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OBJECTIVE: This study evaluates the 24 month follow up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score

Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia.We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity.A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Objective To test the primary hypothesis that extremely preterm children antenatally exposed to both magnesium sulfate and antenatal corticosteroids have a lower rate of severe neurodevelopmental impairment or death compared with those exposed to antenatal corticosteroids alone. Methods This was a prospective observational study of children born at 22 0/7-26 6/7 weeks of gestation from 2011 to 2014 at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hospitals (N=3,093). The primary outcome was severe neurodevelopmental impairment or death at 18-26 months of corrected age follow-up based on exposure to antenatal corticosteroids and magnesium sulfate or antenatal corticosteroids alone. Secondary outcomes included components of severe neurodevelopmental impairment by exposure group and comparisons of severe neurodevelopmental impairment or death between children exposed to both antenatal corticosteroids and magnesium sulfate with those exposed to magnesium sulfate alone or to neither antenatal corticosteroids nor magnesium sulfate. Logistic regression models adjusted for background characteristics. Results Children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of severe neurodevelopmental impairment or death (813/2,239, 36.3%) compared with those exposed to antenatal corticosteroids alone (225/508, 44.3%; adjusted odds ratio [aOR] 0.73; 95% CI 0.58-0.91), magnesium sulfate alone (47/89, 53%; aOR 0.49; 95% CI 0.29-0.82), or neither therapy (121/251; 48.2%; aOR 0.66, 95% CI 0.49-0.89). Similarly, children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of death compared with either or neither therapy, but the rate of severe neurodevelopmental impairment among survivors did not differ between exposure groups. Conclusion In children born between 22 0/7 and 26 6/7 weeks of gestation, exposure to both antenatal corticosteroids and magnesium sulfate was associated with lower rates of severe neurodevelopmental impairment or death and death compared with exposure to antenatal corticosteroids alone. Clinical trial registration ClinicalTrials.gov, NCT00063063.

OBJECTIVE: To determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18–22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage (adjusted relative risk [aRR] = 1.0; 95% confidence interval [CI]: 0.87–1.14). A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (p = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR=0.81; 95% CI: 0.64 to 1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference

Retinopathy of prematurity (ROP) is a serious disease affecting premature infants. Rates of ROP increase with decreasing gestational age. Duration of oxygen exposure is correlated with ROP. Many studies evaluating oxygen have been performed to assess impact on ROP. This article describes recent findings for oxygen saturation target studies and suggests area of future study for ROP.

Importance The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) extremely preterm birth outcome model is widely used for prognostication by practitioners caring for families expecting extremely preterm birth. The model provides information on mean outcomes from 1998 to 2003 and does not account for substantial variation in outcomes among US hospitals. Objective To update and validate the NRN extremely preterm birth outcome model for most extremely preterm infants in the United States. Design, Setting, and Participants This prognostic study included 3 observational cohorts from January 1, 2006, to December 31, 2016, at 19 US centers in the NRN (derivation cohort) and 637 US centers in Vermont Oxford Network (VON) (validation cohorts). Actively treated infants born at 22 weeks’ 0 days’ to 25 weeks’ 6 days’ gestation and weighing 401 to 1000 g, including 4176 in the NRN for 2006 to 2012, 45 179 in VON for 2006 to 2012, and 25 969 in VON for 2013 to 2016, were studied. VON cohorts comprised more than 85% of eligible US births. Data analysis was performed from May 1, 2017, to March 31, 2019. Exposures Predictive variables used in the original model, including infant sex, birth weight, plurality, gestational age at birth, and exposure to antenatal corticosteroids. Main Outcomes and Measures The main outcome was death before discharge. Secondary outcomes included neurodevelopmental impairment at 18 to 26 months’ corrected age and measures of hospital resource use (days of hospitalization and ventilator use). Results Among 4176 actively treated infants in the NRN cohort (48% female; mean [SD] gestational age, 24.2 [0.8] weeks), survival was 63% vs 62% among 3702 infants in the era of the original model (47% female; mean [SD] gestational age, 24.2 [0.8] weeks). In the concurrent (2006-2012) VON cohort, survival was 66% among 45 179 actively treated infants (47% female; mean [SD] gestational age, 24.1 [0.8] weeks) and 70% among 25 969 infants from 2013 to 2016 (48% female; mean [SD] gestational age, 24.1 [0.8] weeks). Model C statistics were 0.74 in the 2006-2012 validation cohort and 0.73 in the 2013-2016 validation cohort. With the use of decision curve analysis to compare the model with a gestational age–only approach to prognostication, the updated model showed a predictive advantage. The birth hospital contributed equally as much to prediction of survival as gestational age (20%) but less than the other factors combined (60%). Conclusions and Relevance An updated model using well-known factors to predict survival for extremely preterm infants performed moderately well when applied to large US cohorts. Because survival rates change over time, the model requires periodic updating. The hospital of birth contributed substantially to outcome prediction.

