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1.  Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy 
JAMA  2014;312(24):2629-2639.
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
PMCID: PMC4335311  PMID: 25536254
2.  Inhaled Nitric Oxide Usage in Preterm Infants in the NICHD Neonatal Research Network: Inter-site Variation and Propensity Evaluation 
The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, an NIH consensus development conference cautioned against use of iNO in preterm infants.
1) To determine prevalence and variability in use of iNO in the NICHD Neonatal Research Network (NRN) before and after the consensus conference and 2) separately, to examine associations between iNO use and severe BPD or death.
The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008–2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.
A total of 4,885 infants were assessed between 2008–2011; 128 (2.6%) received iNO before Day 7, 140 (2.9%) between Day 7 and 28 and 47 (1.0%) at >28 days. Center-specific iNO use during 2008–2010 ranged from 21.9% to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6% to 1.6% (p<0.001) in 2011. Use of iNO started between Day 7 and Day 14 was more prevalent among younger infants with more severe courses in Week 1 and associated with increased risk of severe BPD or death (OR 2.24;95% CI 1.23–4.07).
The variability and total use of iNO decreased in 2011 compared to 2008–2010. iNO administration started at ≥Day 7 was associated with more severe outcomes compared to infants without iNO exposure.
PMCID: PMC4323079  PMID: 24901452
Inhaled nitric oxide; bronchopulmonary dysplasia; extremely premature infant
3.  Death or Neurodevelopmental Impairment at 18 To 22 Months in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2013;164(1):34-39.e2.
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
PMCID: PMC4120744  PMID: 23992673
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up
4.  Cytokines Associated with Necrotizing Enterocolitis in Extremely Low Birth Weight Infants 
Pediatric research  2014;76(1):100-108.
The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period.
Data on 104 extremely low birth weight (ELBW) infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21.
Male gender, non-Caucasian/non-African-American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand (CCL)-2, macrophage inflammatory protein-1β/CCL3, and C-reactive protein.
Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.
PMCID: PMC4062583  PMID: 24732104
5.  Outcomes of Extremely Low Birth Weight Infants with Acidosis at Birth 
To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable.
The study population consisted of ELBW infants born between 2002-2007 at NICHD Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE)<-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed.
3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5[1.6,4.2]; and OR=1.5[1.1,2.0], respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI.
Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI.
PMCID: PMC4274605  PMID: 24554564
Cord blood gas; Premature infant; Preterm infant; Neurodevelopmental impairment
6.  Serum Tocopherol Levels in Very Preterm Infants After a Single Dose of Vitamin E at Birth 
Pediatrics  2013;132(6):e1626-e1633.
Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.
Ninety-three infants <27 weeks’ gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing.
Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL.
A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.
PMCID: PMC3838534  PMID: 24218460
vitamin E; preterm infants
7.  Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants 
PMCID: PMC3960569  PMID: 24569312
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
8.  Incidence, management and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants 
American journal of perinatology  2014;31(11):947-956.
To characterize the incidence, management and short term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating 4 separate pre-specified definitions.
Study Design
Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)
Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotrope therapy was associated with increased mortality (11.1% vs. 1.3%; P < 0.05).
More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.
PMCID: PMC4127379  PMID: 24515617
blood pressure; cardiovascular insufficiency; mechanical ventilation; inotrope; fluid bolus; glucocorticoid; outcomes; newborn
The Journal of pediatrics  2013;163(5):10.1016/j.jpeds.2013.06.025.
Intraventricular hemorrhage is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and Grade 3-4 intraventricular hemorrhage and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of intraventricular hemorrhage, emphasizing the need for more comprehensive genetic strategies.
PMCID: PMC3812267  PMID: 23896193
BMC Pediatrics  2014;14(1):281.
The positive effects of early developmental intervention (EDI) on early child development have been reported in numerous controlled trials in a variety of countries. An important aspect to determining the efficacy of EDI is the degree to which dosage is linked to outcomes. However, few studies of EDI have conducted such analyses. This observational cohort study examined the association between treatment dose and children’s development when EDI was implemented in three low and low-middle income countries as well as demographic and child health factors associated with treatment dose.
