University of New Mexico University of Cincinnati Indiana University Yale University Brown University Stanford University	1996–2001 (15 centers) Case Western Reserve University University of Texas-Dallas Wayne State University University of Tennessee University of Miami Emory University University of New Mexico University of Cincinnati Indiana University Yale University Brown University Stanford University University of Alabama Harvard University (1996–1998) University of Texas-Houston (joined 7/98)
2001–2006 (16 centers) Case Western Reserve University University of Texas-Dallas Wayne State University University of Miami Emory University University of Cincinnati Indiana University Yale University Brown University Stanford University University of Alabama University of Texas-Houston Duke University Wake Forest University University of Rochester University of California-San Diego	2006–2011 (16 centers) Case Western Reserve University University of Texas-Dallas Wayne State University Emory University University of Cincinnati Indiana University Yale University Brown University Stanford University University of Alabama University of Texas-Houston Duke University Tufts University University of Iowa University of Utah University of New Mexico	2011–2016 (18 centers) Case Western Reserve University University of Texas-Dallas Wayne State University Emory University University of Cincinnati Indiana University Brown University Stanford University University of Alabama University of Texas-Houston Duke University University of Iowa University of New Mexico University of Pennsylvania University of Rochester University of California-Los Angeles Ohio State University University of Missouri-Kansas City
2016–2023 (15 centers) Case Western Reserve University University of Texas-Dallas Emory University University of Cincinnati Brown University Stanford University University of Alabama University of Texas-Houston Duke University University of Iowa University of Utah University of New Mexico University of Pennsylvania University of Rochester Ohio State University

Since 1987, the NRN has maintained a registry of extremely preterm infants, known as the Generic Database (GDB). The GDB was designed to monitor trends in antenatal and postnatal care, in-hospital morbidities, and mortality of very low birth weight preterm infants at NRN centers. Trained research coordinators collect the data prospectively in a uniform manner. The GDB now includes more than 91,000 infants. The enrollment criteria have changed over the years based on birth weight and/or gestational age (Table 2). The database has always included extremely low birth weight (≤1000 g) infants who are nearly all extremely preterm (defined in this network as <29 weeks gestation). The current enrollment criteria are birth weight 401–1000 grams inclusive and/or gestational age 20 0/7 through 28 6/7 weeks. Preterm infants enrolled in Network trials or observational studies that would not otherwise be eligible based on gestational age or birth weight are also eligible for enrollment in the GDB.

Table 2.

Enrollment criteria for the Generic Database.

1987–1994	Birth weight 501–1500 grams inborn or outborn and admitted within 14 days
1995–2007	Birth weight 401–1500 grams inborn or outborn and admitted within 14 days
2008 to 2019	Birth weight 401–1000 grams and/or gestational age 22 through 28 weeks, inborn only; or enrollment in a Network trial or observational study that may include preterm infants not otherwise eligible based on gestational age or birth weight
2020 to present	Birth weight 401–1000 grams and/or gestational age 20 through 28 weeks, inborn only; or enrollment in a Network trial or observational study that may include preterm infants not otherwise eligible based on gestational age or birth weight

The current GDB enrollment is approximately 2,000 infants per year. Although not population based, the large number of mothers and infants at NRN centers reflect racial, ethnic, and geographic diversity. The data provide a window into current care and outcomes at tertiary academic centers in the United States and changes over time. The data coordinating center, RTI International, produces annual summaries with key data by center. Because both practice and outcomes vary among centers, these reports provide centers with a useful tool for benchmarking their outcomes and identifying targets for quality improvement efforts. The reports have stimulated ideas for research projects investigating associations between practice and outcome variations that have informed care, such as with antibiotic stewardship.

The GDB is registered with ClinicalTrials.gov (NCT00063063) and approved by the institutional review boards of all participating institutions. Most institutional review boards have granted waivers of consent for collection of deidentified data from the infant’s hospital course, although several require written or verbal parental consent.

