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Ectopic pregnancy has become a surgical epidemic over the past two decades. To minimize the morbidity, mortality, and financial burden created by this rapidly growing health problem, nonsurgical alternatives have been investigated, including treatment with methotrexate. We reviewed current literature to evaluate the safety, efficacy, and costs associated with methotrexate treatment of tubal pregnancy. To date, 17 studies have reported on 400 patients with tubal pregnancies treated with parenteral methotrexate; the overall success rate was 92% (95% confidence interval, 89% to 95%). Single-dose parenteral methotrexate has been shown to be safe, effective, and associated with minimal costs when used in carefully selected patients. A prospective, randomized clinical trial comparing medical and surgical management of ectopic pregnancy is needed to assess the risks, benefits, and costs of these two approaches. [ABSTRACT FROM AUTHOR]

Background and Objectives: Opioid maintenance treatment (OMT), with methadone or buprenorphine, is a key approach for managing opioid use disorder (OUD) during pregnancy. Despite buprenorphine's superior short-term outcomes, its long-term effects remain understudied. This study aims to evaluate the effects of prenatal OMT exposure on the incidence of childhood neurodevelopmental disorders (NDDs) considering timing effect., Methods: A retrospective cohort study using Rhode Island Medicaid data linked to vital statistics from 2008 to 2018 was conducted. The study included pregnancies having live birth from 2008 to 2016 with continuous Medicaid insurance and OUD diagnosis within 3 months preceding conception until delivery. At least one buprenorphine dispensing or a claim of methadone was required for exposure definition. Exposure was evaluated during early (0-90 days) or late (>90 days) gestation, or at any pregnancy phase. NDDs, including autism, attention-deficit/hyperactivity disorder (ADHD), learning disabilities, speech/language disorders, developmental coordination disorder, intellectual disability, and behavioral disorders, were identified using validated algorithms. Applying Cox proportional-hazard models with propensity score overlap weighting, adjusted hazard ratios (aHR) were calculated, mitigating potential confounders. Children were followed up from birth until NDD diagnosis, disenrollment, or study end., Results: Of 416 mother-child dyads with OUD, 40% used methadone and 20% had buprenorphine exposure during pregnancy. NDDs were observed in 36% of children with early methadone exposure compared to 17% in the early buprenorphine exposed group (aHR: 2.75; 95% confidence interval [CI]: 1.42-5.35). Further comparison to late buprenorphine exposure, late methadone exposure was associated with higher NDD risk (aHR: 2.05; 95% CI: 1.09-3.86). Compared to unexposed group, children exposed to methadone during early and late periods showed higher NDD incidences (aHR: 2.33; 95% CI: 1.51-3.60 and aHR: 2.42; 95% CI: 1.54-3.80, respectively)., Discussion: The study suggests that buprenorphine is a good treatment option for OUD during pregnancy due to minimal long-term neurodevelopmental impacts on children. However, further extensive research is necessary to rule-out potential confounding., (© 2024 Pharmacotherapy Publications, Inc.)

The authors summarize the methodology for a new pragmatic comparative effectiveness research investigation, Cooling Prospectively Infants with Mild Encephalopathy (COOLPRIME), which uses sites' existing mild hypoxic-ischemic encephalopathy (HIE) treatment preference (hypothermia or normothermia) to assess hypothermia effectiveness and safety. COOLPRIME's primary aim is to determine the safety and effectiveness of hypothermia compared to normothermia in mild HIE. Engagement of Families and Community Affected by Hypoxic-Ischemic Encephalopathy strongly favored Effectiveness over Efficacy Trials leading to COOL PRIME design., Competing Interests: Disclosure The authors have no conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Off-label treatment of extremely preterm infants with diuretics and inhaled corticosteroids (ICS) for evolving bronchopulmonary dysplasia (BPD) is common. Their effectiveness in reducing mortality or BPD severity, and optimal treatment timing, are unclear., Objectives: To determine whether diuretic treatment or ICS administration for infants with early evolving (between 10-27 days postnatal) and progressively evolving (28th-day-36th-week postnatal) BPD are independently associated with reduced mortality and moderate or severe BPD at 36-weeks postmenstrual age (PMA)., Methods: We examined neonates born before 28 weeks' gestation and admitted to neonatal intensive care units on postnatal Day 0 between 2006 and 2016 using data collected during routine care recorded within the Paediatric Health Information System (PHIS). An early evolving BPD cohort consisted of infants treated with oxygen, positive pressure or mechanical ventilation at 10 days postnatal. The progressively evolving BPD cohort consisted of infants treated with these modalities at 28 days. In new users, we evaluated the effect of diuretic and ICS treatment on mortality or BPD severity at 36 weeks PMA, adjusting for time-dependent confounding by respiratory status using marginal structural models., Results: Early evolving BPD was present in 10,135 patients; progressively evolving BPD in 11,728. New diuretic exposure during early evolving BPD (adjusted risk ratio [aRR] 0.77, 95% confidence interval [CI] 0.65, 0.93) was associated with decreased mortality or moderate/severe BPD risk. New diuretics (aRR 0.86, 95% CI 0.75, 0.99) during progressively evolving BPD between 28-days-36-weeks PMA were less strongly associated with mortality or moderate/severe BPD reduction. There was no strong association for ICS in patients with early evolving (aRR: 1.40; 95% CI: 0.79, 2.51) or progressively evolving BPD (aRR 1.16, 95% CI 0.95, 1.49)., Conclusion: Diuretics, but not ICS, for evolving BPD were associated with mortality and BPD risk reduction., (© 2024 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: Rising admission rates of Hispanic/Latinx families to the neonatal intensive care unit (NICU) have increased the number of non-English-speaking individuals who may wish to participate in research studies. However, a lack of appropriately translated research study materials may limit the opportunity for these families to be involved in research that could impact the care that infants and families receive in the NICU., Purpose: The primary purpose was to pilot test study materials that were transcreated from English to Spanish with the assistance of a bilingual community advisory board with Spanish-speaking parents of NICU infants., Methods: A total of 19 Spanish-speaking parents (15 mothers and 4 fathers) who were representative of the population of interest completed paper-and-pencil surveys, along with a cognitive interview. Preliminary data related to decision-making and goals of care, infant symptoms, and their experiences in the NICU were also collected., Results: The internal reliability of the transcreated study instruments ranged from good to excellent (α= 0.82-0.99). Participants reported that study materials were not offensive and did not make them feel uncomfortable; however, they found some words/phrases to be confusing. Parents had the opportunity to provide suggested wording changes., Implications for Practice and Research: Language barriers and a lack of cultural responsiveness can affect the care that infants and their families receive. More accurate and culturally appropriate transcreation of study materials can remove barriers to research participation and facilitate better communication with non-English-speaking families, which may lead to the development of better-informed evidence-based interventions and clinical practices in the NICU., (Copyright © 2024 by The National Association of Neonatal Nurses.)