Infants (78 males, 67 females) born in rural communities in India, Pakistan, and Zambia received a parent-implemented EDI delivered through biweekly home visits by trainers during the first 36 months of life. Outcome was measured at age 36 months with the Mental (MDI) and Psychomotor (PDI) Development Indices of the Bayley Scales of Infant Development-II. Treatment dose was measured by number of home visits completed and parent-reported implementation of assigned developmental stimulation activities between visits. Sociodemographic, prenatal, perinatal, and child health variables were measures as correlates.
Average home visits dose exceeded 91% and mothers engaged the children in activities on average 62.5% of days. Higher home visits dose was significantly associated with higher MDI (mean for dose quintiles 1–2 combined = 97.8, quintiles 3–5 combined = 103.4, p = 0.0017). Higher treatment dose was also generally associated with greater mean PDI, but the relationships were non-linear. Location, sociodemographic, and child health variables were associated with treatment dose.
Receiving a higher dose of EDI during the first 36 months of life is generally associated with better developmental outcomes. The higher benefit appears when receiving ≥91% of biweekly home visits and program activities on ≥67% of days over 3 years. It is important to ensure that EDI is implemented with a sufficiently high dose to achieve desired effect. To this end groups at risk for receiving lower dose can be identified and may require special attention to ensure adequate effect.
PMCID: PMC4288653  PMID: 25344731
Treatment dose; Early developmental intervention; Neurodevelopmental disability; Birth asphyxia; Developing countries
Pediatrics  1992;90(3):380-384.
Recurrent episodes of hypoxemia may affect the growth, cardiac function, neurologic outcome, and survival of infants with bronchopulmonary dysplasia (BPD). As oral feeding might stress these infants by compromising pulmonary function even after hospital discharge, we measured oxygen saturation (Sao2) via pulse oximetry before, during the initial 10 minutes of, and immediately after oral feeding in 11 patients with BPD, 12 very low birth weight infants, and 23 healthy full-term infants. All infants with BPD had been previously discharged from the hospital after weaning from supplemental oxygen. Studies were done at a mean postconceptional age of 43 weeks while the infants were fed at home by one of their parents. Levels of Sao2 for the three groups were comparable before and during feeds. After feeding, the infants with BPD had significantly lower mean levels of Sao2 (84 ± 8% [SD] vs 93 ± 4% and 93 ± 3%, respectively; P < .01). They also spent more time after feeding with an Sao2 <90% (64 ± 34% of time vs 27 ± 33% for the very low birth weight and 22 ± 20% for the term group; P < .01) and greater time with an Sao2 <80% (37 ± 28% vs 4 ± 10% and 4 ± 8%, respectively; P < .01). Desaturation in infants with BPD was related to larger volume and faster oral intake during feeding. Thus, the data indicate that desaturation after feeding remains a recurrent problem for survivors of BPD after discharge. Individual approaches which incorporate parental education and behavioral interventions might decrease the risk of significant hypoxemia during oral feeding in infants with BPD.
PMCID: PMC4182863  PMID: 1518692
To determine if current retinopathy of prematurity screening guidelines1 adequately identify treatable ROP in a contemporary cohort of extremely low gestation infants.
Study Design
Data from the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial were used. Inborn infants 24 0/7 to 27 6/7 weeks gestational age with consent prior to delivery were enrolled in 2005-2009. Severe retinopathy of prematurity (Type 1 retinopathy of prematurity or treatment with laser, cryotherapy, or bevacizumab) or death was the primary outcome for the randomized trial. Examinations followed then current American Academy of Pediatrics (AAP) screening recommendations, beginning by 31-33 weeks postmenstrual age.2,3
1316 infants were enrolled in the trial. 997 of the 1121 who survived to first eye exam had final retinopathy of prematurity outcome determined. 137 (14% of 997) met criteria for severe retinopathy of prematurity and 128 (93%) of those had sufficient data (without missing or delayed exams) to determine age of onset of severe retinopathy of prematurity. Postmenstrual age at onset was 32.1 to 53.1 wks. In this referral center cohort, 1.4% (14/997) developed severe retinopathy of prematurity after discharge.
