Prenatal Exposure to Zika Virus and Risk of Epilepsy-Related Hospitalization During Early Childhood

Importance Epilepsy is a major clinical concern in children with congenital Zika syndrome (CZS). However, whether in utero exposure to Zika virus (ZIKV) without development of CZS is associated with increased epilepsy risk compared with unexposed children remains unclear. Objective To compare the risk of epilepsy-related hospitalizations during the first 4 years of life among children exposed to ZIKV during pregnancy (with and without CZS) vs an unexposed group. Design, Setting, and Participants This was a population-based cohort study conducted in Brazil among live-born singleton children with 22 or more weeks’ gestation born from January 2015 to November 2018. Data analysis was conducted from December 2024 to March 2025. Exposure In utero exposure to ZIKV by maternal notification during pregnancy. Main Outcomes and Measures The primary outcome was the time from birth to the first epilepsy-related hospitalization. Hazard ratios (HRs) and 95% CIs were estimated using a cause-specific Cox regression model, adjusting for maternal education level, maternal self-reported race and ethnicity, maternal age, year of child birth, and adequacy of the number of antenatal appointments. All-cause deaths were also considered as competing events. Results Among 10 828 887 children (5 275 628 [48.7%] female; mean [SD] gestational age, 38.5 [2.0] weeks), 2780 (0.03%) had CZS and 8361 (0.08%) were exposed to ZIKV during pregnancy without developing CZS. After adjusting for confounders, CZS was associated with an increased risk of epilepsy-related hospital admission (adjusted HR [aHR], 34.22 [95% CI, 29.16-40.16]). Age-specific aHRs peaked at age 7 to 18 months (aHR [95% CI], 33.72 [24.70-46.04] for 0-6 months, 44.58 [35.89-55.36] for 7-18 months, and 20.62 [14.31-29.72] for 19-48 months). Children with CZS who were microcephalic, normocephalic, or macrocephalic showed similar associations with epilepsy-related admissions. Children exposed to ZIKV without CZS did not show increased risk compared with unexposed peers (aHR, 0.66 [95% CI, 0.34-1.27]). Conclusions and Relevance In this population-based cohort study, CZS was associated with elevated risk of epilepsy-related hospitalization in early childhood in Brazil. In contrast, children exposed to ZIKV during pregnancy without CZS did not appear to have higher risk of epilepsy-related admission compared with unexposed children.