Importance Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, setting, and participants This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main outcomes and measures The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and relevance Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial registration ClinicalTrials.gov Identifier: NCT01192776.

Background:Late-onset sepsis (LOS) is an important cause of death and neurodevelopmental impairment in premature infants. The purpose of this study was to assess overall incidence of LOS, distribution of LOS-causative organisms and center variation in incidence of LOS for extremely premature infants

Objective To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. Study design Previously generated GWA data from the Neonatal Research Network9s anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p −5 . Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Results Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10 −8 ); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values Conclusions No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

Importance Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration clinicaltrials.gov Identifier:NCT00614744

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

OBJECTIVE: Among extremely preterm infants, we evaluated whether bevacizumab therapy compared with surgery for retinopathy of prematurity (ROP) is associated with adverse outcomes in early childhood. METHODS: This study was a retrospective analysis of prospectively collected data on preterm (22–26 + 6/7 weeks’ gestational age) infants admitted to the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers who received bevacizumab or surgery exclusively for ROP. The primary outcome was death or severe neurodevelopmental impairment (NDI) at 18 to 26 months’ corrected age (Bayley Scales of Infant and Toddler Development, Third Edition cognitive or motor composite score RESULTS: The cohort (N = 405; 214 [53%] boys; median [interquartile range] gestational age: 24.6 [23.9–25.3] weeks) included 181 (45%) infants who received bevacizumab and 224 (55%) who underwent ROP surgery. Infants treated with bevacizumab had a lower median (interquartile range) birth weight (640 [541–709] vs 660 [572.5–750] g; P = .02) and longer durations of conventional ventilation (35 [21–58] vs 33 [18–49] days; P = .04) and supplemental oxygen (112 [94–120] vs 105 [84.5–120] days; P = .01). Death or severe NDI (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.94 to 2.14) and severe NDI (aOR 1.14; 95% CI 0.76 to 1.70) did not differ between groups. Odds of death (aOR 2.54 [95% CI 1.42 to 4.55]; P = .002), a cognitive score CONCLUSIONS: In this multicenter cohort of preterm infants, ROP treatment modality was not associated with differences in death or NDI, but the bevacizumab group had higher mortality and poor cognitive outcomes in early childhood. These data reveal the need for a rigorous appraisal of ROP therapy.

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking versus delayed cord clamping among infants

Objective To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. Study design Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. Results Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. Conclusions MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia–ischemia. Trial registration Clinicaltrials.gov: NCT00614744 .

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neontal Research Network (NRN) was established in 1986 in response to the need for rigorous studies to guide care and management of sick and premature newborns. The network is comprise of clinical centers that perform clinical protocols to investigate the safety and efficay of treatment and management strategies for newborn infants as well as a data cordinating center. Infrastructure is set up for observational and interventional studies as well as neurodevelopmental follow-up of patients. The network has conducted trials and observational studies on major neonatal problems including pulmonary disease, neuroprotection, sepsis and infection, necrotizing enterocolitis, vaccine administration to preterm infants, retinopathy of prematurity, cardiovascular issues including blood pressure, human milk, growth and nutrition, hematologic issues, resuscitation, pulmonary hypertension, and neurodevelopmental outcome. This mechanism of clinical research for newborns has led to changes in care practices leading to improved outcomes for high-risk infants.

In January 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited an expert panel to a workshop to address numerous knowledge gaps and to provide evidence-based guidelines for the diagnosis and management of pregnant women with what had been commonly called chorioamnionitis and the neonates born to these women. The panel noted that the term chorioamnionitis has been used to label a heterogeneous array of conditions characterized by infection and inflammation or both with a consequent great variation in clinical practice for mothers and their newborns. Therefore, the panel proposed to replace the term chorioamnionitis with a more general, descriptive term: "intrauterine inflammation or infection or both," abbreviated as "Triple I." The panel proposed a classification for Triple I and recommended approaches to evaluation and management of pregnant women and their newborns with a diagnosis of Triple I. It is particularly important to recognize that an isolated maternal fever is not synonymous with chorioamnionitis. A research agenda was proposed to further refine the definition and management of this complex group of conditions. This article provides a summary of the workshop presentations and discussions.

