Risk factors and epidemiology of spontaneous intestinal perforation among infants born at 22-24 weeks' gestational age.

OBJECTIVE: To describe the epidemiology, risk factors, and timing of spontaneous intestinal perforation (SIP) among infants born at 22-24 weeks' gestational age (GA). STUDY DESIGN: Observational cohort study among infants born at 22-24 weeks' GA in 446 neonatal intensive care units. RESULTS: We identified 9712 infants, of whom 379 (3.9%) developed SIP. SIP incidence increased with decreasing GA (P < 0.001). Antenatal magnesium (odds ratio (OR) 1.42; 95% confidence interval (CI), 1.09-1.85), antenatal indomethacin (OR 1.40; 95% CI, 1.06-1.85), postnatal indomethacin (OR 1.61; 95% CI, 1.23-2.11), and postnatal hydrocortisone exposure (OR 2.02; 95% CI 1.50-2.73) were associated with SIP. Infants who lost 15-20% (OR 1.77; 95% CI, 1.28-2.44) or >20% (OR 2.04; 95% CI, 1.46-2.85) of birth weight had higher odds of SIP than infants with weight loss <10%. CONCLUSIONS: Antenatal magnesium exposure, antenatal indomethacin exposure, postnatal hydrocortisone exposure, postnatal indomethacin exposure, and weight loss ≥15% were associated with SIP.

20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis.

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.

The effects of betamethasone on the amplitude integrated EEG of infants born at 34- or 35-weeks gestation.

OBJECTIVE: Assess if maternal betamethasone administration at 34-35 weeks accelerated neonatal amplitude integrated EEG (aEEG) maturation. STUDY DESIGN: Nested, observational cohort in 7 centers participating in the Antenatal Late Preterm Steroid randomized trial. Up to 2 aEEGs were obtained in neonates born from 340-356 weeks gestation before 72 h (aEEG 1) and at 5-7 days (aEEG 2) if hospitalized. Personnel and aEEG central readers were masked to the intervention. The primary outcome was maturation reflected by cycle frequency; secondary outcomes were border voltage, span, and discontinuity. RESULTS: 58 neonates were enrolled (betamethasone, 28, placebo, 30). On aEEG 1, cycle frequency did not differ, but betamethasone exposed infants had a greater lower border voltage and a broader span. On aEEG 2, both groups displayed increases in lower border voltage. CONCLUSIONS: Betamethasone associated changes in lower border voltage support accelerated electrical activity. Further investigation is needed to understand the broader span.

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

The use of supplemental hydrocortisone in the management of persistent pulmonary hypertension of the newborn.

OBJECTIVE: Characterize association between hydrocortisone receipt and hospital outcomes of infants with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: Cohort study of infants ≥34 weeks with PPHN who received inhaled nitric oxide at <7 days of age (2010-2016). We generated propensity scores, and performed inverse probability-weighted regression to estimate hydrocortisone effect on outcomes: death, chronic lung disease (CLD), oxygen at discharge. RESULTS: Of 2743 infants, 30% received hydrocortisone, which was associated with exposure to mechanical ventilation, sedatives, paralytics, or vasopressors (p < 0.001). There was no difference in death, CLD, or oxygen at discharge. In infants with meconium aspiration syndrome, hydrocortisone was associated with decreased oxygen at discharge (odds ratio 0.56; 95% confidence interval 0.21, 0.91). CONCLUSIONS: There was no association between hydrocortisone receipt and death, CLD, or oxygen at discharge in our cohort. Prospective studies are needed to evaluate the effectiveness of hydrocortisone in infants with PPHN.

Augmented Reality-Assisted Video Laryngoscopy and Simulated Neonatal Intubations: A Pilot Study.