Objective: This article evaluates the risk (defined here as incidence per 1,000 infants) of developmental dysplasia of the hip (DDH) in premature infants undergoing hip ultrasound (HUS) for breech presentation only compared with other indications., Study Design: Retrospective study of infants born between January 1, 2009 and December 31, 2018 at <37 weeks' gestation with a HUS obtained in the first year of life, at Nationwide Children's Hospital, the only available facility for pediatric radiology and orthopaedic services in central Ohio. We calculated risk differences and odds ratios of DDH by the indication of HUS., Results: From 2,397 infants reviewed, 89% underwent HUS for breech presentation only. The local incidence of DDH for infants undergoing HUS for breech-only indication was 15 per 1,000 compared with 155 per 1,000 for infants undergoing HUS for other indications. The odds ratio of DDH diagnosis was 12.1 (95% confidence interval: 7.5, 19.6) for infants undergoing HUS for an indication other than breech presentation only relative to infants undergoing HUS for the indication of breech presentation only., Conclusion: The risk of DDH diagnosis in premature infants undergoing HUS for breech presentation is much lower than those undergoing HUS for clinical concerns and other risk factors. Screening these infants with physical examination may be sufficient., Key Points: · Breech presentation is the most common indication for hip ultrasound in premature infants.. · The risk of DDH is lower in premature infants with breech presentation compared with premature infants with other clinical concerns.. · The risk of DDH is higher in infants born at 33 to 36 weeks of gestation compared with those born at an earlier gestation.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Acid reflux index (ARI) is a biomarker for gastroesophageal reflux disease (GERD). The effects of short-term proton pump inhibitor (PPI) therapy on pharyngoesophageal motility and clearance mechanisms in infants remain unknown. We hypothesized that pharyngoesophageal reflexes and response to PPI are distinct between infants with 3%-7% and >7% ARI., Methods: Secondary analysis was performed from a subset of infants who participated in a randomized controlled trial (NCT: 02486263). Infants (N = 36, 29.9 ± 4.3 weeks gestation) underwent 4 weeks of PPI therapy, 1 week of washout, and longitudinal testing to assess: (a) clinical outcomes; (b) pH-impedance and symptom metrics including ARI, distal baseline impedance, clearance time, refluxate height, symptoms, I-GERQ-R scores, symptom association probability; (c) pharyngoesophageal motility reflexes and sensory motor characteristics. Comparisons were performed between infants with 3%-7% versus >7% ARI., Key Results: From the 36 hospitalized infants treated: Pharyngoesophageal reflex latencies were prolonged (p > 0.05) and duration in ARI 3%-7% group only (p = 0.01); GER frequency, proximal ascent and clearance increased (ARI 3%-7%); weight gain velocity, oral feeding success, and fine motor score decreased while length of hospital stays increased in the ARI >7% group despite the decrease in symptoms and I-GERQ-R scores., Conclusions & Inferences: Distinct changes in pharyngoesophageal sensory motor aspects of motility and reflex mechanisms exist after using PPI therapy in infants. Contributory factors may include the effects of maturation and aerodigestive comorbidities (GERD and BPD). Controlled studies incorporating placebo are needed to delineate the effects of PPI on causal and adaptive GERD mechanisms in infants with aerodigestive and feeding-related comorbidities., (© 2023 John Wiley & Sons Ltd.)

