Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis

BACKGROUND: Regulatory authorities have raised concerns about potential teratogenic and neurodevelopmental disorders (NDDs) risks associated with paternal valproate use during spermatogenesis, leading to restrictions. We aimed to investigate the association between paternal valproate exposure during spermatogenesis and the risk of NDDs in offspring in Sweden and Norway. METHODS: We conducted a population-based cohort study of two nationwide cohorts from Sweden and Norway, including all singleton live births (≥22 gestational weeks) from 2007 to 2020. Paternal monotherapy exposure to valproate, lamotrigine or levetiracetam was defined as ≥1 prescription filled for only one of these medications during the 3 months prior to conception. NDDs were identified from health registers from age 1 through 2022. Cox proportional hazards models were used to estimate adjusted HRs (aHRs), accounting for relevant confounders. A random-effects meta-analysis combined results from both countries. RESULTS: The Swedish cohort included 1588 children with paternal valproate and 3093 with lamotrigine/levetiracetam monotherapy, while the Norwegian cohort included 463 and 1109, respectively. Compared with paternal lamotrigine/levetiracetam monotherapy, paternal valproate exposure was not associated with increased pooled risk of any NDD (aHR, 1.06; 95% CI 0.81 to 1.22), including autism spectrum disorder (aHR, 1.29; 95% CI 0.89 to 1.85), attention-deficit/hyperactivity disorder (aHR, 0.98; 95% CI 0.76 to 1.25), intellectual disability (aHR, 1.20; 95% CI 0.65 to 2.21; Sweden only) or psychological development disorders (aHR, 1.28; 95% CI 0.84 to 1.97). Findings remained consistent in dose-response analyses and when restricted to fathers with epilepsy. CONCLUSIONS: In this large Nordic study, paternal valproate use during spermatogenesis was not associated with increased risk of NDDs in offspring, suggesting current regulatory restrictions may warrant re-evaluation.