BACKGROUND: For novice providers, achieving competency in neonatal intubation is becoming increasingly difficult, possibly because of fewer intubation opportunities. In the present study, we compared intubation outcomes on manikins using direct laryngoscopy (DL), indirect video laryngoscopy (IVL) using a modified disposable blade, and augmented reality-assisted video laryngoscopy (ARVL), a novel technique using smart glasses to project a magnified video of the airway into the intubator's visual field. METHODS: Neonatal intensive care nurses (n = 45) with minimal simulated intubation experience were randomly assigned (n = 15) to the following 3 groups: DL, IVL, and ARVL. All participants completed 5 intubation attempts on a manikin using their assigned modalities and received verbal coaching by a supervisor, who viewed the video while assisting the IVL and ARVL groups. The outcome and time of each attempt were recorded. RESULTS: The DL group successfully intubated on 32% of attempts compared to 72% in the IVL group and 71% in the ARVL group (P < .001). The DL group intubated the esophagus on 27% of attempts, whereas there were no esophageal intubations in either the IVL or ARVL groups (P < .001). The median (interquartile range) time to intubate in the DL group was 35.6 (22.9-58.0) seconds, compared to 21.6 (13.9-31.9) seconds in the IVL group and 20.7 (13.2-36.5) seconds in the ARVL group (P < .001). CONCLUSIONS: Simulated intubation success of neonatal intensive care nurses was significantly improved by using either IVL or ARVL compared to DL. Future prospective studies are needed to explore the potential benefits of this technology when used in real patients.

Survival, Morbidities, and Developmental Outcomes among Low Birth Weight Infants with Congenital Heart Defects.

OBJECTIVE: Prematurity and low birth weight (LBW) are risk factors for increased morbidity and mortality in infants with congenital heart defects (CHDs). We sought to describe survival, inhospital morbidities, and 2-year neurodevelopmental follow-up in LBW infants with CHD. STUDY DESIGN: We included infants with birth weight (BW) <2,500 g diagnosed with CHD (except isolated patent ductus arteriosus) admitted January 2013 to March 2016 to a single level-IV academic neonatal intensive care unit. We reported CHD prevalence by BW and gestational age; selected in-hospital morbidities and mortality by infant BW, CHD type, and surgical intervention; and developmental outcomes by Bayley's scales of infant and toddler development, third edition (BSID-III) scores at age 2 years. RESULTS: Among 420 infants with CHD, 28 (7%) underwent cardiac surgery. Median (25th and 75th percentiles) gestational age was 30 (range: 27-33) weeks and BW was 1,258 (range: 870-1,853) g. There were 134 of 420 (32%) extremely LBW (<1,000 g) infants, 82 of 420 (20%) were small for gestational age, and 51 of 420 (12%) multiples. Most common diagnosis: atrial septal defect (260/420, 62%), followed by congenital anomaly of the pulmonary valve (75/420, 18%). Most common surgical procedure: pulmonary artery banding (5/28, 18%), followed by the tetralogy of Fallot corrective repair (4/28, 14%). Survival to discharge was 88% overall and lower among extremely LBW (<1,000 g, 81%) infants and infants undergoing surgery (79%). Comorbidities were common (35%); retinopathy of prematurity and bronchopulmonary dysplasia were most prevalent. BSID-III scores were available on 148 of 176 (84%); any scores <85 were noted in 73 of 148 (49%), with language being most commonly affected. CONCLUSION: Among LBW infants with congenital heart disease, hospital mortality varied by BW and cardiac diagnosis. KEY POINTS: · In low birth weight infants with congenital heart disease, survival varied by birth weight and cardiac diagnosis.. · Overall survival was higher than previously reported.. · There were fewer morbidities than previously reported.. · Bayley's scale-III scores at 2 years of age were <85 for nearly half..

Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.

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.

Racial/Ethnic Disparities Among Extremely Preterm Infants in the United States From 2002 to 2016.

