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Aim: To define a developmental trajectory in infants with neonatal opioid withdrawal syndrome (NOWS) and determine whether the impacted developmental domain varies with the type of antenatal exposure.Methods: We performed a retrospective cohort study of infants treated pharmacologically for NOWS and assessed using a standardized schedule for follow-up visits. We compared outcomes of the study population to published norms using one-sample t-tests. Multivariable models examined associations with exposures in addition to opioids.Results: In our cohort of 285 infants with 9–12-months testing, 164 (55.7%) were seen at 3–4 months, and 125 (44%), at 15–18 months. The majority (58%) had intrauterine drug exposures in addition to opioids. Neurodevelopmental scores of infants with NOWS at 3–4 and 9–12 months were not different from published norms. Cognitive and language scores at 15–18 months were worse than published norms. Male sex, older maternal age, and additional barbiturate or alcohol exposure were associated with worse outcomes.Conclusion: Infants with pharmacologically treated NOWS had development similar to unexposed infants during the 1st year but worse cognitive and language scores during the 2nd year. These data support the need for a prospective follow-up of large cohorts of infants with NOWS, with systematic assessments and an evaluation of contributing factors.

BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background. Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1+/−;Nos3−/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1+/−;Nos3−/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1+/−;Nos3−/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1fl/+;Tie2‐Cre+/−;Nos3−/− mice recapitulate the congenital cardiac phenotype of Notch1+/−;Nos3−/− embryos. ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.