Neonatal Research Network

Overview

Formed in 1986, NRN is a collaborative network of neonatal intensive care units across the United States. It comprises 15 clinical centers and a data coordinating center. Focused on newborns, particularly extremely low birth weight (ELBW) infants, 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. To fulfill this mission, NRN has completed or is implementing 22 observational studies and 40 interventional trials (details of which are available http://neonatal.rti.org/ External Web Site Policy).

Topic Areas

Preterm birth complications and outcomes. NRN studies in this area include:

  • Generic Database (GDB) of Very Low Birth Weight Infants. 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. As of December 2017, NRN has registered more than 82,000 infants in this database since its inception. These data also form the basis of NRN's Extremely Preterm Birth Outcome Data tool, which gives physicians 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.
  • Follow-Up Study of High-Risk Infants. Begun in 1993, NRN's Follow-Up Study is a cohort of surviving ELBW infants who have neurodevelopmental, neurosensory, and functional assessments at a corrected age of 24 months to identify maternal and neonatal risk and protective factors for neurodevelopmental outcome. As of December 2017, NRN has followed more than 20,000 children in this study.

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. Some studies within this topic area include:

  • 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 (PMID: 20472937). It also found that continuous positive airway pressure (CPAP) was as effective as traditional ventilator/surfactant therapy in treating BPD in these infants, but CPAP may result in fewer complications (PMID: 20472939). Follow-up results at a corrected age of 18 to 22 months 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 (PMID: 23268664).
  • Hydrocortisone for BPD (NCT01353313). This study is testing the safety and efficacy of a 10-day course of hydrocortisone for infants with a gestational age of less than 30 weeks who are intubated at 14 to 28 days of life.
  • Do Antenatal Steroids Affect Maturation of the Amplitude Integrated Electroencephalogram (aEEG) in Late Preterm Infants? This study aims to determine 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% to 15% of ELBW infants, and isolated intestinal perforation (IP), which leaks fluid into the abdominal cavity, affects an estimated 4% of these infants. Outcome for infants with NEC or IP is poor: 49% die, and half of the surviving infants are impaired.

  • Necrotizing Enterocolitis Surgery Trial (NEST) (NCT01029353). 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 an adjusted age of 18 to 22 months. 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% receive one or more blood transfusions for a variety of reasons.

  • Transfusion of Prematures (TOP) trial (NCT01702805). This trial randomizes infants with a birth weight under 1,000 grams and a gestational age of less than 29 weeks to receive red blood cell transfusions at either a higher (liberal transfusion) or lower (restrictive transfusion) hemoglobin threshold to see whether maintaining a higher level will improve survival and neurodevelopmental outcomes at 24 months of age.

Birth asphyxia. 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% to 75% of infants with severe HIE die, and 55% of these deaths occur in the first month. Up to 80% of survivors develop significant long-term disabilities, such as intellectual impairment, epilepsy, and cerebral palsy. NRN studies in this area include:

  • Late Hypothermia for Hypoxic-Ischemic Encephalopathy (NCT00614744). This randomized trial is testing whether whole-body hypothermia initiated between 6 and 24 hours after birth and continued for 96 hours will benefit infants with HIE as measured by reduced death or disability at 18 to 22 months of age.
  • Optimizing Cooling Strategies at <6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy (NCT01192776). This trial examined ways to fine-tune whole-body hypothermia treatment.

Sepsis. 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 (GBS) 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 GBS or non-GBS disease.

Congenital anomalies. 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.
  • Infants with Trisomy 18 and Trisomy 13. As part of its GDB, NRN collects data on very low birth weight infants born with trisomy 13 and trisomy 18, rare genetic conditions in which infants have additional copies of chromosome 13 or 18. Trisomy 13 and 18 result in life-threatening conditions—Patau syndrome and Edwards syndrome, respectively. Analysis for the NRN data from 1994-2009 (PMID24446439) found that of the 52,262 infants in GDB, 38 (0.07%) had T13 and 128 (0.24%) had T18.

Reducing neonatal morbidities. In addition to reducing neonatal mortality, NRN is interested in methods to reduce or ameliorate neonatal morbidities:

  • Neurodevelopmental Effects of Donor Human Milk vs. Preterm Formula in ELBW infants (The MILK trial, NCT01534481). 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 rehospitalizations 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 a corrected age of 24 months.
  • Inositol for reducing ROP. Co-funded by the National Eye Institute, the inositol trials are testing whether 6-myoinositol can reduce severe ROP. NRN has completed three pilot studies testing the safety and efficacy of administering inositol in concentrations similar to those occurring naturally in utero. NRN completed recruitment for a large, randomized, Phase III trial of inositol (NCT01954082); analyses are ongoing.

High-Impact Results

Over its history, the Neonatal Research Network has published more than 350 peer-reviewed papers. Some high-impact results from NRN studies are below. A complete listing of NRN studies and papers is available on the NRN website External Web Site Policy.

  • Hypothermia as a safe and effective therapy for birth asphyxia. NRN conducted pioneering research on hypothermia as a treatment for birth asphyxia and HIE. The whole-body hypothermia randomized, controlled trial involved 208 infants less than 6 hours old who had evidence of moderate to severe brain injury caused by restricted blood flow. In seeking to learn whether hypothermia treatment can reduce death or disability, the investigators used cooling blankets with careful esophageal temperature monitoring to decrease some of the infants' body temperatures to 33.5°C (92.3°F) for 72 hours, followed by slow re-warming. The trial found that whole-body hypothermia is both a safe and effective therapy—infants with moderate or severe HIE who received hypothermia were more likely to survive to a corrected age of 18-22 months with less neurodevelopmental impairment (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 (PMID: 22646631).
  • Earlier jaundice treatment with phototherapy reduces brain injury in extremely premature infants. Jaundice results when newborn infants have high levels of bilirubin in their blood—high levels of bilirubin can cause brain injury or kernicterus. Bilirubin can, however, also function as an antioxidant, and so modest amounts may have some benefit. Phototherapy is commonly used in infants and has been shown to reduce levels of bilirubin. NRN's Phototherapy Trial tested whether phototherapy initiated at a lower bilirubin threshold (aggressive phototherapy) versus a higher threshold (conservative phototherapy) would affect neurodevelopmental impairment or death in infants weighing less than 1,000 grams at birth. Aggressive phototherapy reduced the rate of neurodevelopmental impairment at a corrected age of 18 to 22 months from 30% to 26%, and the rate of rate of profound neurodevelopmental impairment from 13% to 9%. However, the reduction in impairment may be offset by an increase in death in the smaller infants weighing 501to 750 grams at birth. (PMID: 18971491).
  • Vitamin A. Evidence suggests that supplementation with vitamin A may help to reduce the risk of chronic lung disease and sepsis among ELBW infants. NRN conducted a multicenter, randomized trial to assess the effectiveness and safety of 5,000 IU of vitamin A administered intramuscularly three times per week for 4 weeks to 807 infants in need of respiratory support 24 hours after birth, compared to a sham treatment. The trial showed that this regimen reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in ELBW infants. (PMID: 10379020).

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