Kaashif Aqeeb Ahmad

Importance Neonatal clinical trials frequently encounter low enrolment rates, challenges obtaining consent and biased research populations. Alternative approaches to consent have been proposed to address these concerns but introduce complex ethical trade-offs. Objective Using a modified Delphi approach with diverse stakeholders, we aimed to create recommendations for the use of alternative methods of consent in neonatal clinical trials. Findings Our process resulted in 21 recommendations within three categories. In ‘deciding whether to use alternative methods of consent’, we present five statements to guide whether alternative methods are appropriate. For example, heightened justification may be required for early phase research or allocation arms that are highly preference-sensitive for families. In ‘preallocation information and ability to opt-out’, we present 11 statements related to information sharing with families of potential participants. These include guidance on researcher communication and guidance for passive information sharing such as via flyers. In ‘postallocation information and decision to continue participation’, we present five statements to guide later information sharing. These focus on best practices for researcher communication postallocation. For two items, our Working Group could not reach consensus. These items were not included in our recommendations. Conclusions and relevance Our recommendations may guide researchers, clinicians, regulators and funders in the consideration and conduct of alternative methods of consent for neonatal clinical trials. Future work must evaluate these recommendations within neonatal clinical trials and the areas of lack of consensus among our Working Group.

Colpocephaly is a congenital brain defect characterized by enlargement of the occipital horns of the lateral ventricles. Few population-based studies have focused on this central nervous system (CNS) defect. This study aimed to evaluate the birth prevalence and survival of Texas infants with colpocephaly delivered between 1999 and 2020.Cases from the Texas Birth Defects Registry (TBDR) with a diagnosis of colpocephaly were identified. Unadjusted birth prevalence, 1-year survival estimates, and crude hazard ratios with 95% confidence intervals (CIs) were calculated from data collected from the medical record abstraction and linked vital records. Select maternal and infant variables were assessed overall and across four medical classification groups (presence of isolated, chromosomal, syndromic, or multiple major defects).From 1999 to 2020, 1,146 cases with colpocephaly were identified. The overall birth prevalence of colpocephaly was 1.36/10,000 live births (95% CI: 1.28–1.44). Significantly higher prevalence was noted for male infants, infants with low birth weight (<2,500 g), and very preterm (<32 weeks) infants. Overall, 1-year survival was 89.5%, with statistically significant differences observed in each medical classification group (e.g., isolated) across levels of maternal education, Texas/Mexico border maternal residence at delivery, infant birth weight, and gestational age.These findings have important implications for pediatric neurology and future research, such as counseling on the prevalence and prognosis of colpocephaly. Additionally, these findings highlight that the population burden of CNS defects may be higher than previously believed, supporting the expansion of research of rare brain defects.

Background and Objectives: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin (Epo) or placebo for neonates with HIE treated with therapeutic hypothermia. Methods: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at five one-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire cEEG recording was calculated using the arithmetic mean of the five EEG background ratings (normal=0; discontinuous=1; severely abnormal=2) as follows: “predominantly normal” (mean=0), “normal/discontinuous” (0<mean<1), “predominantly discontinuous” (mean=1), “discontinuous/severely abnormal” (1<mean<2), or “predominantly severely abnormal” (mean=2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1 or cognitive score <90 on Bayley Scales of Infant Toddler Development, 3rd edition at age two years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, or severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for effects of treatment group, sex, HIE severity, and study recruitment site. Results: Among 142 neonates, predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n=36, 25%) were significantly more likely to die or have severe neurodevelopmental impairment at two years (adjusted relative risk: 7.95, 95% confidence interval 3.49–18.12). Discussion: EEG background is strongly associated with NDI at age two years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision making related to goals of care. NCT02811263.

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Its etiology is multifactorial and is attributed to genetic susceptibility to prenatal and postnatal factors. As advancements in neonatology have led to the increased survival of premature infants, a parallel increase in the incidence of BPD has occurred. Over time, the definition and diagnostic criteria for BPD have evolved, as have management strategies. However, challenges continue to exist in the management of these infants, which is not surprising given the complexity of the disease. We summarize the key diagnostic criteria and provide insight into the challenges related to various aspects of BPD definitions, data comparisons, and clinical care implementation.

Objective Clinical decision support tools (CDSTs) are common in neonatology, but utilization is rarely examined. We examined the utilization of four CDSTs in newborn care. Study Design A 72-field needs assessment was developed. It was distributed to listservs encompassing trainees, nurse practitioners, hospitalists, and attendings. At the conclusion of data collection, responses were downloaded and analyzed. Results We received 339 fully completed questionnaires. BiliTool and the Early-Onset Sepsis (EOS) tool were used by > 90% of respondents, the Bronchopulmonary Dysplasia tool by 39%, and the Extremely Preterm Birth tool by 72%. Common reasons CDSTs did not impact clinical care included lack of electronic health record integration, lack of confidence in prediction accuracy, and unhelpful predictions. Conclusion From a national sample of neonatal care providers, there is frequent but variable use of four CDSTs. Understanding the factors that contribute to tool utility is vital prior to development and implementation. Key Points

Background The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). Methods A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks’ gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. Results Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks’ 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. Conclusions We find no support for an increased risk of BPD with iron supplementation. Trial registration number NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 Impact Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24–27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Objective Since 2010, the American College of Obstetrics and Gynecology have released three committee opinions to recommend and reaffirm the utility of magnesium sulfate for neuroprotection and later for tocolysis to achieve antenatal steroid course completion in preterm labor. We sought to determine changes in antenatal magnesium sulfate exposure and other tocolytic agents for pregnancies resulting in neonatal intensive care unit (NICU)-admitted preterm infants. Study Design Using the Pediatrix Clinical Data Warehouse, we evaluated all inborn infants delivered between 22 and 33 weeks' gestation and admitted to the intensive care units from 2009 to 2018. We classified patients based on antenatal exposure to tocolytic medications: calcium channel blockers (nifedipine and amlodipine), betamimetics (terbutaline, theophylline, and ritodrine), prostaglandin inhibitors (indomethacin), and magnesium sulfate. Results A total of 229,781 patients met inclusion criteria. During the study period, magnesium sulfate exposure increased from 27.6 to 57.7% of births while betamimetic exposure decreased from 10.2 to 5.2%. Increasing magnesium sulfate exposure over time was seen at all gestational ages examined and magnesium exposure was most common between 23 and 31 weeks' gestation. By 2017 to 2018, 70.5% of 24 to 29 weeks' gestation NICU infants received exposure to at least one tocolytic agent while this remained at 53.7% of 32 to 33 weeks' NICU admitted infants. Antenatal steroid exposure increased from 74.8 to 87.4% during the study period. Conclusion For NICU-admitted preterm infants, prenatal exposure patterns to tocolytic agents has shifted since 2009 with prenatal magnesium sulfate exposure increasing significantly. Antenatal steroid exposure has risen concurrently. Exposure to tocolytic agents is the highest among preterm infants born between 24 and 29 weeks' gestation. Key Points