Formed in 1986, the NICHD Neonatal Research Network (NRN) is a collaborative network of neonatal intensive care units across the United States. The NRN comprises 18 clinical centers and a data coordinating center. Focused on newborns, particularly extremely low birth weight (ELBW) infants, the NRN aims “to facilitate the advancement of neonatal care by establishing a network of academic centers that, by rigorous patient evaluation using common protocols, can study the required numbers of patients and can provide answers more rapidly than individual centers acting alone (RFA HD10-003).” To fulfill this mission, the NRN has completed or is implementing 18 observational studies and 34 interventional trials (details of which are available at www.clinicaltrials.gov and on the NRN Web site at neonatal.rti.org). As of March 2012, ongoing clinical trials and observational studies focus on several topic areas that are discussed below.
- Preterm birth complications. According to Hostetter (Hostetter, M. K. . What we don’t see. New England Journal of Medicine, 366, 1328–34. PMID: 22475596), in 2008, 12 percent of neonatal deaths worldwide were caused by complications from preterm birth. NRN studies in this area include:
- Overall preterm birth complications and outcomes
- Generic Database of Very Low Birth Weight Infants (GDB). The GDB is a registry of very low birth weight infants born alive in NRN centers. Centers collect data on mothers and their infants, the therapies they received, and the infants’ outcomes at discharge. These data are analyzed to find associations and trends in baseline data, treatments, and infant outcomes and to develop future NRN trials. The NRN has registered more than 70,000 infants in this database since its inception. These data also form the basis of the NRN’s Web-based outcome tool, which gives physicians and parents predictive estimates of infant mortality and morbidity using five key factors: gestational age, birth weight, sex, singleton/multiple birth, and whether the mother received corticosteroids before delivery (http://www.nichd.nih.gov/about/org/der/branches/ppb/epbo/).
- Moderate Preterm Registry. In March 2012, the NRN began collecting similar baseline data on infants born between 29 and 33 weeks’ gestational age to estimate the frequency of maternal and perinatal events, morbidities, and hospital outcomes of moderate preterm infants.
- Follow-Up Study of High Risk Infants. Begun in 1998, the NRN’s Follow-Up Study is a cohort of surviving ELBW infants who participate in neurodevelopmental, neurosensory, and functional assessments at 18 to 22 months’ corrected age/24-month assessment (after 2012) to identify maternal and neonatal risk and protective factors for neurodevelopmental outcome. To date, the NRN has followed more than 12,000 children.
- Bronchopulmonary dysplasia (BPD), also called chronic lung disease, is a serious respiratory condition that affects premature infants. These babies generally have inflammation or scarring of the lungs and must be on some form of oxygen therapy via nasal prongs, a mask, or a breathing tube.
- Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT). This trial, co-funded by the National Heart, Lung, and Blood Institute, found that higher oxygen levels improved preterm infants’ survival but increased the risk of retinopathy of prematurity (SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo, W. A., Finer, N. N., Walsh, M. C., Rich, W., Gantz, M. G., . . . Higgins, R. D. . Target ranges of oxygen saturation in extremely preterm infants. New England Journal of Medicine, 362, 1959–1969. PMID: 20472937). It also found that continuous positive airway pressure (CPAP) was as effective as the traditional ventilator/surfactant therapy in treating BPD in these infants, but CPAP may result in fewer complications (SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer, N. N., Carlo, W. A., Walsh, M. C., Rich, W., Gantz, M.G., . . . Higgins, R. D. . Early CPAP versus surfactant in extremely preterm infants. New England Journal of Medicine, 362, 1970–9. PMID: 20472939). Follow-up results at 18 to 22 months’ corrected age showed no significant difference in death or neurodevelopmental impairment between infants who received CPAP and those who received surfactant/intubation, and no difference between those who received lower and higher oxygen levels (manuscript in press). Infants recruited into a neuroimaging secondary study examining early head ultrasound and MRI findings compared with neurodevelopmental outcomes at 18 to 22 months are currently being followed up at between 6 and 7 years of age to see how well the initial MRIs predict outcomes at school age.
- Hydrocortisone for Extubation. This study is testing the safety and efficacy of a 10-day course of hydrocortisone for infants less than 30 weeks’ gestational age who are intubated with breathing tubes at 14 to 28 days of life. Infants are randomized to receive either hydrocortisone or a saline placebo. This study will determine whether hydrocortisone improves infants’ survival without moderate or severe BPD and without moderate or severe neurodevelopmental impairment at 24 months’ corrected age.