This study explores natural direct and joint natural indirect effects (JNIE) of prenatal opioid exposure on neurodevelopmental disorders (NDDs) in children mediated through pregnancy complications, major and minor congenital malformations, and adverse neonatal outcomes, using Medicaid claims linked to vital statistics in Rhode Island, United States, 2008-2018. A Bayesian mediation analysis with elastic net shrinkage prior was developed to estimate mean time to NDD diagnosis ratio using posterior mean and 95% credible intervals (CrIs) from Markov chain Monte Carlo algorithms. Simulation studies showed desirable model performance. Of 11,176 eligible pregnancies, 332 had ≥2 dispensations of prescription opioids anytime during pregnancy, including 200 (1.8%) having ≥1 dispensation in the first trimester (T1), 169 (1.5%) in the second (T2), and 153 (1.4%) in the third (T3). A significant JNIE of opioid exposure was observed in each trimester (T1, JNIE = 0.97, 95% CrI: 0.95, 0.99; T2, JNIE = 0.97, 95% CrI: 0.95, 0.99; T3, JNIE = 0.96, 95% CrI: 0.94, 0.99). The proportion of JNIE in each trimester was 17.9% (T1), 22.4% (T2), and 56.3% (T3). In conclusion, adverse pregnancy and birth outcomes jointly mediated the association between prenatal opioid exposure and accelerated time to NDD diagnosis. The proportion of JNIE increased as the timing of opioid exposure approached delivery., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To test the hypothesis that elevations in the respiratory severity score (RSS) are associated with increased probability of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH)., Study Design: Retrospective cohort study of infants born extremely preterm admitted to a BPD center between 2010 and 2018. Echocardiograms obtained ≥ 36 weeks' post-menstrual age (PMA) were independently adjudicated by two blinded cardiologists to determine the presence/absence of BPD-PH. Multivariable logistic regression estimated the association between RSS and BPD-PH., Result: BPD-PH was observed in 68/223 (36%) of subjects. The median RSS at time of echocardiography was 3.04 (Range 0-18.3). A one-point increase in the RSS was associated with BPD-PH, aOR 1.3 (95% CI 1.2-1.4), after adjustment for gestational age and PMA at time of echocardiography., Conclusion: Elevations in the RSS were associated with a greater probability of BPD-PH. Prospective studies are needed to determine the validity and performance of RSS as a clinical susceptibility/risk biomarker for BPD-PH., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To describe the current practices in invasive patent ductus arteriosus (PDA) closure (surgical ligation or transcatheter occlusion) in very low birth weight (VLBW) infants and changes in patient characteristics and outcomes from 2016 to 2021 among US children's hospitals., Study Design: We evaluated a retrospective cohort of VLBW infants (birth weight 400-1499 g and gestational age 22-31 weeks) who had invasive PDA closure within 6 months of age from 2016 to 2021 in children's hospitals in the Pediatric Health Information System. Changes in patient characteristics and outcomes over time were evaluated using generalized linear models and generalized linear mixed models., Results: 2418 VLBW infants (1182 surgical ligation; 1236 transcatheter occlusion) from 42 hospitals were included. The proportion of infants receiving transcatheter occlusion increased from 17.2% in 2016 to 84.4% in 2021 (P < .001). In 2021, 28/42 (67%) hospitals had performed transcatheter occlusion in > 80% of their VLBW infants needing invasive PDA closure, compared with only 2/42 (5%) in 2016. Although median postmenstrual age (PMA) at PDA closure did not change for the overall cohort, PMA at transcatheter occlusion decreased from 38 weeks in 2016 to 31 weeks by 2020, P < .001. Among those infants not intubated prior to PDA closure, extubation within 3 days postprocedure increased over time (yearly adjusted odds ratios of 1.26 [1.08-1.48]). Length of stay and mortality did not change over time., Conclusion: We report rapid adoption of transcatheter occlusion for PDA among VLBW infants in US children's hospitals over time. Transcatheter occlusions were performed at younger PMA over time., Competing Interests: Declaration of Competing Interest D.M. is a consultant for Abbott, Edwards, and Medtronic. J.L.S. receives supplemental grant funding from Abbott for the NHLBI-sponsored PIVOTAL trial (UH3HL161338). The other authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Off-label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision-makers in applying research evidence to inform off-label medicines use. We aimed to critically evaluate current evidence informing decision-making for off-label use and to develop consensus recommendations to improve future practice and research., Methods: We conducted a scoping review to summarize the literature on available off-label use guidance, including types, extent and scientific rigor of evidence incorporated. Findings informed the development of consensus recommendations by an international multidisciplinary Expert Panel using a modified Delphi process. Our target audience includes clinicians, patients and caregivers, researchers, regulators, sponsors, health technology assessment bodies, payers and policy makers., Results: We found 31 published guidance documents on therapeutic decision-making for off-label use. Of 20 guidances with general recommendations, only 35% detailed the types and quality of evidence needed and the processes for its evaluation to reach sound, ethical decisions about appropriate use. There was no globally recognized guidance. To optimize future therapeutic decision-making, we recommend: (1) seeking rigorous scientific evidence; (2) utilizing diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking off-label use with timely conduct of clinically meaningful research (including real-world evidence) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision-makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations., Conclusions: We provide comprehensive consensus recommendations to optimize therapeutic decision-making for off-label medicines use and concurrently drive clinically relevant research. Successful implementation requires appropriate funding and infrastructure support to engage necessary stakeholders and foster relevant partnerships, representing significant challenges that policy makers must urgently address., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Fluid overload leads to poor neonatal outcomes. Diuretics may lower the rates of mechanical ventilation (MV) and mortality in neonates with fluid overload., Methods: This is a retrospective study of preterm neonates ≤ 36 weeks of gestational age (GA) in the first 14 postnatal days in a level IV NICU in 2014-2020. We evaluated the epidemiology of fluid balance in the first 14 postnatal days and its association with MV and mortality and studied the association of diuretics with fluid balance, MV, and mortality., Results: In 1383 included neonates, the overall median lowest and peak fluid balances were - 7.8% (IQR: - 11.7, - 4.6) and 8% (3, 16) on days 3 (2, 5) and 13 (5, 14), respectively. Fluid balance distribution varied significantly by GA. Peak fluid balance of ≥ 10% was associated with increased odds of MV on days 7 and 14 with highest odds ratios (OR) of MV in neonates with fluid balance ≥ 15%. Peak fluid balance of ≥ 15% was associated with the greatest odds of mortality. Diuretics were used more frequently in neonates with younger GA, smaller birthweight, positive fluid balance, and those on MV., Conclusions: Positive fluid balance negatively impacts pulmonary status. The odds of MV and death increase significantly as peak fluid balance percentage increases in all GA groups. The impact of diuretics on MV and death in preterm neonates needs further evaluation. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Admission rates of Hispanic/Latinx families to the neonatal intensive care unit (NICU) are rising, yet knowledge regarding their experiences is limited. Non-English-speaking families are often excluded from research because study measures are not available in their language. The inclusion of these families in NICU research is crucial to understand the impact of cultural and language barriers in infant and family care, and the translation of study measures into Spanish could better ensure that these families' perspectives are included. However, previous research has utilized the standard translation-backtranslation method with which problems have been noted., Purpose: This article describes the planning, preparation, and action phases that were completed with the use of a community advisory board (CAB) to prepare and transcreate research study materials from English to Spanish for pilot testing., Methods: Community members of interest were invited to form the CAB, and 2 meetings were held to review study materials in the English and Spanish versions. Prior to the second meeting, a professional translation company translated study materials from English to Spanish., Results: Feedback from the CAB ensured consistent content and reading levels, and culturally appropriate language usage. The CAB also provided suggestions to the research protocol and advised sensitive methods of recruitment and measure administration., Implications for Practice and Research: More accurate and culturally appropriate transcreation of study measures can reduce barriers to research participation and facilitate better communication with non-English-speaking families in health equity research to better inform evidence-based interventions and clinical practices across diverse groups., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 by The National Association of Neonatal Nurses.)

Objective: Estimate hospital variation in echocardiography (echo) among very preterm infants., Study Design: Retrospective cohort study of very preterm (<32 weeks) infants discharged between 2012 and 2019 from US children's hospitals. Echo exposure was identified using daily billing, and hospital variation was estimated after adjustment for illness severity. Variation in very early echo use (<3 days of life) was compared to exposure to treatment of a patent ductus arteriosus (PDA), and other practice patterns., Results: 27,498 subjects across 39 children's hospitals were included. Very early echo use had the greatest hospital variation (3-34%). Increasing very early echo use was not associated with PDA treatment (p = 0.93), but was associated with nitric oxide (p < 0.01) and vasoactive medications (p < 0.01)., Conclusions: Hospital variation in echo use among preterm infants was greatest in the first few days of life and was associated with increasing nitric oxide and vasoactive medication use. The impact of this variation on clinical outcomes is uncertain and warrants further investigation., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To evaluate serum creatinine (SCr) patterns and the development of acute kidney injury (AKI), as potential biomarkers of necrotizing enterocolitis (NEC)., Study Design: Retrospective chart review of preterm infants with and without NEC born 23-32 weeks gestation admitted to Nationwide Children's Hospital NICU. Medical versus surgical NEC was determined by radiographic and clinical findings. Available inpatient SCr levels obtained on days 8 through 365 were included., Result: In this cohort, 77 NEC and a randomly selected group of 82 non-NEC infants met inclusion criteria. Fifteen of the 70 (21.4%) with NEC met criteria for AKI versus 0 of 43 (0.0%) without NEC. One of the 13 with AKI had AKI within 7 days prior to NEC diagnosis (7.7%)., Conclusion: AKI is more prevalent in infants with NEC. The temporal association between AKI and NEC could not be evaluated due to inconsistent SCr surveillance and should be evaluated in future studies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Importance: Anti-vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) has potential ocular and systemic advantages compared with laser, but we believe the systemic risks of anti-VEGF therapy in preterm infants are poorly quantified., Objective: To determine whether there was an association with increased risk of pulmonary hypertension (PH) in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment., Design, Setting, and Participants: This multicenter retrospective cohort study took place at neonatal intensive care units of 48 children's hospitals in the US in the Pediatric Health Information System database from 2010 to 2020. Participants included preterm infants with gestational age at birth 22 0/7 to 31 6/7 weeks who had ROP treated with anti-VEGF therapy or laser photocoagulation., Exposures: Anti-VEGF therapy vs laser photocoagulation., Main Outcomes and Measures: New receipt of pulmonary vasodilators at least 7 days after ROP therapy was compared between exposure groups, matched using propensity scores generated from preexposure variables, and adjusted for birth year and hospital. The odds of receiving an echocardiogram after 30 days of age was also included to adjust for secular trends and interhospital variation in PH screening., Results: Among 1577 patients (55.9% male) meeting inclusion criteria, 689 received laser photocoagulation and 888 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab). Patients were first treated for ROP at median 36.4 weeks' postmenstrual age (IQR, 34.6-38.7). A total of 982 patients (491 in each group) were propensity score matched. Good covariate balance was achieved, as indicated by a model variance ratio of 1.15. More infants who received anti-VEGF therapy were treated for PH, but when adjusted for hospital and year, this was no longer statistically significant (6.7%; 95% CI, 2.6-6.9 vs 4.3% 95% CI, 4.4-10.2; adjusted odds ratio, 1.62; 95% CI, 0.90-2.89; P = .10)., Conclusions and Relevance: Anti-VEGF therapy was not associated with greater use of pulmonary vasodilators after adjustment for hospital and year. Our findings suggest exposure to anti-VEGF may be associated with PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities or hospital variation in practice. Future studies investigating this possible adverse effect seem warranted.