Importance: Racial/ethnic disparities in quality of care among extremely preterm infants are associated with adverse outcomes. Objective: To assess whether racial/ethnic disparities in major outcomes and key care practices were changing over time among extremely preterm infants. Design, Setting, and Participants: This observational cohort study used prospectively collected data from 25 US academic medical centers. Participants included 20 092 infants of 22 to 27 weeks' gestation with a birth weight of 401 to 1500 g born at centers participating in the National Institute of Child Health and Human Development Neonatal Research Network from 2002 to 2016. Of these infants, 9316 born from 2006 to 2014 were eligible for follow-up at 18 to 26 months' postmenstrual age (excluding 5871 infants born before 2006, 2594 infants born after 2014, and 2311 ineligible infants including 64 with birth weight >1000 g and 2247 infants with gestational age >26 6/7 weeks), of whom 745 (8.0%) did not have known follow-up outcomes at 18 to 26 months. Main Outcomes and Measures: Rates of mortality, major morbidities, and care practice use over time were evaluated using models adjusted for baseline characteristics, center, and birth year. Data analyses were conducted from 2018 to 2019. Results: In total, 20 092 infants with a mean (SD) gestational age of 25.1 (1.5) weeks met the inclusion criteria and were available for the primary outcome: 8331 (41.5%) black infants, 3701 (18.4%) Hispanic infants, and 8060 (40.1%) white infants. Hospital mortality decreased over time in all groups. The rate of improvement in hospital mortality over time did not differ among black and Hispanic infants compared with white infants (black infants went from 35% to 24%, Hispanic infants went from 32% to 27%, and white infants went from 30% to 22%; P = .59 for race × year interaction). The rates of late-onset sepsis among black infants (went from 37% to 24%) and Hispanic infants (went from 45% to 23%) were initially higher than for white infants (went from 36% to 25%) but decreased more rapidly and converged during the most recent years (P = .02 for race × year interaction). Changes in rates of other major morbidities did not differ by race/ethnicity. Death before follow-up decreased over time (from 2006 to 2014: black infants, 14%; Hispanic infants, 39%, white infants, 15%), but moderate-severe neurodevelopmental impairment increased over time in all racial/ethnic groups (increase from 2006 to 2014: black infants, 70%; Hispanic infants, 123%; white infants, 130%). Rates of antenatal corticosteroid exposure (black infants went from 72% to 90%, Hispanic infants went from 73% to 83%, and white infants went from 86% to 90%; P = .01 for race × year interaction) and of cesarean delivery (black infants went from 45% to 59%, Hispanic infants went from 49% to 59%, and white infants went from 62% to 63%; P = .03 for race × year interaction) were initially lower among black and Hispanic infants compared with white infants, but these differences decreased over time. Conclusions and Relevance: Among extremely preterm infants, improvements in adjusted rates of mortality and most major morbidities did not differ by race/ethnicity, but rates of neurodevelopmental impairment increased in all groups. There were narrowing racial/ethnic disparities in important care practices, including the use of antenatal corticosteroids and cesarean delivery.

Gastrostomy Tube Feeding in Extremely Low Birthweight Infants: Frequency, Associated Comorbidities, and Long-term Outcomes.

OBJECTIVE: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes. STUDY DESIGN: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables. RESULTS: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up. CONCLUSIONS: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure.

Growth failure during infancy is a major global problem that has adverse effects on long-term health and neurodevelopment. Preterm infants are disproportionately affected by growth failure and its effects. Herein we found that extremely preterm infants with postnatal growth failure have disrupted maturation of the intestinal microbiota, characterized by persistently low diversity, dominance of pathogenic bacteria within the Enterobacteriaceae family, and a paucity of strictly anaerobic taxa including Veillonella relative to infants with appropriate postnatal growth. Metabolomic profiling of infants with growth failure demonstrated elevated serum acylcarnitines, fatty acids, and other byproducts of lipolysis and fatty acid oxidation. Machine learning algorithms for normal maturation of the microbiota and metabolome among infants with appropriate growth revealed a pattern of delayed maturation of the microbiota and metabolome among infants with growth failure. Collectively, we identified novel microbial and metabolic features of growth failure in preterm infants and potentially modifiable targets for intervention.

Genetic variants associated with patent ductus arteriosus in extremely preterm infants.

OBJECTIVE: Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants. STUDY DESIGN: Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables. RESULTS: SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons. CONCLUSION: We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants.

Prolonged furosemide exposure and risk of abnormal newborn hearing screen in premature infants.