- Do Antenatal Steroids Affect Maturation of the Amplitude Integrated Electroencephalogram (aEEG) in Late Preterm Infants? The NICHD Maternal-Fetal Medicine Units (MFMU) Network’s Antenatal Late Preterm Steroid (ALPS) study is a randomized trial to determine whether corticosteroids given to mothers before birth decrease the need for respiratory support among their late preterm infants. The NRN is working with the MFMU Network to enroll infants from the ALPS trial into a secondary study to see whether infants whose mothers received antenatal corticosteroids show aEEG patterns consistent with increased maturity (e.g., more periods of quiet sleep) compared to those whose mothers received a placebo.
- Necrotizing enterocolitis (NEC) is a condition in which the intestines lack oxygen or blood flow. NEC occurs in 5 percent to 15 percent of ELBW infants, and isolated intestinal perforation (IP), in which a hole develops in the intestines leaking fluid into the abdominal cavity, affects an estimated 4 percent of these infants. Outcome for infants with NEC or IP is poor: 49 percent die, and half of the surviving infants are impaired.
- Necrotizing Enterocolitis Surgery Trial (NEST). This trial is testing the hypothesis that treatment with an initial laparotomy (an extensive surgery that removes the damaged intestines), rather than a less-invasive initial drainage, will increase survival without neurodevelopmental impairment at 18 to 22 months’ adjusted age. Infants are randomized to receive one of the initial surgeries; infants not recruited into the randomized trial may be included in a parallel observational cohort.
- Anemia. Virtually all ELBW infants become anemic in early life, and approximately 90 percent receive one or more blood transfusions for a variety of reasons.
- Transfusion of Prematures (TOP). Different physicians decide to start transfusions at different hemoglobin thresholds. This NRN trial randomizes infants with birth weight under 1,000 grams and less than 29 weeks’ gestational age to receive red blood cell transfusions at either a higher (liberal transfusion) or lower (restrictive transfusion) hemoglobin threshold to see whether maintaining a higher hemoglobin level will improve survival and neurodevelopmental outcomes at 24 months of age.
- Birth asphyxia. Nine percent of neonatal deaths worldwide in 2008 were caused by birth asphyxia (Hostetter 2012). Hypoxic-ischemic encephalopathy (HIE) is a rare but life-threatening condition characterized by brain injury due to a lack of oxygen at or shortly after birth. An estimated 50 percent to 75 percent of infants with severe HIE die, and 55 percent of these deaths occur in the first month. Up to 80 percent of survivors develop significant long-term disabilities, such as intellectual impairment, epilepsy, and cerebral palsy. NRN studies in this area include:
- Whole-Body Hypothermia Trial. The NRN conducted pioneering research on hypothermia as treatment for HIE, finding that in infants with moderate or severe HIE, whole-body hypothermia reduces the risk of death or disability among children between 18 and 22 months’ corrected age (Shankaran, S., Laptook, A. R., Ehrenkranz, R. A., Tyson, J. E., McDonald, S. A., Donovan, E. F., . . . National Institute of Child Health and Human Development Neonatal Research Network. . Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. New England Journal of Medicine, 353, 1574–84. PMID: 16221780). Surviving children were recently re-examined at school age; the study found that those who received hypothermia were more likely to survive to 6 or 7 years of age and were no more likely than the routine care group to experience a physical or cognitive impairment (Shankaran, S., Pappas, A., McDonald, S. A., Vohr, B. R., Hintz, S. R., Yolton, K., . . . Eunice Kennedy Shriver NICHD Neonatal Research Network. . Childhood outcomes after hypothermia for neonatal encephalopathy. New England Journal of Medicine, 366, 2085–92. PMID: 22646631).
- Late Hypothermia for Hypoxic-Ischemic Encephalopathy. Some infants with birth asphyxia do not reach hospitals or do not exhibit symptoms of HIE until after 6 hours of age. This randomized trial is testing whether whole-body hypothermia initiated between 6 and 24 hours of age and continued for 96 hours will benefit infants with HIE, reducing death or disability at 18 to 22 months of age.
- Optimizing Cooling Strategies at <6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy (HIE). The Optimizing Cooling trial is examining ways to fine-tune the whole-body hypothermia treatment. Infants are randomized to receive hypothermia for either 72 hours or 120 hours and cooled to either 33.5°C or 32.0°C to see which options may improve the chance of survival and neurodevelopmental outcomes at 18 to 22 months’ corrected age.