The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter closure is preferable over surgical ligation, but data on longer-term outcomes, particularly among preterm infants, are lacking. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the practice of evidence-based medicine.

Competing Interests: FINANCIAL/CONFLICT OF INTEREST DISCLOSURES: Dr Newman reported providing expert witness consultation in medical malpractice litigation. Dr Maisels reported providing expert witness review and testimony in kernicterus medical malpractice litigation. Dr Watchko disclosed a financial relationship with McGraw Hill. Dr Grout reported receiving grant funding from Pfizer for a non-pediatric study. Dr Bogen disclosed a Board of Directors relationship with Mid-Atlantic Mothers’ Milk Bank. No other disclosures were reported., (Copyright © 2022 by the American Academy of Pediatrics.)

Context: Severe hyperbilirubinemia is associated with kernicterus. Informed guidance on hyperbilirubinemia management, including preventive treatment thresholds, is essential to safely minimize neurodevelopmental risk., Objective: To update the evidence base necessary to develop the 2022 American Academy of Pediatrics clinical practice guideline for management of hyperbilirubinemia in the newborn infant ≥35 weeks' gestation., Data Source: PubMed., Study Selection: English language randomized controlled trials and observational studies. Excluded: case reports or series, nonsystematic reviews, and investigations focused on <35-weeks' gestation infants., Data Extraction: Topics addressed in the previous clinical practice guideline (2004) and follow-up commentary (2009) were updated with new evidence published through March 2022. Evidence reviews were conducted for previously unaddressed topics (phototherapy-associated adverse effects and effectiveness of intravenous immune globulin [IVIG] to prevent exchange transfusion)., Results: New evidence indicates that neurotoxicity does not occur until bilirubin concentrations are well above the 2004 exchange transfusion thresholds. Systematic review of phototherapy-associated adverse effects found limited and/or inconsistent evidence of late adverse effects, including cancer and epilepsy. IVIG has unclear benefit for preventing exchange transfusion in infants with isoimmune hemolytic disease, with a possible risk of harm due to necrotizing enterocolitis., Limitations: The search was limited to 1 database and English language studies., Conclusions: Accumulated evidence justified narrowly raising phototherapy treatment thresholds in the updated clinical practice guideline. Limited evidence for effectiveness with some evidence of risk of harm support the revised recommendations to limit IVIG use., Competing Interests: FINANCIAL/CONFLICT OF INTEREST DISCLOSURES: Dr Newman reported providing expert witness consultation in medical malpractice litigation. No other disclosures were reported., (Copyright © 2022 by the American Academy of Pediatrics.)

Importance: Birth in the periviable period between 22 weeks 0 days and 25 weeks 6 days' gestation is a major source of neonatal morbidity and mortality, and the decision to initiate active life-saving treatment is challenging., Objective: To assess whether the frequency of active treatment among live-born neonates in the periviable period has changed over time and whether active treatment differed by gestational age at birth and race and ethnicity., Design, Setting, and Participants: Serial cross-sectional descriptive study using National Center for Health Statistics natality data from 2014 to 2020 for 61 908 singleton live births without clinical anomalies between 22 weeks 0 days and 25 weeks 6 days in the US., Exposures: Year of delivery, gestational age at birth, and race and ethnicity of the pregnant individual, stratified as non-Hispanic Asian/Pacific Islander, non-Hispanic Black, Hispanic/Latina, and non-Hispanic White., Main Outcomes and Measures: Active treatment, determined by whether there was an attempt to treat the neonate and defined as a composite of surfactant therapy, immediate assisted ventilation at birth, assisted ventilation more than 6 hours in duration, and/or antibiotic therapy. Frequencies, mean annual percent change (APC), and adjusted risk ratios (aRRs) were estimated., Results: Of 26 986 716 live births, 61 908 (0.2%) were periviable live births included in this study: 5% were Asian/Pacific Islander, 37% Black, 24% Hispanic, and 34% White; and 14% were born at 22 weeks, 21% at 23 weeks, 30% at 24 weeks, and 34% at 25 weeks. Fifty-two percent of neonates received active treatment. From 2014 to 2020, the overall frequency (mean APC per year) of active treatment increased significantly (3.9% [95% CI, 3.0% to 4.9%]), as well as among all racial and ethnic subgroups (Asian/Pacific Islander: 3.4% [95% CI, 0.8% to 6.0%]); Black: 4.7% [95% CI, 3.4% to 5.9%]; Hispanic: 4.7% [95% CI, 3.4% to 5.9%]; and White: 3.1% [95% CI, 1.1% to 4.4%]) and among each gestational age range (22 weeks: 14.4% [95% CI, 11.1% to 17.7%] and 25 weeks: 2.9% [95% CI, 1.5% to 4.2%]). Compared with neonates born to White individuals (57.0%), neonates born to Asian/Pacific Islander (46.2%; risk difference [RD], -10.81 [95% CI, -12.75 to -8.88]; aRR, 0.82 [95% CI, [0.79-0.86]), Black (51.6%; RD, -5.42 [95% CI, -6.36 to -4.50]; aRR, 0.90 [95% CI, 0.89 to 0.92]), and Hispanic (48.0%; RD, -9.03 [95% CI, -10.07 to -7.99]; aRR, 0.83 [95% CI, 0.81 to 0.85]) individuals were significantly less likely to receive active treatment., Conclusions and Relevance: From 2014 to 2020 in the US, the frequency of active treatment among neonates born alive between 22 weeks 0 days and 25 weeks 6 days significantly increased, and there were differences in rates of active treatment by race and ethnicity.