Generic Database Publications

Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, representing approximately half of all NRN publications. If we include the additional articles resulting from clinical trials that included data from the GDB, 361 of 437 (82.6%) of papers published from the NRN through early February 2022 relied on the GDB. These publications have had a significant impact on the field of neonatology. Every few years, NRN investigators have published summary articles on the changing epidemiology of extreme prematurity and its complications.^1–9 The first six GDB summary papers reported outcomes by birth weight.^1–6 Since 2010, outcomes have been reported by gestational age.^7–9

The most recent paper in this series was the first to include not only survival to hospital discharge and in-hospital morbidities but also 2-year neurodevelopmental and health outcomes.⁹ The key findings of this most recent overview paper were that survival to discharge has continued to increase and was 78.3% for infants of gestational age 22–28 weeks who were born 2013–2018. The biggest increase in survival was seen at 22 weeks gestation, where the survival rate increased to 10.9% of liveborn infants from 6.6% in 2008–2012. The survival rate for actively treated 22-week infants was 30.0%. The rates of necrotizing enterocolitis, severe intracranial hemorrhage, and retinopathy of prematurity were lower in 2013–2018 compared to 2008–2012, but the rate of bronchopulmonary dysplasia was higher. By 2-year follow-up assessment (completed only for infants <27 weeks gestation), 8.4% of infants had moderate or severe cerebral palsy, 1.5% were blind in both eyes, 2.5% required hearing aids or cochlear implants, 15.4% required mobility aids or other supportive devices, 11.5% required at least some tube feeding, 5.3% received oxygen, 1.7% required a ventilator or continuous positive airway pressure, and 49.9% had required rehospitalization. Of those with complete neurodevelopmental assessments, 48.7% had no or only mild impairment, 29.3% had moderate impairment, and 21.2% had severe impairment.

Other papers based on GDB data have covered a wide range of topics, including delivery room management, neonatal nutrition, neonatal infections, and neonatal lung disease. Collectively, these overview and topic-specific papers have influenced clinical practice and the practice recommendations of professional organizations, thus having an impact on the field of neonatology. In addition, GDB data are often used to generate hypotheses or calculate sample sizes for prospective studies.

The NICHD Extremely Preterm Birth Outcomes Tool (https://www.nichd.nih.gov/research/supported/EPBO) was developed using GDB data. The tool allows estimation of the survival probability of extremely preterm infants from five factors available at birth: infant sex, birth weight, gestational age, plurality, and exposure to antenatal corticosteroids given for fetal maturation. This open-source tool is accessible and widely used by professionals and the public to estimate potential outcomes for extremely preterm infants and also to help with counseling parents.^18,26 This website is accessed approximately 30,000 times annually.

As another example of impact, NRN publications based on GDB data have contributed to practice changes and guideline development. For example, survival data from the GDB prompted the American College of Obstetricians and Gynecologists to recommend in a new practice advisory that antenatal corticosteroids may be considered at 22 0/7 weeks to 22 6/7 weeks of gestation if neonatal resuscitation is planned and after appropriate counseling (https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2021/09/use-of-antenatal-corticosteroids-at-22-weeks-of-gestation).^27,28

Of the 20 most highly cited NRN publications, 19 included data from the GDB, and 19 of the NRN’s papers (18 using GDB data) have been cited more than 500 times by other publications (Table 3).^{5–8,10–25} Many of the NRN’s publications that use GDB data are in high impact journals, such as the New England Journal of Medicine^{10,16,18,19,22,28,30–37} and JAMA.^{8,9,12,27,38,39} Many GDB-based publications have been written by or with the participation and authorship of trainees and junior faculty members, thereby helping to advance their careers during early stages.

Table 3.

Most highly cited Neonatal Research Network publications.

