Paternal Valproate Exposure and Offspring Neurodevelopmental Outcomes

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BACKGROUND AND OBJECTIVES: Evidence remains inconclusive on whether paternal valproate exposure during spermatogenesis is associated with adverse offspring outcomes, with findings lacking beyond Nordic countries. This study aimed to assess the risks of neurodevelopmental disorders (NDDs) and congenital malformations in offspring attributable to paternal exposure to valproate and other antiseizure medications (ASMs) during sperm development. METHODS: This nationwide birth cohort study used data from the Taiwan National Health Insurance Research Database, including individuals born 2001-2016 who were followed up through 2021. Paternal exposure to valproate or other ASMs was defined during the time of spermatogenesis (3 months before conception). Exposure discordant sibling sets were identified for sibling-comparison analysis to control for shared genetic and lifestyle factors. NDDs-including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability (ID), and tic disorder-and congenital malformations were defined by outpatient and inpatient medical record(s). Relative risks were estimated through Cox proportional hazards models for NDDs (hazard ratios [HRs]) and logistic regression for congenital malformations (odds ratios [ORs]). RESULTS: In the population cohort of 2,583,503 individuals, 1,701 were exposed to paternal use of valproate and 548 exposure-discordant sibling sets were available for sibling-comparison analysis. In population-based analyses, paternal valproate exposure was not associated with the risk of NDDs (HRs = 0.86 [95% CI 0.61-1.22] for ASD, 1.02 [0.88-1.18] for ADHD, 0.80 [0.53-1.20] for tic disorders, and 0.81 [0.55-1.19] for ID) or congenital malformations (OR = 1.07 [0.83-1.37]) in offspring. These null effects persisted when restricting analyses to children of fathers with epilepsy to control for confounding by indication, and when the sibling-comparison analysis was conducted. For other ASMs, a few associations appeared at nominal significance, but none remained in sibling-comparison analyses. DISCUSSION: In this large population-based study in Asia, we found no increased risk of NDDs in offspring following paternal exposure to valproate or other ASMs. These findings may contribute to ongoing debates about the management of valproate in men of reproductive age, although additional evidence is needed before drawing conclusions about changes to current practice.