Our contemporary data support the 2013 AAP screening guidelines for ROP for infants 24 0/7 to 27 6/7 weeks gestational age.1 Some infants do not meet treatment criteria until after discharge home. Post-discharge follow-up of infants who are still at risk for severe ROP is crucial for timely detection and treatment.
PMCID: PMC3969774  PMID: 24503911
extremely premature infant
Expert review of ophthalmology  2010;5(5):583-585.
PMCID: PMC4155506  PMID: 25197316
blindness; developmental disabilities; hyperoxia; oxygen inhalation therapy; retinopathy of prematurity
The Journal of pediatrics  2013;163(3):652-657.e2.
To test the hypothesis that increasing severity of the fetal inflammatory response would have a dose-dependent relationship with severe neurodevelopmental impairment (NDI) or death in extremely preterm infants.
Study design
We report 347 infants 23 to 28 weeks gestational age admitted to a tertiary neonatal intensive care unit between 2006 and 2008. The primary outcome was death or NDI at 18–22 month follow-up. Exposure status was defined by increasing stage of funisitis (stage 1: phlebitis; stage 2: arteritis with or without phlebitis; stage 3: subacute necrotizing funisitis) and severity of chorionic plate vasculitis (inflammation with or without thrombosis).
A fetal inflammatory response was detected in 110 placentas (32%). Severe NDI/death rate was higher in infants with subacute necrotizing funisitis compared with infants without placental/umbilical cord inflammation (60% vs. 35%; p<0.05). Among infants with stage 1 or 2 funisitis, the presence of any chorionic vasculitis was associated with higher rates of severe NDI/death (47% vs. 23%; p<0.05). After adjustment for confounding factors, only subacute necrotizing funisitis (RR: 1.87; 95% CI: 1.04 – 3.35; p=0.04) and chorionic plate vasculitis with thrombosis (RR: 2.21; 95% CI: 1.10 – 4.46; p=0.03) were associated with severe NDI/death.
Severe fetal inflammatory response characterized by subacute necrotizing funisitis and severe chorionic plate vasculitis with thrombosis are associated with severe NDI/death in preterm infants.
PMCID: PMC3744601  PMID: 23664630
chorioamnionitis; infant; premature; prognosis; funisitis; chorionic plate vasculitis
Pediatrics  2013;132(3):e656-e661.
Term infants in resource-poor settings frequently develop hypothermia during the first hours after birth. Plastic bags or wraps are a low-cost intervention for the prevention of hypothermia in preterm and low birth weight infants that may also be effective in term infants. Our objective was to test the hypothesis that placement of term neonates in plastic bags at birth reduces hypothermia at 1 hour after birth in a resource-poor hospital.
This parallel-group randomized controlled trial was conducted at University Teaching Hospital, the tertiary referral center in Zambia. Inborn neonates with both a gestational age ≥37 weeks and a birth weight ≥2500 g were randomized 1:1 to either a standard thermoregulation protocol or to a standard thermoregulation protocol with placement of the torso and lower extremities inside a plastic bag within 10 minutes after birth. The primary outcome was hypothermia (<36.5°C axillary temperature) at 1 hour after birth.
Neonates randomized to plastic bag (n = 135) or to standard thermoregulation care (n = 136) had similar baseline characteristics (birth weight, gestational age, gender, and baseline temperature). Neonates in the plastic bag group had a lower rate of hypothermia (60% vs 73%, risk ratio 0.76, confidence interval 0.60–0.96, P = .026) and a higher axillary temperature (36.4 ± 0.5°C vs 36.2 ± 0.7°C, P < .001) at 1 hour after birth compared with infants receiving standard care.
Placement in a plastic bag at birth reduced the incidence of hypothermia at 1 hour after birth in term neonates born in a resource-poor setting, but most neonates remained hypothermic.
PMCID: PMC3876758  PMID: 23979082
infant, term; infant, newborn; infant, hypothermia/prevention and control; plastic bag; bedding and linens; body temperature, regulation; polyethylenes; delivery, obstetrics
Pediatric research  2013;75(3):424-430.
Adults with the apolipoprotein E gene (APOE) alleles e4 and e2 are at high risk of poor neurologic outcome after brain injury. The e4 allele has been associated with cerebral palsy and the e2 allele has been associated with worse neurologic outcome with congenital heart disease. This study was done to test the hypothesis that APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).