Objective To assess outcomes following post-hemorrhagic ventricular dilatation (PHVD) among infants born at ≤26 weeks of gestation. Study design Observational study of infants born April 1, 2011, to December 31, 2015, in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and categorized into 3 groups: PHVD, intracranial hemorrhage without ventricular dilatation, or normal head ultrasound. PHVD was treated per center practice. Neurodevelopmental impairment at 18-26 months was defined by cerebral palsy, Bayley Scales of Infant and Toddler Development, 3rd edition, cognitive or motor score Results Of 4216 infants, 815 had PHVD, 769 had hemorrhage without ventricular dilatation, and 2632 had normal head ultrasounds. Progressive dilatation occurred among 119 of 815 infants; the initial intervention in 66 infants was reservoir placement and 53 had ventriculoperitoneal shunt placement. Death or impairment occurred among 68%, 39%, and 28% of infants with PHVD, hemorrhage without dilatation, and normal head ultrasound, respectively; aOR (95% CI) were 4.6 (3.8-5.7) PHVD vs normal head ultrasound scan and 2.98 (2.3-3.8) for PHVD vs hemorrhage without dilatation. Death or impairment was more frequent with intervention for progressive dilatation vs no intervention (80% vs 65%; aOR 2.2 [1.38-3.8]). Death or impairment increased with parenchymal hemorrhage, intervention for PHVD, male sex, and surgery for retinopathy; odds decreased with each additional gestational week. Conclusions PHVD was associated with high rates of death or impairment among infants with gestational ages ≤26 weeks; risk was further increased among those with progressive ventricular dilation requiring intervention.

Importance Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies. Objective To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants. Design, setting, and participants This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020. Main outcomes and measures Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death. Results A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008). Conclusions and relevance In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.

ObjectiveTo identify achieved oxygen saturations (SpO2) associated with increased risk of severe retinopathy of prematurity (ROP).DesignThis is a secondary analysis of the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT)randomised controlled trial. SpO2was recorded up to 36 weeks’ postmenstrual age. Saturations through 9 postnatal weeks were explored graphically, and logistic regression models were created to predict severe ROP.Setting20 centres of theEunice Kennedy ShriverNational Institute of Child Health and Human Development Neonatal Research Network.Patients984 surviving infants of 24–27 weeks’ gestational age born in 2005–2009.InterventionsSUPPORT targeted SpO2to a lower (85%–89%) or higher (91%–95%) range through 36 weeks’ postmenstrual age or off respiratory support.Main outcome measuresSevere ROP defined as threshold ROP, ophthalmological surgery or bevacizumab treatment.ResultsThere were statistically significant interactions between duration of oxygen supplementation and percentage of time in certain achieved saturation ranges. Specifically, for infants who spent at least 2 weeks on oxygen in postnatal weeks 1–5, a higher percentage of time at 91%–96% SpO2was associated with increased odds of severe ROP. For infants who spent at least 3 weeks on oxygen in postnatal weeks 6–9, a higher percentage of time at 97%–100% SpO2was associated with increased odds of severe ROP. Other significant risk factors were lower gestational age and birth weight, non-Hispanic white versus black race, prospectively defined severe illness, late-onset sepsis or meningitis, and clinical centre.ConclusionsAmong extremely preterm survivors to discharge, the association between SpO2and severe ROP depended on the timing and duration of oxygen supplementation.