Citations*	First Author	Title	Journal and Year	Reference Number	Used GDB Data?
2004	Shankaran	Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy	N Engl J Med 2005	10	no
1746	Stoll	Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network	Pediatrics 2010	7	yes
1639	Stoll	Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network	Pediatrics 2002	11	yes
1314	Stoll	Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012	JAMA 2015	8	yes
1099	Stoll	Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection	JAMA 2004	12	yes
1049	Lemons	Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network	Pediatrics 2001	5	yes
946	Vohr	Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994	Pediatrics 2000	13	yes
908	Ehrenkranz	Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants	Pediatrics 2006	14	yes
896	Fanaroff	Trends in neonatal morbidity and mortality for very low birthweight infants	Am J Obstet Gynecol 2007	6	yes
829	Ehrenkranz	Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia	Pediatrics 2005	15	yes
778	Finer	Early CPAP versus surfactant in extremely preterm infants	N Engl J Med 2010	16	yes
738	Stoll	Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network	J Pediatr 1996	17	yes
694	Tyson	Intensive care for extreme prematurity – moving beyond gestational age	N Engl J Med 2008	18	yes
687	Carlo	Target ranges of oxygen saturation in extremely preterm infants	N Engl J Med 2010	19	yes
687	Stoll	Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues	Pediatrics 2011	20	yes
665	Ehrenkranz	Longitudinal growth of hospitalized very low birth weight infants	Pediatrics 1999	21	yes
632	Stoll	Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants	N Engl J Med 2002	22	yes
590	Cotten	Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants	Pediatrics 2009	23	yes
517	Hintz	Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis	Pediatrics 2005	24	yes
465	Benjamin	Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months	Pediatrics 2006	25	yes

^*Citations from Scopus on 04/12/22.

This brief overview has focused on publications that were based primarily on data from the GDB. The related NRN follow-up study, reporting neurodevelopmental and health outcomes at 2 years for infants born before 27 weeks gestational age, is closely linked to the GDB and relies on GDB data. The follow-up study is one of the NRN’s greatest strengths, as no other US neonatal network provides such high-quality systematic follow-up of its extremely preterm infants. The NRN’s publications reporting follow-up outcomes also rely on data from the GDB about the infant’s hospital course. The neurodevelopmental follow-up component of the NRN is the subject of another article in this issue of Seminars in Perinatology.

Generic Database Data Use to Develop Clinical Trials

The GDB has provided baseline data needed in the development of dozens of clinical trials involving preterm infants (Table 4).^{16,19,29–38,40–47} Many of the 27 trials shown in Table 4 had ancillary studies that were also informed by data from the GDB. The GDB provides information about the number of available subjects for trials and the expected event rates for conditions to be studied.

Table 4.

Clinical trials designed using data from the Generic Database.

First Author	Title	Journal and Year	Reference Number
Horbar	A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. National Institute of Child Health and Human Development Neonatal Research Network	J Pediatr 1993	40
Fanaroff	A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network	N Engl J Med 1994	29
Shankaran	The effect of antenatal phenobarbital therapy on neonatal intracranial hemorrhage in preterm infants	N Engl J Med 1997	30
Papile	A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants	N Engl J Med 1998	31
Tyson	Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network	N Engl J Med 1999	32
Phelps	Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes	Pediatrics 2000	41
Stark	Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network	N Engl J Med 2001	33
Ohls	Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial	Pediatrics 2001	42
Poindexter	Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants	Pediatrics 2004	43
Van Meurs	Inhaled nitric oxide for premature infants with severe respiratory failure	N Engl J Med 2005	34
Walsh	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 1250 grams	Pediatrics 2007	44
Morris	Aggressive vs. conservative phototherapy for infants with extremely low birth weight	N Engl J Med 2008	35
Carlo	Target ranges of oxygen saturation in extremely preterm infants	N Engl J Med 2010	19
Finer	Early CPAP versus surfactant in extremely preterm infants	N Engl J Med 2010	16
Oh	Effects of delayed cord clamping in very-low-birth-weight infants	J Perinatol 2011	45
Bell	Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth	Pediatrics 2013	46
Phelps	Effects of Myo-inositol on type 1 retinopathy of prematurity among preterm infants <28 weeks’ gestational age: a randomized clinical trial	JAMA 2018	38
Kirpalani	Higher or lower hemoglobin transfusion thresholds for preterm infants	N Engl J Med 2020	36
Blakely	Initial laparotomy versus peritoneal drainage in extremely low birthweight infants with surgical necrotizing enterocolitis or isolated intestinal perforation: a multicenter randomized clinical trial	Ann Surg 2021	47
Watterberg	Hydrocortisone to improve survival without bronchopulmonary dysplasia	N Engl J Med 2022	37
DeMauro	Early school age follow-up of the NRN Hydrocortisone for BPD Trial	NCT01353313	*
Colaizy	Effects of donor milk vs formula on neurocognitive outcome	NCT01534481	*
Conrad & DeMauro	Transfusion of Prematures Trial early school age follow-up (TOP 5)	NCT01702805	*
Ohls	Darbepoetin trial to improve red cell mass and neuroprotection in preterm infants	NCT03169881	*
Laughon	Management of the patent ductus arteriosus in premature infants trial (PDA Trial)	NCT03456336	*
Tyson	Cycled phototherapy: a safer effective method to control the serum bilirubin of extremely premature infants?	NCT03927833	*
Ambalavanan	Randomized controlled trial of budesonide + surfactant versus surfactant alone in extremely preterm infants	NCT04545866	*