Objectives: Hospitalized neonates are often treated with nephrotoxic medications, a known risk factor for acute kidney injury (AKI). Nephrotoxic medications and AKI, especially in periviable neonates, could be detrimental to nephrogenesis. Our objectives were to evaluate the prevalence of neonatal treatment with nephrotoxic medications and its relationship with AKI in in the first 28 days of life, and to delineate the associated demographics and diagnoses., Study Design: Multicenter retrospective analysis using the national Pediatric Hospital Information System database, including 49 pediatric hospitals. Neonates admitted within the first two postnatal days were included. Treatment with 37 nephrotoxic medications across demographics and clinical variables, and relationship with AKI were evaluated. AKI was determined by using the International Classification of Diseases codes., Results: Of 192,229 neonates, 74% were treated with at least one nephrotoxic medication. Incidence of AKI was significantly higher in the treated group (aRR 3.68 [95% CI: 2.85, 4.75]). The aRRs of treatment were increased in infants born < 32-week, and < 2000 g. Nephrotoxic medications were prescribed to 90-95% of  neonates born ≤ 28-week gestational age. Most treatments (95-98%) occurred in the first 3 days. Intravascular aminoglycosides were the most frequent type; 28% of neonates were treated for ≥ 4 calendar days. Most common diagnoses were infections (25%) and patent ductus arteriosus (20%)., Conclusions: Neonatal treatment with nephrotoxic medications is common, especially among the smallest, most immature preterm neonates and demonstrates a need for initiatives to reduce neonatal exposure to these agents, when feasible. Across all gestational age categories, the prevalence of AKI is higher in the neonates treated with nephrotoxic drugs. The long-term effects of treatment with nephrotoxic medications and subsequent AKI on nephrogenesis and nephron endowment will need to be evaluated., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: Infants born preterm are affected by a hypothalamic-pituitary-thyroid axis that is immature and still developing as they progress closer to corrected term gestation. Multiple risk factors place preterm infants at risk for a hypothyroid state. However, there is variability in thyroid-stimulating hormone cutoff values and limited data on free thyroxine reference intervals to guide clinicians., Methods: 1584 thyroid-stimulating hormone and 1576 free thyroxine laboratory samples that were originally collected to screen hospitalized infants for delayed-onset of hypothyroidism were retrospectively evaluated from a group of 1087 infants who ranged in postmenstrual age from 25 to 43 weeks gestation at the time of laboratory sample collection. Median thyroid hormone values and reference intervals were established using R and the mixtools package., Results: Thyroid-stimulating hormone reference intervals remained similar across gestational ages from 0.340-9.681 µIU/mL in 25-27 6/7-week infants to 1.090-7.627 µIU/mL in 40-43-weeks infants. For the same age groups, free thyroxine reference intervals increased from 0.42-0.91 ng/dL to 0.87-1.32 ng/dL., Conclusion: The reference intervals identified suggest that infants <31 weeks gestation have a higher thyroid-stimulating hormone and lower free thyroxine level at baseline than previously anticipated., Impact: The increasing free thyroxine values in preterm to term infants indicate a maturing hypothalamic-pituitary-thyroid axis. Clinicians need thyroid hormone reference intervals that also vary by postmenstrual age to aid the evaluation of sick preterm infants who are at risk of a delayed hypothyroidism diagnosis that can be missed on the initial newborn screen. This study provides one of the largest samples of thyroid-stimulating hormone and free thyroxine data to establish reference intervals in preterm infants. Clinicians may utilize the identified postmenstrual age-based reference intervals to inform follow-up thyroid testing in preterm infants at several weeks postnatal age., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Percutaneous-based patent ductus arteriosus closure is technically feasible among infants less than 1.5 kg. However, marked heterogeneity in the type and nature of adverse events obscures current safety profile assessments. Although data on the risks of postdevice closure syndrome remain promising, a lack of comparative trials of surgical ductal ligation and inconsistent surveillance across published studies obscure confidence in present estimates of safety and efficacy. To minimize risk and yield the greatest benefits, clinical studies of patent ductus arteriosus treatment should consider incorporating more robust assessments to ensure that infants at greatest risk for adverse ductal consequences are included., Competing Interests: Disclosure The authors have no financial relationships relative to this article to disclose. All authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: To evaluate and compare gastro-esophageal reflux (GER) symptom scores with pH-impedance and test the effects of acid-suppressive medications with or without feeding modifications on pH-impedance in high-risk infants., Methods: Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) and 24-hour pH-impedance data were analyzed from 94 infants evaluated in a tertiary care setting for GER disease. Longitudinal data from 40 infants that received randomized GER therapy (proton pump inhibitor [PPI] with or without feeding modifications) for 4 weeks followed by 1-week washout were analyzed. Relationships between I-GERQ-R and pH-impedance metrics (acid reflux index, acid and bolus GER events, distal baseline impedance, and symptoms) were examined and effects of treatments compared., Results: (A) Correlations between I-GERQ-R and pH-impedance metrics were weak. (B) I-GERQ-R sensitivity, specificity, and positive predictive values were suboptimal when correlated with pH-impedance metrics. I-GERQ-R negative predictive value (NPV) was high for acid symptom-association probability (NPV = 84%) and distal baseline impedence (NPV = 86%) thresholds. (C) PPI with feeding modifications (vs PPI alone) did not alter pH-impedance metrics or symptom scores ( P > .05); however, bolus clearance metrics worsened for both treatment groups ( P < .05)., Conclusions: In high-risk infants (1) I-GERQ-R may be a helpful clinical screening tool to exclude acid-GER disease diagnosis and minimize unnecessary acid-suppressive treatment, but further testing is needed for diagnosis. (2) Acid-suppressive therapy with feeding modifications has no effect on symptom scores or pH-impedance metrics. Clearance of refluxate worsened despite PPI therapy, which may signal development of pharyngoesophageal dysmotility and persistence of symptoms. (3) Placebo-controlled trials are needed in high-risk infants with objective pH-impedance criteria to determine efficacy, safety, and underlying mechanisms. Clinicaltrials.gov ID: NCT02486263., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.

