A nationwide cohort study in Denmark evaluated the association between paternal use of valproate during spermatogenesis and the risk of congenital malformations and neurodevelopmental disorders in offspring. The study included 1,235,353 live births, of which 1,336 children had fathers who filled valproate prescriptions during spermatogenesis. The median follow-up was 10.1 years for valproate-exposed children and 10.3 years for unexposed children. The study found no increased risk of major congenital malformations or neurodevelopmental disorders, including autism spectrum disorder, among children exposed to valproate during spermatogenesis. Adjusted relative risks (ARRs) for congenital malformations were 0.89 (95% CI, 0.67-1.18), and adjusted hazard ratios (AHRs) for neurodevelopmental disorders were 1.10 (95% CI, 0.88-1.37). These findings were consistent across multiple analyses, including dose-response, sibling, and comparator studies. The study concluded that paternal valproate use during spermatogenesis was not associated with increased risk of congenital malformations or neurodevelopmental disorders in offspring. The results suggest that the previous findings reported by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee may not be replicated in this study. The study highlights the importance of considering confounding factors and the limitations of observational studies in assessing drug effects. The findings indicate that paternal valproate exposure during spermatogenesis does not increase the risk of congenital malformations or neurodevelopmental disorders in offspring.A nationwide cohort study in Denmark evaluated the association between paternal use of valproate during spermatogenesis and the risk of congenital malformations and neurodevelopmental disorders in offspring. The study included 1,235,353 live births, of which 1,336 children had fathers who filled valproate prescriptions during spermatogenesis. The median follow-up was 10.1 years for valproate-exposed children and 10.3 years for unexposed children. The study found no increased risk of major congenital malformations or neurodevelopmental disorders, including autism spectrum disorder, among children exposed to valproate during spermatogenesis. Adjusted relative risks (ARRs) for congenital malformations were 0.89 (95% CI, 0.67-1.18), and adjusted hazard ratios (AHRs) for neurodevelopmental disorders were 1.10 (95% CI, 0.88-1.37). These findings were consistent across multiple analyses, including dose-response, sibling, and comparator studies. The study concluded that paternal valproate use during spermatogenesis was not associated with increased risk of congenital malformations or neurodevelopmental disorders in offspring. The results suggest that the previous findings reported by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee may not be replicated in this study. The study highlights the importance of considering confounding factors and the limitations of observational studies in assessing drug effects. The findings indicate that paternal valproate exposure during spermatogenesis does not increase the risk of congenital malformations or neurodevelopmental disorders in offspring.