^*Trial in progress

GDB data have also been used to inform the Data and Safety Monitoring Committees (DSMCs) for NRN clinical trials. Before initiation of a trial in the extremely preterm population, lists of potential adverse events and event rates for common complications, such as death, intracranial hemorrhage, and sepsis, are generated for the eligible population for the individual trial. This provides a baseline rate of complications to inform DSMC reviews, especially if there is divergence between the treatment and control groups early in a clinical trial. Further, the data can be examined by gestational age subgroup (e.g., 26 weeks and above or 25 weeks and lower). This information can be valuable in a high-risk population where significant morbidity and mortality can occur.

The GDB also provides a rich data source to compare infants enrolled with those eligible but not enrolled in clinical trials. Such analyses allow assessment of generalizability of the trials.^39,48,49

Generic Database Ancillary Studies

The NRN has expanded the GDB format to other patient populations, resulting in related registry studies.

Two comprehensive studies of early-onset sepsis (EOS) among infants of all gestational ages with birth weights above 400 grams born at NRN centers (EOS I, 2006–2009, and EOS II, 2015–2017) expanded surveillance for EOS that began with preterm infants enrolled in the GDB.^20,50 Collectively, these surveillance studies, conducted in partnership with the CDC, provided data on the changing epidemiology of EOS.

The Moderate Preterm Registry enrolled 7,057 infants with gestational ages of 29 through 33 weeks in 2012 and 2013 and examined their rates of mortality and morbidity.^51,52 The Moderate Preterm Registry stimulated several published analyses of data from the registry,^53–58 a completed clinical trial (Weaning of Moderately Preterm Infants from the Incubator to the Crib: a Randomized Clinical Trial),⁵⁹ and another clinical trial that is still in progress (Moderately Preterm Infants with Caffeine at Home for Apnea Trial; NCT03340727).

The All-Birth Cohort Study is a registry of intrapartum stillbirths that occurred between 2017 and 2022 at gestational ages of 20 through 28 weeks, the same gestational age range as the GDB. The purpose of the All-Birth Cohort Study is to examine the prevalence of intrapartum stillbirth and its associated factors by gestational age week at NRN sites.

Conclusions

The Neonatal Research Network’s Generic Database (GDB) has collected data on extremely preterm infants since 1987 and now includes more than 91,000 infants. The GDB has been a valuable resource for studying the changing epidemiology of extreme prematurity and its complications and for generating hypotheses for prospective studies. GDB data have been used to help develop 27 clinical trials. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals. Of the 20 most highly cited NRN publications, 19 included data from the GDB and 18 of these have been cited more than 500 times. The NRN’s Generic Database is a unique source of epidemiologic data that serves multiple valuable purposes for the benefit of the scientific community and the lay public.

Abbreviations

DCC

Data coordinating center

DSMC

Data and Safety Monitoring Committee

EOS

Early-onset sepsis

GDB

Generic Database

NICU

Neonatal intensive care unit

NRN

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network