Late pregnancy antiseizure medication exposure and offspring neurodevelopmental risk: a multi-child cohort study

Objective — Antiseizure medication (ASM) use during pregnancy has increased over the past decade. However, evidence linking prenatal ASM exposure to neurodevelopmental disorders (NDDs) in offspring remains inconsistent. This study evaluated whether prenatal ASM exposure increases the risk of NDDs in children.

Methods — We analyzed data from 5 population-based cohorts of live-born children in Canada (Alberta, Manitoba, Ontario, Quebec; the Canadian Mother-Child Cohort [CAMCCO] cohorts) and the United States (AM-PREGNANT cohort). ASM exposure was defined as maternal prescription fills overlapping the 60 days before birth. NDDs were identified using validated algorithm based on the International Classification of Disease-9/10 codes from inpatient and outpatient records. Within each cohort, Cox proportional hazards models were applied, with adjustment performed separately using (1) covariates and (2) propensity scores. Pooled estimates were obtained using random-effects meta-analysis.

Results — Of 2,910,206 children, 0.47% were exposed to ASMs in the 60 days before birth. Prenatal ASM exposure was associated with a 29% increased risk of NDDs (pooled-adjusted hazard ratio [p-aHR], 1.29; 95% CI: 1.22–1.37; 1,805 exposed cases). In the Canadian cohorts, risks of combined NDDs varied by medication: carbamazepine (p-aHR: 1.50; 95% CI: 1.20–1.87; 262 exposed cases), clonazepam (p-aHR 1.22; 95% CI: 1.12–1.33; 585 exposed cases), topiramate (p-aHR 1.56; 95% CI: 1.04–2.34; 69 exposed cases), and valproic acid (p-aHR 1.38; 95% CI: 1.16–1.65; 134 exposed cases). Although point estimates were higher for polytherapy than monotherapy, the difference was not statistically significant.

Interpretation — Prenatal exposure to certain ASMs was consistently associated with increased risks of NDDs in offspring. These findings support careful, individualized decision-making regarding prenatal ASM use to minimize neurodevelopmental risks. ANN NEUROL 2025