Objective To describe discordance in antenatal corticosteroid use and resuscitation following extremely preterm birth and its relationship with infant survival and neurodevelopment. Study design A multicenter cohort study of 4858 infants 22-26 weeks of gestation born 2006-2011 at 24 US hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, with follow-up through 2013. Survival and neurodevelopmental outcomes were available at 18-22 months of corrected age for 4576 (94.2%) infants. We described antenatal interventions, resuscitation, and infant outcomes. We modeled the effect on infant outcomes of each hospital increasing antenatal corticosteroid exposure for resuscitated infants born at 22-24 weeks of gestation to rates observed at 25-26 weeks of gestation. Results Discordant antenatal corticosteroid use and resuscitation, where one and not the other occurred, were more frequent for births at 22 and 23 but not 24 weeks (rate ratio [95% CI] at 22 weeks: 1.7 [1.3-2.2]; 23 weeks: 2.6 [2.2-3.2]; 24 weeks: 1.0 [0.8-1.2]) when compared with 25-26 weeks. Among infants resuscitated at 23 weeks, adjusting each hospital's rate of antenatal corticosteroid use to the average at 25-26 weeks (89.2%) was projected to increase infant survival by 7.1% (95% CI 5.4-8.8%) and survival without severe impairment by 6.4% (95% CI 4.7-8.1%). No significant change in outcomes was projected for infants resuscitated at 22 weeks, where few (n = 22) resuscitated infants received antenatal corticosteroids. Conclusions Infants born at 23 weeks were more frequently resuscitated without antenatal corticosteroids than other extremely preterm infants. When resuscitation is intended, consistent provision of antenatal corticosteroids may increase infant survival and survival without impairment. Trial registration ClinicalTrials.gov NCT00063063 (Generic Database) and NCT00009633 (Follow-Up Study)

BACKGROUND AND OBJECTIVES: Former preterm infants are at increased risk of hypertension with increasing age. Our objective was to identify rates of high blood pressure (BP) (≥90th percentile) and hypertension (BP ≥95th percentile) and associated risk factors among extreme preterm (EPT) infants at 6 to 7 years of age. METHODS: Assessment included BP and anthropometrics. Comparisons were made by BP ≥90th versus RESULTS: Among 379 EPT infants, 20.6% had systolic high BP, 10.8% systolic hypertension, 21.4% diastolic high BP, and 11.4% diastolic hypertension. Children with systolic high BP had higher rates of BMI, triceps skinfolds >85th percentile, and waist circumference >90th percentile. In regression analyses, weight gain velocity from 18 months to school age (RR = 1.36), and maternal gestational diabetes (MGD) (RR = 2.04) predicted systolic and either systolic and/or diastolic high BP (RR = 1.27 and RR = 1.67). Among children with BMI CONCLUSIONS: Both overweight and normal weight EPT children are at risk for high BP and hypertension. Public insurance, MGD, and weight gain velocity are risk factors. Findings of high BP among EPT children at early school age are worrisome and indicate a need for close follow-up.

Objective To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE). Methods We compared infants with and without PPHN enrolled in 2 randomized trials of therapeutic hypothermia: the induced hypothermia trial of cooling to 33.5°C for 72 hours vs normothermia, and the “usual-care” arm (33.5°C for 72 hours) of the optimizing cooling trial. Results Among 303 infants with HIE from these 2 studies, 67 (22%) had PPHN and 236 (78%) did not. We compared infants with PPHN with those without PPHN. The proportion of patients treated with therapeutic hypothermia was similar in PPHN and no-PPHN groups (66% vs 65%). Medication use during resuscitation (58% vs 44%), acidosis after birth (pH: 7.0 ± 0.2 vs 7.1 ± 0.2), severe HIE (43% vs 28%), meconium aspiration syndrome (39% vs 7%), pulmonary hemorrhage (12% vs 3%), culture-positive sepsis (12% vs 3%), systemic hypotension (65% vs 28%), inhaled nitric oxide therapy (64% vs 3%), and extracorporeal membrane oxygenation (12% vs 0%) were more common in the PPHN group. Length of stay (26 ± 21 vs 16 ± 14 days) and mortality (27% vs 16%) were higher in the PPHN group. Conclusions PPHN is common among infants with moderate/severe HIE and is associated with severe encephalopathy, lung disease, sepsis, systemic hypotension, and increased mortality. The prevalence of PPHN was not different between those infants receiving therapeutic hypothermia at 33.5°C in these 2 trials (44/197 = 22%) compared with infants receiving normothermia in the induced hypothermia trial (23/106 = 22%).

Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

Importance Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective To characterize the outcomes of extremely preterm neonates younger than 27 weeks’ gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks’ postmenstrual age. Design, Setting, and Participants This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks’ gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks’ postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Importance Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration clinicaltrials.gov Identifier:NCT00614744

Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease.We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks' postmenstrual age.Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks' gestational age with a birthweight of ≥401 g born from Jan. 1, 2006, through Dec. 31, 2014, were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks' postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch.Infants exposed to any antenatal corticosteroids had a lower rate of death (2193/9670 [22.7%]) compared to infants without exposure (540/1302 [41.5%]) (adjusted relative risk, 0.71; 95% confidence interval, 0.65-0.76; P.0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death (654/2520 [26.0%]) compared to infants without exposure (540/1302 [41.5%]); (adjusted relative risk, 0.77; 95% confidence interval, 0.70-0.85; P.0001). In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23-27 weeks' gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks' gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure.Among infants 22-28 weeks' gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ.

Importance Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. Objective To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. Interventions A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). Main Outcomes and Measures The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. Results The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, −1.0% [95% CI, −10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, −3.1% [95% CI, −12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed ( P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. Conclusions and Relevance Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. Trial Registration clinicaltrials.gov Identifier:NCT01192776

Objectives To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. Study design This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated. Results WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. Conclusions Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. Trial registration ClinicalTrials.gov : NCT00063063 .

OBJECTIVES: To describe the frequency and findings of cranial imaging in moderately preterm (MPT) infants (born at 29 0/7–33 6/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics. STUDY DESIGN: We used data from the Neonatal Research Network MPT Registry, including the most severe early (≤28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age (GA), antenatal steroids and center. RESULTS: Among 7,021 infants, 4,184 (60%) underwent cranial imaging. These infants had lower GAs and birth weights and higher rates of birth weight small-for-gestation, outborn birth, cesarean delivery; neonatal resuscitation and treatment with surfactant, compared with those without imaging (P < .0001). Imaging abnormalities noted in 15% of the infants included any intracranial hemorrhage (13.2%), grades 3–4 intracranial hemorrhage (1.7%), cystic periventricular leukomalacia (2.6%) and ventriculomegaly (6.6%). Histological chorioamnionitis [OR 1.47; 95% C.I.:1.19–1.83], GA [0.95; 95% C.I.: 0.94–0.97], antenatal steroids [OR 0.55; 95% C.I.: 0.41–0.74] and cesarean delivery [OR 0.66; 95% C.I.: 0.53–0.81] were associated with abnormal imaging. The center with the highest rate of cranial imaging, compared with the lowest, had a higher risk of abnormal imaging [OR 2.08; 95% CI: 1.10–3.92]. On the CART model, cesarean delivery, center, antenatal steroids and chorioamnionitis, in that order, predicted abnormal imaging. CONCLUSIONS: Among the 60% of MPT infants with cranial imaging, 15% had intracranial hemorrhage, cystic periventricular leukomalacia or late ventriculomegaly. Further correlation of imaging and long-term neurodevelopmental outcomes in MPT infants is needed.

BackgroundExtremely preterm infants (EPT

Objectives To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. Study design This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Network's Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks' gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. Results Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non-small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/ bronchopulmonary dysplasia (OR 3.27). Conclusions Higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. Trial registration ClinicalTrials.gov : NCT00233324 .

BackgroundCongenital diaphragmatic hernia (CDH) is commonly associated with pulmonary hypoplasia and pulmonary hypertension (PH). PH associated with CDH (CDH-PH) is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO) possibly due to right and left ventricular dysfunction. Milrinone is an intravenous inotrope and lusitrope with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PH. We developed this pilot study to determine if milrinone infusion would improve oxygenation in neonates ≥36weeks postmenstrual age (PMA) with CDH.Methods/designData on pulmonary vasodilator management and outcome of CDH patients was collected from 18 university NICUs affiliated with the Neonatal Research Network (NRN) from 2011 to 2012. The proposed pilot will be a masked, placebo-controlled, multicenter, randomized trial of 66 infants with CDH with an oxygenation index (OI) ≥10 or oxygen saturation index (OSI) ≥5. The primary outcome is the oxygenation response, as determined by change in OI at 24h after initiation of study drug. As secondary outcomes, we will determine oxygenation at 48h and 72h post-infusion, right ventricular pressures on echocardiogram and the incidence of systemic hypotension, arrhythmias, intracranial hemorrhage, survival without extracorporeal membrane oxygenation, and chronic lung disease (oxygen need at 28days postnatal age). Finally, we will evaluate the pulmonary and nutritional status at 4, 8 and 12months of age using a phone questionnaire.ResultsThree hundred thirty-seven infants with CDH were admitted to NRN NICUs in 2011 and 2012 of which 275 were ≥36weeks PMA and were exposed to the following pulmonary vasodilators: iNO (39%), sildenafil (17%), milrinone (17%), inhaled epoprostenol (6%), intravenous epoprostenol (3%), and intravenous PGE1 (1%). ECMO was required in 36% of patients. Survival to discharge was 71%.DiscussionCDH is an orphan disease with high mortality with few randomized trials evaluating postnatal management. Intravenous milrinone is a commonly used medication in neonatal/pediatric intensive care units and is currently used in 17% of patients with CDH within the NRN. This pilot study will provide data and enable further studies evaluating pulmonary vasodilator therapy in CDH.Trial registrationClinicalTrials.gov; NCT02951130; registered 14 October 2016.