Background: Acute kidney injury (AKI) in preterm infants is associated with prolonged hospitalization and high mortality. Diuretic therapy has been used to enhance urine output in preterm infants with AKI. Treatment with diuretics, prescription patterns, and relationship with length of stay (LOS), mechanical ventilation (MV), and mortality in preterm infants who also had AKI have not been fully evaluated., Methods: This multicenter retrospective study used the Pediatric Hospital Information System database. We included 2121 preterm infants with AKI diagnosis from 46 hospital Neonatal Intensive Care Units (NICUs) born <37 weeks gestational age (GA). Treatment with diuretics, practice patterns across 46 NICUs in the USA, and associated outcomes including LOS, MV, and mortality were evaluated., Results: Seventy-six percent of infants received at least one dose of diuretics (median treatment 18 days). Diuretic prescription varied significantly across hospitals and ranged from 42 to 96%. Diuretics were used more frequently in infants with younger GA and smaller birth weight. Infants with older GA who received diuretics at or before 28 days postnatally had worse survival even after adjusting for known confounders., Conclusions: Preterm infants with AKI diagnosis were frequently treated with diuretics. Moreover, infants with younger GA and smaller birth weight were more likely to receive diuretics. Worse survival in infants with older GA who received diuretics could be the result of more underlying severe illness in these infants and not the cause of more severe illness. Prospective studies are needed to best determine patient safety and outcomes with diuretic treatment in preterm infants with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. IPNA.)

Objective: Create a prioritization framework for value-based improvement in neonatal care., Study Design: A retrospective cohort study of very low birth weight (<1500 g) and/or very preterm (<32 weeks) infants discharged between 2012 and 2019 using the Pediatric Health Information System Database. Resource use was compared across hospitals and adjusted for patient-level differences. A prioritization score was created combining cost, patient exposure, and inter-hospital variability to rank resource categories., Results: Resource categories with the greatest cost, patient exposure, and inter-hospital variability were parenteral nutrition, hematology (lab testing), and anticoagulation (for central venous access and therapy), respectively. Based on our prioritization score, parenteral nutrition was identified as the highest priority overall., Conclusions: We report the development of a prioritization score for potential value-based improvement in neonatal care. Our findings suggest that parenteral nutrition, central venous access, and high-volume laboratory and imaging modalities should be priorities for future comparative effectiveness and quality improvement efforts., (© 2021. The Author(s).)

Objectives: Describe outcomes among preterm infants diagnosed with single-vessel primary pulmonary vein stenosis (PPVS) initially treated using conservative management (active surveillance with deferral of treatment)., Study Design: Retrospective cohort study at a single, tertiary-center (2009-2019) among infants <37 weeks' gestation with single-vessel PPVS. Infants were classified into two categories: disease progression and disease stabilization. Cardiopulmonary outcomes were examined, and a Kaplan-Meier survival analysis performed., Results: Twenty infants were included. Compared to infants in the stable group (0/10, 0%), all infants in the progressive group had development of at least severe stenosis or atresia (10/10, 100%; P < 0.01). Severe pulmonary hypertension at diagnosis was increased in the progressive (5/10, 50%) versus the stable group (0/10, 0%; P = 0.03). Survival was lower among infants in the progressive than the stable group (log-rank test, P < 0.01)., Conclusion: Among preterm infants with single-vessel PPVS, risk stratification may be possible, wherein more targeted, individualized therapies could be applied., (© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: To identify the relationship between prophylactic indomethacin (PI) administration and (1) mortality and bronchopulmonary dysplasia (BPD) at 36-week postmenstrual age (PMA) (primary outcome), and (2) to evaluate for PI-associated acute kidney injury., Study Design: Retrospective cohort investigation of 22-28 weeks gestation infants (N = 1167) who were admitted to Nationwide Children's Hospital on postnatal days 0-1 between May 2009 and September 2017 and survived ≥24-h postnatal. The associations of PI treatment with mortality or BPD, and other secondary outcomes, were evaluated via multivariable robust-error-variance Poisson regression., Results: The adjusted risks of death or BPD (1.02, 95% CI: 0.83, 1.25), BPD (0.97, 95% CI: 0.77, 1.21), and death 1.33 (95% CI: 0.84, 2.10) by 36-week PMA were unchanged following PI treatment after multivariable adjustment. No changes in mean creatinine levels were detected in exposed versus unexposed infants to suggest PI-induced AKI., Conclusion: Prophylactic indomethacin treatment was unrelated to mortality or BPD outcomes.

Objective: This study aims to describe the frequency and characteristics of anticonvulsant medication treatments initiated in the neonatal period., Study Design: We analyzed a cohort of neonates with a seizure diagnosis who were discharged from institutions in the Pediatric Health Information System between 2007 and 2016. Adjusted risk ratios and 95% confidence intervals for characteristics associated with neonatal (≤ 28 days postnatal) anticonvulsant initiation were calculated via modified Poisson regression., Results: A total of 6,245 infants from 47 institutions were included. There was a decrease in both phenobarbital initiation within the neonatal period (96.9 to 91.3%, p  = 0.015) and continuation at discharge (90.6 to 68.6%, p <0.001). Levetiracetam (7.9 to 39.6%, p  < 0.001) initiation within the neonatal period and continuation at discharge (9.4 to 49.8%, p  < 0.001) increased. Neonates born at ≥ 37 weeks' gestation and those diagnosed with intraventricular hemorrhage, ischemic/thrombotic stroke, other hemorrhagic stroke, and hypoxic ischemic encephalopathy (HIE) had a higher probability of anticonvulsant administration. The most prevalent diagnosis was HIE ( n  = 2,223, 44.4%)., Conclusion: Phenobarbital remains the most widely used neonatal seizure treatment. Levetiracetam is increasingly used as a second line therapy. Increasing levetiracetam use indicates a need for additional study to determine its effectiveness in reducing seizure burden and improving long-term outcomes., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To rank clinician-driven tests and treatments (CTTs) by their total cost during the birth hospitalization for preterm infants., Study Design: Retrospective cohort of very low birth weight (<1500 g) and/or very preterm (<32 weeks) subjects admitted to US children's hospital Neonatal Intensive Care Units (2012-2018). CTTs were defined as pharmaceutical, laboratory and imaging services and ranked by total cost., Results: 24,099 infants from 51 hospitals were included. Parenteral nutrition ($85M, 32% of pharmacy costs), blood gas analysis ($34M, 29% of laboratory costs), and chest radiographs ($18M, 31% of imaging costs) were the costliest CTTs overall. More than half of CTT-related costs occurred during 10% of hospital days., Conclusions: The majority of CTT-related costs were from commonly used tests and treatments. Targeted efforts to improve value in neonatal care may benefit most from focusing on reducing unnecessary utilization of common tests and treatments, rather than infrequently used ones.

