BackgroundStroke affects surgical decision making and outcomes of neonatal cardiac surgery (CHS). We sought to assess the burden of stroke in this population from a large multicenter database. MethodsWe analyzed neonates undergoing CHS with cardiopulmonary bypass from the Pediatric Health Information System database (2004-2022). The cohort was divided into the stroke group, which included preoperative/postoperative ischemic, hemorrhagic subtypes, and grade III to IV intraventricular hemorrhages, and compared in-hospital and follow-up outcomes to a nonstroke group. ResultsA perioperative stroke occurred in 800 of 14,228 neonates (5.6%). The stroke group was more likely to have hypoplastic left heart syndrome (HLHS; 30.5% vs 20.7%), born preterm (19.4% vs 11.7%), low birth weight (17.8% vs 11.9%), and require extracorporeal membrane oxygenation (ECMO; 48.8% vs 13.8%; all P < .001). Outcomes comparing stroke vs no stroke were mortality, 33.1% vs 8.9%; nonhome discharge, 12.5% vs 6.9%; length of stay, 41 vs 24 days; and hospitalization costs, $354,521 vs $180,489 (all, P < .05). Stroke increased the odds of mortality by 2-fold (odds ratio, 2.20; 95% CI, 1.75-2.77; P < .001) after adjusting for ECMO, prematurity among other significant factors. On follow-up, the stroke group had a higher incidence of hydrocephalus (9.5% vs 1.3%), cerebral palsy (6.2% vs 1.3%), and autism spectrum disorder (7.1% vs 3.5%), and survivors of the index admission had higher 1- and 5-year mortality (5.3% and 11.3% vs 3.3% and 5.9%, respectively; all P < .05). ConclusionsNeonatal CHS patients born prematurely, diagnosed with HLHS, or those requiring ECMO are disproportionately affected by stroke. The occurrence of stroke is marked by significantly higher mortality. Future research should seek to identify factors leading to stroke to increase rescue after stroke and for improvement of long-term outcomes.