A panel of experts convened by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, developed proposed guidelines for the evaluation of adverse events in newborns of women participating in clinical trials of maternal immunization in the United States.

Objective To determine the association of arterial partial pressure of carbon dioxide PaCO 2 with severe intraventricular haemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18–22 months in premature infants. Design Secondary exploratory data analysis of Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT). Setting Multiple referral neonatal intensive care units. Patients 1316 infants 24 0/7 to 27 6/7 weeks gestation randomised to different oxygenation (SpO 2 target 85–89% vs 91–95%) and ventilation strategies. Main outcome measures Blood gases from postnatal day 0 to day14 were analysed. Five PaCO 2 variables were defined: minimum (Min), maximum (Max), SD, average (time-weighted), and a four level categorical variable (hypercapnic (highest quartile of Max PaCO 2 ), hypocapnic (lowest quartile of Min PaCO 2 ), fluctuators (hypercapnia and hypocapnia), and normocapnic (middle two quartiles of Max and Min PaCO 2 )). PaCO 2 variables were compared for infants with and without sIVH, BPD and NDI (±death). Multivariable logistic regression models were developed for adjusted results. Results sIVH, BPD and NDI (±death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO 2 and outcomes persisted after adjustment (per 10 mm Hg increase: sIVH/death: OR 1.27 (1.13 to 1.41); BPD/death: OR 1.27 (1.12 to 1.44); NDI/death: OR 1.23 (1.10 to 1.38), death: OR 1.27 (1.12 to 1.44), all p 2 category and SpO 2 treatment group for sIVH/death, NDI/death or death. Max PaCO 2 was positively correlated with maximum FiO 2 (r s 0.55, p s 0.61, p Conclusions Higher PaCO 2 was an independent predictor of sIVH/death, BPD/death and NDI/death. Further trials are needed to evaluate optimal PaCO 2 targets for high-risk infants.

OBJECTIVE: Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP. METHODS: This was a cohort study of 15 751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP. RESULTS: Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49–1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37–0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36–0.777, P = .0011). CONCLUSIONS: The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.

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 24(0/7)-27(6/7) 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 24(0/7)-27(6/7) weeks' gestational age, excluding infants with syndromes or major malformations and those on comfort care only.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, p0.0001) 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.NCT00063063 (GDB) and NCT00233324 (SUPPORT).

BACKGROUND: 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.METHODS: Data on 104 extremely-low-birth-weight 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.RESULTS: Male gender, non-Caucasian/non-African American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2 levels, 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-2, macrophage inflammatory protein-1β/CC-motif ligand-3, and C-reactive protein.CONCLUSION: 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.

OBJECTIVE: Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects. METHODS: Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18. RESULTS: Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis. CONCLUSIONS: In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.

Objective 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 Results 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. Conclusion 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.

Objective To determine the impact of policy changes for pulse oximetry oxygen saturation (SpO2) alarm limits on neonatal mortality and morbidity among infants born very preterm. Study design This was a retrospective cohort study of infants born very preterm in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants were classified based on treatment at a hospital with an SpO2 alarm policy change and study epoch (before vs after policy change). We used a generalized linear mixed model to determine the effect of hospital group and epoch on the primary outcomes of mortality and severe retinopathy of prematurity (ROP) and secondary outcomes of necrotizing enterocolitis, bronchopulmonary dysplasia, and any ROP. Results There were 3809 infants in 10 hospitals with an SpO2 alarm policy change and 3685 infants in 9 hospitals without a policy change. The nature of most policy changes was to narrow the SpO2 alarm settings. Mortality was lower in hospitals without a policy change (aOR 0.63; 95% CI 0.50-0.80) but did not differ between epochs in policy change hospitals. The odds of bronchopulmonary dysplasia were greater for hospitals with a policy change (aOR 1.65; 95% CI 1.36-2.00) but did not differ for hospitals without a policy change. Severe ROP and necrotizing enterocolitis did not differ between epochs for either group. The adjusted odds of any ROP were lower in recent years in both hospital groups. Conclusions Changing SpO2 alarm policies was not associated with reduced mortality or increased severe ROP among infants born very preterm.