BACKGROUND: At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. AIMS: Evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants. STUDY DESIGN: Using propensity scoring, infants with prolonged (≥28 days) exposure to furosemide were matched to infants never exposed. The matched sample was used to estimate the impact of prolonged furosemide exposure on the probability of an abnormal hearing screen prior to hospital discharge. SUBJECTS: A cohort of infants 501-1250 g birth weight and 23-29 weeks gestational age discharged home from 210 neonatal intensive care units in the United States (2004-2013). OUTCOME MEASURES: We defined abnormal hearing screen as a result of either "fail" or "refer" for either ear. RESULTS: Altogether, 1020 infants exposed to furosemide for ≥28 days were matched to 790 unique infants never exposed, yielding a total of 1042 matches due to sampling with replacement and propensity score ties. Matching resulted in a population similar in baseline characteristics. After adjusting for covariates, the proportion of infants with an abnormal hearing screen in the furosemide-exposed group was not significantly higher than the never-exposed group (absolute difference 3.0% [95% CI -0.2-6.2%], P = 0.07). CONCLUSIONS: Prolonged furosemide exposure was associated with a positive, but not statistically significant, difference in abnormal hearing screening in premature infants. Additional studies with post-hospital discharge audiology follow-up are needed to further evaluate the safety of furosemide in this population.

Outcomes of preterm infants treated with hypothermia for hypoxic-ischemic encephalopathy.

BACKGROUND: Therapeutic hypothermia reduces the risk of death, or moderate to severe neurodevelopmental impairment (NDI) in term infants with hypoxic-ischemic encephalopathy (HIE). Reports of its safety and efficacy in preterm infants are scarce. OBJECTIVE: Report short and long-term outcomes of preterm infants with HIE who received therapeutic hypothermia. METHODS: A retrospective cohort analysis of all preterm infants <36 weeks' gestation with HIE who received whole body hypothermia in a single center from January 2007 to April 2015. The primary outcome was death or moderate to severe NDI defined by moderate or severe cerebral palsy, severe hearing or visual impairment, or cognitive score < 85 on the Bayley Scales of Infant Development III (BSID III) at 18-24 months' adjusted age. RESULTS: 30 infants with a median gestational age and birthweight of 35 weeks' (range; 33-35) and 2575 g (1850-4840) and a median first postnatal blood pH of 6.81 (6.58-7.14). Complications included coagulopathy (50%), early clinical seizures (43.3%), arterial hypotension (40%), persistent metabolic acidosis (37%) and thrombocytopenia (20%). Four infants died before or soon after discharge (18.2%). Eighteen surviving infants (69.2%) had follow up data; 7 of them had moderate to severe NDI (38.9%). Cognitive, motor and language mean composite BSID III scores were 84 (54-110), 83 (46-118), and 78 (46-112). Death or moderate to severe NDI occurred in 11/22 (50%) infants with known outcomes. CONCLUSION: Large randomized trials on efficacy and safety are needed in this highly vulnerable population as the incidence of complications and the combined outcome of death and NDI is concerning.

Antifungal Susceptibility and Clinical Outcome in Neonatal Candidiasis.

BACKGROUND: Invasive candidiasis is an important cause of sepsis in extremely low birth weight infants (ELBW, < 1000 g), is often fatal, and frequently results in neurodevelopmental impairment (NDI) among survivors. We sought to assess the antifungal minimum inhibitory concentration (MIC) distribution for Candida in ELBW infants and evaluate the association between antifungal resistance and death or NDI. METHODS: This was a secondary analysis of a National Institute of Child Health and Human Development Neonatal Research Network study. MIC values were determined for fluconazole, amphotericin B and micafungin. NDI was assessed at 18-22 months adjusted age using the Bayley Scales of Infant Development. An infant was defined as having a resistant Candida isolate if ≥ 1 positive cultures from normally sterile sites (blood, cerebrospinal fluid, or urine) were resistant to ≥ 1 antifungal agent. In addition to resistance status, we categorized fungal isolates according to MIC values (low and high). The association between death/NDI and MIC level was determined using logistic regression, controlling for gestational age and Bayley Scales of Infant Development (II or III). RESULTS: Among 137 ELBW infants with IC, MICs were determined for 308 isolates from 110 (80%) infants. Three Candida isolates from 3 infants were resistant to fluconazole. None were resistant to amphotericin B or micafungin. No significant difference in death, NDI, or death/NDI between groups with low and high MICs was observed. CONCLUSIONS: Antifungal resistance was rare among infecting Candida isolates, and MIC level was not associated with increased risk of death or NDI in this cohort of ELBW infants.

Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids.

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

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.

Markers of Successful Extubation in Extremely Preterm Infants, and Morbidity After Failed Extubation.

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.

Genome-wide association study of sepsis in 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 Network's 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<10-5. 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<0.001 and FDR<20%). 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.