We conducted a cohort study of infants who survived HIE and had 18 – 22 month standardized neurodevelopmental evaluations to assess associations between disability and APOE genotypes e3/e3, e4/-, and e2/-
139 survivors were genotyped. 86 (62%) were e3/e3, 41 (29%) were e4/-, and 14 (10%) were e2/-. 129 infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30% and 19% among those with and without e3/e3 genotype, 25% and 26% among those with and without the e2 allele, and 18% and 29% among those with and without the e4 allele. None of the differences were statistically significant. Cerebral palsy prevalence was also similar among genotype groups.
Disability was not associated with APOE genotype in this cohort of HIE survivors.
PMCID: PMC4095992  PMID: 24322171
To test the hypothesis that the proportion of endotracheal intubation (ETI) in the delivery room (DR) decreased in Neonatal Research Network (NRN) centres after the National Institute of Child Health and Human Development NRN Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT).
Retrospective cohort study using the prospective NRN generic database.
Eleven centres that participated in the SUPPORT trial and remained part of the NRN. Preterm neonates 240/7–276/7 weeks’ gestational age enrolled in the SUPPORT trial were randomised to: (1) DR continuous positive airway pressure or DR ETI with early surfactant administration; and (2) oxygen saturation targets of 85–89% or 91–95%. The prior NRN feasibility trial had assessed the feasibility of randomisation to continuous positive airway pressure versus ETI.
Infants 240/7–276/7 weeks’ gestational age, excluding infants with syndromes or major malformations and those on comfort care only.
Main outcome measure
Proportion of DR ETI.
The proportion of DR ETI decreased significantly in the group of infants from centres that had not participated in the feasibility trial (91% before vs 75% after SUPPORT, adjusted relative risk 0.86, 95% CI 0.83–0.89, p<0.0001) but not in the group of infants from the other centres, where the proportion of ETI was already lower prior to initiation of the SUPPORT trial (61% before vs 58% after SUPPORT, adjusted relative risk 0.96, 95% CI 0.89 to 1.05, p=0.40).
This study shows that DR ETI changed after SUPPORT only in NRN centres that had not participated in a similar trial.
PMCID: PMC4134421  PMID: 24876196
The New England journal of medicine  2012;367(26):2495-2504.
Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.
Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.
The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P = 0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P = 0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P = 0.046).
We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT number, NCT00233324.)
PMCID: PMC4140695  PMID: 23268664
Pediatrics  2013;132(1):e175-e184.
To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.
We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and ≥25 weeks.
Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs ≥25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants ≥25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates.
Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks’ GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA ≥25 weeks these differences account for only a small part of the variation in mortality.
PMCID: PMC3691533  PMID: 23753096
mortality rates; outcome; NICU; preterm infants; extremely preterm infants
Pediatrics  2013;132(1):49-61.
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
PMCID: PMC3691532  PMID: 23733791
birth defects; prematurity; Neonatal Research Network; low birth weight
Pediatrics  2013;132(1):e128-e134.
Hypothermia contributes to neonatal mortality and morbidity, especially in preterm and low birth weight infants in developing countries. Plastic bags covering the trunk and extremities of very low birth weight infants reduces hypothermia. This technique has not been studied in larger infants or in many resource-limited settings. The objective was to determine if placing preterm and low birth weight infants inside a plastic bag at birth maintains normothermia.
Infants at 26 to 36 weeks’ gestational age and/or with a birth weight of 1000 to 2500 g born at the University Teaching Hospital in Lusaka, Zambia, were randomized by using a 1:1 allocation and parallel design to standard thermoregulation (blanket or radiant warmer) care or to standard thermoregulation care plus placement inside a plastic bag at birth. The primary outcome measure was axillary temperature in the World Health Organization–defined normal range (36.5–37.5°C) at 1 hour after birth.