Objective: To test the hypothesis that a feeding bundle concurrent with acid suppression is superior to acid suppression alone in improving gastroesophageal reflux disease (GERD) attributed-symptom scores and feeding outcomes in neonatal ICU infants., Methods: Infants (N = 76) between 34 and 60 weeks' postmenstrual age with acid reflux index > 3% were randomly allocated to study (acid-suppressive therapy + feeding bundle) or conventional (acid-suppressive therapy only) arms for 4 weeks. Feeding bundle included: total fluid volume < 140 mL/kg/day, fed over 30 min in right lateral position, and supine postprandial position. Primary outcome was independent oral feeding and/or ≥6-point decrease in symptom score (I-GERQ-R). Secondary outcomes included growth (weight, length, head circumference), length of hospital stay (LOHS, days), airway (oxygen at discharge), and developmental (Bayley scores) milestones., Results: Of 688 screened: 76 infants were randomized and used for the primary outcome as intent-to-treat, and secondary outcomes analyzed for 72 infants (N = 35 conventional, N = 37 study). For study vs. conventional groups, respectively: (a) 33% (95% CI, 19-49%) vs. 44% (95% CI, 28-62%), P = 0.28 achieved primary outcome success, and (b) secondary outcomes did not significantly differ (P > 0.05)., Conclusions: Feeding strategy modifications concurrent with acid suppression are not superior to PPI alone in improving GERD symptoms or discharge feeding, short-term and long-term outcomes., Impact: Conservative feeding therapies are thought to modify GERD symptoms and its consequences. However, in this randomized controlled trial in convalescing neonatal ICU infants with GERD symptoms, when controlling for preterm or full-term birth and severity of esophageal acid reflux index, the effectiveness of acid suppression plus a feeding modification bundle (volume restriction, intra- and postprandial body positions, and prolonged feeding periods) vs. acid suppression alone, administered over a 4-week period was not superior in improving symptom scores or feeding outcomes. Restrictive feeding strategies are of no impact in modifying GERD symptoms or clinically meaningful outcomes. Further studies are needed to define true GERD and to identify effective therapies in modifying pathophysiology and outcomes. The improvement in symptoms and feeding outcomes over time irrespective of feeding modifications may suggest a maturational effect. This study justifies the use of placebo-controlled randomized clinical trial among NICU infants with objectively defined GERD.

In view of the known complications of drug therapy and open surgical ligation, and the potential for prolonged patent ductus arteriosus (PDA) exposure to be harmful, health care practitioners have sought new approaches to achieve definitive ductal closure. Interest in percutaneous (catheter-based) PDA closure has emerged within the neonatal community as a viable treatment option, because it has been fueled by recent procedural and device modifications, as well as mounting feasibility and safety data. Herein, we provide a contemporary review of percutaneous PDA closure among infants at the crux of the medical debate-very-low-weight infants (≤1,500 g), including: 1) characterization of traditional PDA treatments (drug therapy, open surgical ligation) and conservative (nonintervention) management options; 2) a general overview of the major procedural steps of percutaneous ductal closure, including efforts to reduce thrombotic complications and the emergence of a novel US Food and Drug Administration-approved device; 3) a systematic review and meta-analysis to better understand risk profiles of percutaneous PDA closure in this population; and 4) discussion of current gaps in our understanding of optimal PDA care, including the critical need for well-designed, randomized, controlled clinical trials., (Copyright © 2020 by the American Academy of Pediatrics.)

Aerodigestive disorders, those affecting the upper and lower airway or upper gastrointestinal tract, are interrelated anatomically during fetal development and functionally after birth. Successful respiration and feeding requires careful coordination to promote effective swallowing and prevent aspiration. I describe the epidemiology, including the prevalence of the most common aerodigestive disorders. The ability of an infant to feed by mouth at discharge, without a surgically placed feeding tube, is an important neurodevelopmental marker. Therefore, aerodigestive disorders have a high potential for lifelong morbidities and health care expenditures. When available, published research on related medical costs for these disorders is provided., Competing Interests: Disclosure The author has no commercial or financial conflicts of interest to disclose. The author is funded by the National Heart, Lung, and Blood Institute of the US National Institutes of Health (R03HL140272) (R01HL145032). However, that funding is unrelated to the topic of this article and did not contribute to this work product., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI)., Study Design: Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks' postmenstrual age was used to produce adjusted odds ratios (aOR)., Results: Compared with infants in the reference group (22-28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8 and 49 but higher among infants treated at DOL 50-63 (aOR 1.77, 95% CI 1.03-3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44-6.48). The aOR for NDI did not vary significantly by age of PNS exposure., Conclusion: For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.

Background: Patent ductus arteriosus (PDA), the most commonly diagnosed cardiovascular condition in preterm infants, is associated with increased mortality and harmful long-term outcomes (chronic lung disease, neurodevelopmental delay). Although pharmacologic and/or interventional treatments to close PDA likely benefit some infants, widespread routine treatment of all preterm infants with PDA may not improve outcomes. Most PDAs close spontaneously by 44-weeks postmenstrual age; treatment is increasingly controversial, varying markedly between institutions and providers. Because treatment detriments may outweigh benefits, especially in infants destined for early, spontaneous PDA closure, the relevant unanswered clinical question is not whether to treat all preterm infants with PDA, but whom to treat (and when). Clinicians cannot currently predict in the first month which infants are at highest risk for persistent PDA, nor which combination of clinical risk factors, echocardiographic measurements, and biomarkers best predict PDA-associated harm., Methods: Prospective cohort of untreated infants with PDA (n=450) will be used to predict spontaneous ductal closure timing. Clinical measures, serum (brain natriuretic peptide, N-terminal pro-brain natriuretic peptide) and urine (neutrophil gelatinase-associated lipocalin, heart-type fatty acid-binding protein) biomarkers, and echocardiographic variables collected during each of first 4 postnatal weeks will be analyzed to identify those associated with long-term impairment. Myocardial deformation imaging and tissue Doppler imaging, innovative echocardiographic techniques, will facilitate quantitative evaluation of myocardial performance. Aim1 will estimate probability of spontaneous PDA closure and predict timing of ductal closure using echocardiographic, biomarker, and clinical predictors. Aim2 will specify which echocardiographic predictors and biomarkers are associated with mortality and respiratory illness severity at 36-weeks postmenstrual age. Aim3 will identify which echocardiographic predictors and biomarkers are associated with 22 to 26-month neurodevelopmental delay. Models will be validated in a separate cohort of infants (n=225) enrolled subsequent to primary study cohort., Discussion: The current study will make significant contributions to scientific knowledge and effective PDA management. Study results will reduce unnecessary and harmful overtreatment of infants with a high probability of early spontaneous PDA closure and facilitate development of outcomes-focused trials to examine effectiveness of PDA closure in "high-risk" infants most likely to receive benefit., Trial Registration: ClinicalTrials.gov NCT03782610. Registered 20 December 2018.