Importance Birth weight (BW) is an important predictor of mortality and morbidity. At extremely early gestational ages (GAs), BW may influence decisions regarding initiation of resuscitation. Objective To characterize outcomes of liveborn infants with a BW less than 400 g. Design, Setting, and Participants This retrospective multicenter cohort study analyzed extremely preterm infants born between January 2008 and December 2016 within the National Institute of Child Health and Human Development Neonatal Research Network. Infants with a BW less than 400 g and a GA of 22 to 26 weeks were included. Active treatment was defined as the provision of any potentially lifesaving intervention after birth. Survival was analyzed for the entire cohort; neurodevelopmental impairment (NDI) was examined for those born between January 2008 and December 2015 (birth years with outcomes available for analysis). Neurodevelopmental impairment at 18 to 26 months’ corrected age (CA) was defined as a Bayley Scales of Infant and Toddler Development, Third Edition, cognitive composite score less than 85, a motor composite score less than 85, moderate or severe cerebral palsy, gross motor function classification system score of 2 or greater, bilateral blindness, and/or hearing impairment. Data were analyzed from September 2017 to October 2018. Exposures Birth weight less than 400 g. Main Outcomes and Measures The primary outcome was survival to discharge among infants who received active treatment. Analysis of follow-up data was limited to infants born from 2008 to 2015 to ensure children had reached assessment age. Within this cohort, neurodevelopmental outcomes were assessed for infants who survived to 18 to 26 months’ CA and returned for a comprehensive visit. Results Of the 205 included infants, 121 (59.0%) were female, 133 (64.9%) were singletons, and 178 (86.8%) were small for gestational age. Almost half (101 of 205 [49.3%]) received active treatment at birth. A total of 26 of 205 infants (12.7%; 95% CI, 8.5-18.9) overall survived to discharge, and 26 of 101 actively treated infants (25.7%; 95% CI, 17.6-35.4) survived to discharge. Within the subset of infants with a BW less than 400 g and a GA of 22 to 23 weeks, 6 of 36 actively treated infants (17%; 95% CI, 6-33) survived to discharge. Among infants born between 2008 and 2015, 23 of 90 actively treated infants (26%; 95% CI, 17-36) survived to discharge. Two infants died after discharge, and 2 were lost to follow-up. Thus, 19 of 90 actively treated infants (21%; 95% CI, 13-31) were evaluated at 18 to 26 months’ CA. Moderate or severe NDI occurred in 14 of 19 infants (74%). Conclusions and Relevance Infants born with a BW less than 400 g are at high risk of mortality and significant morbidity. Although 21% of infants survived to 18 to 26 months’ CA with active treatment, NDI was common among survivors.

Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH. Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: (i) unilateral vs bilateral ICH; and (ii) presence vs absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI). Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI. Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.

Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the 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 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/–, and e2/–. A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/–, and 14 (10%) were of the e2/– genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the 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, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups. Disability was not associated with the APOE genotype in this cohort of HIE survivors.

OBJECTIVE Determine if higher temperature after hypoxia-ischemia is associated with death or IQ < 70 at 6-7 yr among infants treated with intensive care without hypothermia.

Objective Preterm infants with intrauterine growth restriction are at increased risk of respiratory distress syndrome and bronchopulmonary dysplasia (BPD). A randomized clinical trial by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network demonstrated that vitamin A supplementation in extremely low-birth-weight (ELBW) preterm infants requiring early respiratory support decreased the risk of developing BPD. Study Design A subgroup analysis of small-for-gestational-age (SGA) infants from the original NICHD trial was performed to test the hypothesis that in infants requiring early respiratory support, vitamin A supplementation decreases the relative risk of BPD or death in premature SGA infants to a greater extent than in gestational age–equivalent vitamin A–treated appropriate-for-gestational-age (AGA) infants. Results Although vitamin A supplementation significantly increased serum retinol concentrations in AGA ELBW infants (median [5th percentile, 95th percentile]: 16.3 [−7.0, 68.8] versus 2.4 [−13.9, 55.1]; p Conclusions Given the limited power of this analysis due to a low number of SGA infants, these data did not provide evidence to support the hypothesis that vitamin A supplementation in preterm SGA infants requiring early respiratory support decreases the relative risk of BPD or death as compared with preterm AGA infants.