A total of 104 infants were randomized. At 1 hour after birth, infants randomized to plastic bag (n = 49) were more likely to have a temperature in the normal range as compared with infants in the standard thermoregulation care group (n = 55; 59.2% vs 32.7%; relative risk 1.81; 95% confidence interval 1.16–2.81; P = .007). The temperature at 1 hour after birth in the infants randomized to plastic bag was 36.5 ± 0.5°C compared with 36.1 ± 0.6°C in standard care infants (P < .001). Hyperthermia (>38.0°C) did not occur in any infant.
Placement of preterm/low birth weight infants inside a plastic bag at birth compared with standard thermoregulation care reduced hypothermia without resulting in hyperthermia, and is a low-cost, low-technology tool for resource-limited settings.
PMCID: PMC3691528  PMID: 23733796
hypothermia/prevention and control; infant newborn; infant premature; diseases/prevention and control; perinatal care/methods
Obstetrics and gynecology  2010;116(6):1288-1295.
To compare outcomes among neonates delivered after documentation of fetal lung maturity prior to 39 weeks and those delivered at 39 or 40 weeks.
This was a retrospective cohort study of women with singleton pregnancy delivered at 36 0/7 to 38 6/7 weeks after positive fetal lung maturity testing (based on amniotic fluid lecithin to sphingomeylin ratio) or at 39 0/7 to 40 6/7 weeks (without maturity testing) at our center from 1999-2008. Women with major congenital anomalies, cord prolapse, non-reassuring antepartum testing, placental abruption, or oligohydramnios were excluded. A primary composite neonatal outcome included death, adverse respiratory outcomes, hypoglycemia, treated hyperbilirubinemia, generalized seizures, necrotizing enterocolitis, hypoxic ischemic encephalopathy, periventricular leukomalacia, and suspected or proven sepsis.
There were 459 neonates delivered at 36-38 weeks and 13,339 delivered at 39-40 weeks; mean birth weight was 3107±548 and 3362±439 grams, respectively. The risk of the composite adverse neonatal outcome was 6.1% for the 36-38 week group compared to 2.5% for the 39-40 week group; RR 2.4; 1.7-3.5. After multivariable adjustment, early delivery remained significantly associated with an increased risk of the composite outcome (adjusted OR 1.7; 1.1-2.6) as well as several individual outcomes, including respiratory distress syndrome (7.6; 2.2-26.6), treated hyperbilirubinemia (11.2; 3.6-34) and hypoglycemia (5.8; 2.4-14.3).
Neonates delivered at 36-38 weeks after confirmed fetal lung maturity are at higher risk of adverse outcomes than those delivered at 39-40 weeks.
PMCID: PMC4074509  PMID: 21099593
Pediatrics  2013;131(6):e1865-e1873.
To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.
Prospective observational study of infants 230/7 to 266/7 weeks’ gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.
Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.
Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.
PMCID: PMC3666108  PMID: 23650301
extremely preterm infant; antihypotensive therapy; blood pressure; hypotension
Pediatric research  2013;74(5):570-575.
Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality.
This is a secondary analysis of clinical and HRC data from 2989 VLBW infants enrolled in a randomized controlled trial of HRC monitoring in 9 NICUs from 2004–2010.
LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and non-display groups. Mortality within 30 days of LOS was lower in the HRC display compared to the non-display group (11.8% vs 19.6%, RR 0.61, 95% CI 0.43, 0.87, p<0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed.
Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.
PMCID: PMC4026205  PMID: 23942558
The Journal of pediatrics  2013;162(5):942-948.e3.
To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).
Study design
Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the NICHD Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤72 hr of birth (EOS) or >72 hr (LOS) and antimicrobial therapy for ≥5 days or death <5 d while receiving therapy. Regression models were used to assess risk of death or LOS by 120d and LOS by 120d among survivors to discharge or 120d, adjusting for gestational age and other covariates.
Of 34,396 infants studied 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120d did not differ overall for infants with EOS compared with those without EOS [RR:0.99 (0.89-1.09)] but was reduced in infants born at <25wk gestation [RR:0.87 (0.76-0.99), p=0.048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR:0.88 (0.75-1.02)], but LOS risk was shorter in infants with BW 401-750 g who had EOS [RR:0.80 (0.64-0.99), p=0.047].
Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.
PMCID: PMC3622770  PMID: 23295144
Very low birth weight; early-onset sepsis; late-onset sepsis

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