Objectives: To describe longer term outcomes for infants <6 kg undergoing percutaneous occlusion of the patent ductus arteriosus (PDA)., Study Design: This was a retrospective cohort study of infants <6 kg who underwent isolated percutaneous closure of the PDA at a single, tertiary center (2003-2017). Cardiopulmonary outcomes and device-related complications (eg, left pulmonary artery obstruction) were examined for differences across weight thresholds (very low weight, <3 kg; low weight, 3-<6 kg). We assessed composite measures of respiratory status during and beyond the initial hospitalization using linear mixed effects models., Results: In this cohort of lower weight infants, 92 of 106 percutaneous occlusion procedures were successful. Median age and weight at procedure were 3.0 months (range, 0.5-11.1 months) and 3.7 kg (range, 1.4-5.9 kg), respectively. Among infants with pulmonary artery obstruction on initial postprocedural echocardiograms (n = 20 [22%]), obstruction persisted through hospital discharge in 3 infants. No measured variables were associated with device-related complications. Rates of oxygenation failure (28% vs 8%; P < .01) and decreased left ventricular systolic function (29% vs 5%; P < .01) were higher among very low weight than low weight infants. Pulmonary scores decreased (indicating improved respiratory status) following percutaneous PDA closure., Conclusions: Percutaneous PDA occlusion among lower weight infants is associated with potential longer term improvements in respiratory health. Risks of device-related complications and adverse cardiopulmonary outcomes, particularly among very low weight infants, underscore the need for continued device modification. Before widespread use, clinical trials comparing percutaneous occlusion vs alternative treatments are needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Despite some clinician advocacy for the use of gabapentin to treat neonatal irritability of presumed neurological origin, the extent of gabapentin administration to hospitalized neonates is unknown. We aimed to identify trends in gabapentin utilization among infants hospitalized in neonatal intensive care units (NICUs) across the United States and to evaluate the associations between clinical diagnoses and gabapentin treatment., Methods: We analyzed neonates admitted to the NICU using the Pediatric Health Information System (2005 to 2016) to measure treatment timing, duration, and frequency. We used modified Poisson regression with a robust between-cluster variance estimator to calculate a probability (adjusted relative risk) for gabapentin administration., Results: Of 278,403 neonates, 374 were administered gabapentin (0.13%). The median treatment duration was 16 days (25th to 75th percentile: 8; 40). Gabapentin use increased from 0% in 2005 to 0.39% in 2016. Treatment was prescribed to neonates at 31 of 48 studied hospitals; 73% of total treated infants localized to five neonatal intensive care units. Term (0.16%) and ≤28 weeks' gestation preterm infants (0.22%) were most likely to receive gabapentin. Varying by gestational age, a diagnosis of chromosomal abnormalities, severe bronchopulmonary dysplasia, hemorrhagic stroke, and neonatal abstinence syndrome were associated with higher treatment with gabapentin. The majority (88.8%) of treated infants did not have a seizure diagnosis., Conclusion: Gabapentin use in NICU in the United States increased in recent years and varies markedly between institutions. Term infants, ≤28 weeks' gestation preterm infants, and neonates with chronic genetic, neurological, and gastrointestinal diagnoses were more likely to receive gabapentin., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The optimal treatment method for infants with a patent ductus arteriosus (PDA) necessitating closure remains a subject of controversy and debate. While the risks associated with surgical PDA ligation are well described, the available evidence base for alternative management strategies during infancy, including percutaneous closure or conservative (nonintervention) management, are not well explored. Among infants, the goals of this review are to: (a) use rigorous systematic review methodology to assess the quality and quantity of published reports on percutaneous closure vs surgical ligation; (b) compare outcomes of percutaneous closure vs conservative management; and (c) based on recommendations from the International PDA symposium, to elucidate needs and opportunities for future research and interdisciplinary collaboration. The available evidence base, as well as on broad consensus reached at the International PDA Symposium, suggests that a contemporary, pragmatic clinical trial comparing PDA treatment strategies is warranted. Additionally, quality assurance safeguards are necessary in the implementation of newer PDA closure devices. Finally, to determine best approaches to treatment for infants with PDA, tools for consistent data collection and reporting across centers and disciplines are needed to minimize heterogeneity and permit pooled analysis., (© 2019 Wiley Periodicals, Inc.)

We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636&#95;1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy., (© 2018 Koboldt et al.; Published by Cold Spring Harbor Laboratory Press.)

Introduction: As survival has improved in the Neonatal Intensive Care Unit (NICU), there has been a 10-fold increase in the proportion of infants requiring a tracheostomy. At our institution, we observed a wide variation in the duration of opioid use posttracheostomy from 6 to 148 days. We aimed to decrease the duration of opioid exposure in postoperative tracheostomy patients in the NICU from a baseline average of 24 days to 7 days by December 31, 2017., Methods: We established a multidisciplinary team to develop change ideas to implement in 3 Plan-Do-Study-Act cycles that focused on enhanced care plan standardization and communication in patient care rounds with subsequent documentation in the medical record and the timely addition of dexmedetomidine to the postoperative care plan., Results: Baseline population was from October 2014 to December 2016. The mean posttracheostomy opioid duration was 24.6 days (range, 6-148 days); neuromuscular blockade was 2.89 days (range, 0-9 days), and benzodiazepine exposure was 20.9 days (range, 1-114 days). Following our interventions, the mean duration of posttracheostomy opioid duration was 5.4 days (range, 4-21 days); neuromuscular blockade was 3.14 days (range, 1-5 days), benzodiazepine duration was 8.88 days (range, 4-25 days), and dexmedetomidine was 4.6 days (range, 0-32 days)., Conclusions: We utilized quality improvement methodology to standardize posttracheostomy management and demonstrate that we could significantly reduce the duration of opioid and benzodiazepine use after tracheostomy with the timely addition of dexmedetomidine, a structured written daily care plan, and clarification of roles and responsibilities.

On December 8, 2016, the New England Journal of Medicine published a sounding board on Real World Evidence (RWE) 1 by the US Food and Drug Administration (FDA) leadership. While the value of RWE based on nonrandomized observational studies was appreciated, such as for hypothesis generating, safety, and measuring quality in healthcare delivery, the authors expressed concerns on the quality of data sources and the ability of methodologies to control for confounding. In response, we offer a few considerations regarding these concerns., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Risks associated with drug therapy and surgical ligation have led health care providers to consider alternative strategies for patent ductus arteriosus (PDA) closure. Catheter-based PDA closure is the procedure of choice for ductal closure in adults, children, and infants ≥6kg. Given evidence among older counterparts, interest in catheter-based closure of the PDA in lower weight (<6kg) infants is growing. Among these smaller infants, the goals of this review are to: (1) provide an overview of the procedure; (2) review the types of PDA closure devices; (3) review the technical success (feasibility); (4) review the risks (safety profile); (5) discuss the quality of evidence on procedural efficacy; (6) consider areas for future research. The review provided herein suggests that catheter-based PDA closure is technically feasible, but the lack of comparative trials precludes determination of the optimal strategy for ductal closure in this subgroup of infants., (Copyright © 2018 Elsevier Inc. All rights reserved.)