Objective To characterize actual achieved patterns of oxygenation in infants born appropriate vs small for gestational age (SGA) randomized to a lower (85-89%) vs higher (91%-95%) oxygen saturation target in the Surfactant Positive Pressure and Oxygen Trial. To determine the association between achieved oxygen saturation levels and survival in infants born appropriate vs SGA enrolled in the Surfactant Positive Pressure and Oxygen Trial. Study design Median oxygen saturation and intermittent hypoxemia events ( 0/7 -27 6/7 weeks of gestation while receiving supplemental oxygen during the first 3 days of life. Results Lower target infants who were small for gestational age had the lowest oxygen saturation and highest incidence of intermittent hypoxemia during the first 3 days of life. The lowest quartile of oxygen saturation (≤92%) during the first 3 days of life was associated with lower 90-day survival for both infants born appropriate and SGA. An increased incidence of intermittent hypoxemia events during the first 3 days of life was associated with lower 90-day survival only in infants born SGA. Conclusion Lower achieved oxygen saturation during the first 3 days of life was associated with lower 90-day survival in extremely preterm infants. Infants born SGA had enhanced vulnerability to lower oxygen saturation targets as evidenced by lower achieved oxygen saturation and an association between increased intermittent hypoxemia events and lower survival. Trial registration ClinicalTrials.gov: NCT00233324.

Importance Many premature infants are born without exposure to antenatal steroids (ANS) or with incomplete courses. This study evaluates the dose-dependent effect of ANS on rates of neonatal morbidities and early childhood neurodevelopmental outcomes of extremely premature infants. Objective To compare rates of neonatal morbidities and 18- to 22-month neurodevelopmental outcomes of extremely premature infants exposed to no ANS or partial or complete courses of ANS. Design, Setting, and Participants In this observational cohort study, participants were extremely premature infants (birth weight range, 401-1000 g; gestational age, 22-27 weeks) who were born at participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 2006 and December 2011. Data were analyzed between October 2013 and May 2016. Main Outcomes and Measures Rates of death or neurodevelopmental impairment at 18 to 22 months’ corrected age. Neurodevelopmental impairment was defined as the presence of any of the following: moderate to severe cerebral palsy, a cognitive score less than 85 on the Bayley Scales of Infant and Toddler Development III, blindness, or deafness. Results There were 848 infants in the no ANS group, 1581 in the partial ANS group, and 3692 in the complete ANS group; the mean (SD) birth weights were 725 (169), 760 (173), and 753 (170) g, respectively, and the mean (SD) gestational ages were 24.5 (1.4), 24.9 (2), and 25.1 (1.1) weeks. Of 6121 eligible infants, 4284 (70.0%) survived to 18- to 22-month follow-up, and data were available for 3892 of 4284 infants (90.8%). Among the no, partial, and complete ANS groups, there were significant differences in the rates of mortality (43.1%, 29.6%, and 25.2%, respectively), severe intracranial hemorrhage among survivors (23.3%, 19.1%, and 11.7%), death or necrotizing enterocolitis (48.1%, 37.1%, and 32.5%), and death or bronchopulmonary dysplasia (74.9%, 68.9%, and 65.5%). Additionally, death or neurodevelopmental impairment occurred in 68.1%, 54.4%, and 48.1% of patients in the no, partial, and complete ANS groups, respectively. Logistic regression analysis revealed that complete (odds ratio, 0.63; 95% CI, 0.53-0.76) and partial (odds ratio, 0.77; 95% CI, 0.63-0.95) ANS courses were associated with lower rates of death or neurodevelopmental impairment compared with the no ANS group. The reduction in the rate of death or neurodevelopmental impairment associated with exposure to a complete ANS course may be mediated through a reduction in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia in the neonatal period. Conclusions and Relevance Antenatal steroid exposure was associated with a dose-dependent protective effect against death or neurodevelopmental impairment in extremely preterm infants. The effect was partly mediated by ANS-associated reductions in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia. These results support prompt administration of ANS, with the goal of a complete course prior to delivery.