The physiologic definition of BPD reduced the overall rate of BPD and reduced the variation among centers. Significant center differences in the impact of the physiologic definition were seen, and differences remained even with the use of this standardized definition. The magnitude of the change in BPD rate is comparable to the magnitude of treatment effects seen in some clinical trials in BPD. The physiologic definition of BPD facilitates the measurement of BPD as an outcome in clinical trials and the comparison between and within centers over time.

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures. METHODS:The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a firstline treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists.RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P , .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). CONCLUSIONS:In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.WHAT'S KNOWN ON THIS SUBJECT: In 1999, a randomized controlled trial comparing phenobarbital and phenytoin in neonates revealed that each drug had 45% efficacy. These treatments remain the standard of care for neonatal seizures. Levetiracetam has a better safety profile; however, its efficacy is unproven in neonates.WHAT THIS STUDY ADDS: In this study conducted in the hypothermia era and with near real-time response to continuous video EEG monitoring, phenobarbital was more effective than levetiracetam in achieving seizure cessation. Dose-finding studies and phase III trials with long-term outcomes are needed.

Objective To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. Study design A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. Results At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). Conclusions In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. Trial registration ClinicalTrials.gov: NCT01958320.

IMPORTANCE Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation. OBJECTIVE To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping. DESIGN, SETTING, AND PARTICIPANTS Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks' gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018. INTERVENTIONS Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin. RESULTS Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, −2% to 9%]; P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%]; P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks' gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%]; P = .002). CONCLUSIONS AND RELEVANCE In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks' gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulti...

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.