- Sepsis. Six percent of neonatal deaths worldwide in 2008 were caused by sepsis (Hostetter 2012). NRN studies in this area include:
- Clinical Presentation of Neonatal Sepsis Among Neonates Born to Mothers with Chorioamnionitis. This study, co-funded by the Centers for Disease Control and Prevention, is a retrospective review of infants in the NRN Early-Onset Sepsis study, which found that the pathogens most frequently associated with early onset sepsis were group B streptococci and Escherichia coli. This review will look at how many of the babies born to mothers with chorioamnionitis were asymptomatic at birth but later developed signs or symptoms of early-onset neonatal group B streptococcal (GBS) disease or non-GBS disease.
- Congenital anomalies. Three percent of neonatal deaths worldwide in 2008 were caused by congenital anomalies (Hostetter 2012). NRN studies include:
- Anonymized Database for Studies of Genomic Impact on Morbidity and Mortality Among High-Risk Infants. Serum samples and baseline data were collected from 934 early preterm infants. These samples are currently undergoing DNA analysis; resulting data will be analyzed looking for genetic associations with a variety of neonatal conditions.
- Survival and Morbidity Outcomes of Very Low Birth Weight Infants with Trisomy 18 and Trisomy 13. The NRN is collecting data on infants born with trisomy 13 and trisomy 18, rare genetic conditions in which infants have additional copies of chromosomes 13 or 18. Trisomy 13 and trisomy 18 result in life-threatening conditions—Patau syndrome and Edwards syndrome, respectively. The NRN is using its GDB to examine delivery room interventions and mortality and morbidity rates for early preterm infants in the network born with these anomalies.
- Reducing neonatal morbidities. In addition to reducing neonatal mortality, the NRN is interested in methods to reduce or ameliorate resulting neonatal morbidities:
- Neurodevelopmental Effects of Donor Human Milk vs. Preterm Formula in ELBW infants (MILK). Strong preliminary evidence suggests that maternal breast milk confers multiple health benefits to ELBW infants, including up to an additional 8 points in IQ over non-breastfed counterparts. In addition, rates of sepsis and NEC are lower in these infants, and they experience shorter hospital stays and fewer re-hospitalizations in the first year of life. The MILK trial is testing whether fortified donor human milk versus preterm formula will improve neurodevelopmental and other health outcomes for ELBW infants receiving no or minimal maternal milk at 24 months’ corrected age.
- Inositol for Reducing Retinopathy of Prematurity. Retinopathy of prematurity (ROP) is an abnormal growth of the blood vessels in the eye that occurs primarily in very premature infants when these blood vessels, sensitive to extreme oxygen levels, must finish developing outside the protective environment of the uterus. ROP is a leading cause of blindness and other vision impairments. Co-funded by the National Eye Institute, the inositol trials are testing whether 6-myoinositol can reduce severe ROP. Inositol is a naturally occurring sugar alcohol produced by the fetus and placenta and is present in high levels in fetal blood throughout pregnancy. Normal blood inositol levels fall rapidly after birth. The NRN has completed three studies testing the safety and efficacy of administering inositol in concentrations similar to those occurring naturally in utero. A large, randomized, Phase III trial is currently under review with the U.S. Food and Drug Administration.
Current clinical sites within the NRN include:
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island
Case Western Reserve University
Children’s Mercy Hospital (Kansas City, MO)
Cincinnati Children’s Hospital Medical Center
Nationwide Children’s Hospital and The Ohio State University Medical Center
University of Alabama at Birmingham
University of California, Los Angeles
University of Iowa
University of New Mexico
University of Pennsylvania
University of Rochester
University of Texas Health Science Center at Houston
University of Texas Southwestern Medical Center at Dallas
Wayne State University
Collaborating clinical sites (collecting follow-up data on recruited subjects) include:
Tufts New England Medical Center
University of California, San Diego
University of Utah
RTI International serves as the Data Coordinating Center for the NRN.
NRN Web Site (maintained by the NRN Data Coordinating Center at RTI International)
NICHD NRN Extremely Preterm Birth Outcome Data Tool
Pregnancy and Perinatology Branch (PPB), NICHD, Report to the NACHHD Council, September 2008 (PDF – 1174 KB) (see pages 33–39 of the printed report, or pages 38–44 of the PDF)
NICHD Contact: Rosemary Higgins