FINDINGS from a comprehensive nationwide cohort study from Denmark have demonstrated the safety of paternal valproate use during spermatogenesis. Epilepsy is a prevalent neurological disorder among men of reproductive age, and valproate remains a standard and effective treatment. There are well-established risks associated with maternal exposure to valproate related to increased congenital malformations. However, the risk of congenital malformations and neurodevelopmental disorders associated with paternal exposure to valproate is not delineated.
A large-scale study involving over 1.2 million children born between 1997 and 2017 in Denmark specifically investigated whether valproate use by fathers prior to conception was associated with an increased risk of major congenital malformations and neurodevelopmental disorders, autism spectrum disorder, in their offspring. The study included 1,235,353 singletons, with 1336 children born to fathers who had filled prescriptions for valproate in the three months leading up to conception. The research utilised data from the Medical Birth Register to track congenital malformations within the first year of life and neurodevelopmental disorders from the age of one until the end of 2018.
The findings showed no significant association between paternal valproate use and an increased risk of adverse outcomes in offspring. Specifically, the adjusted relative risk (ARR) for major congenital malformations was 0.89, and the adjusted hazard ratio (AHR) for neurodevelopmental disorders was 1.10, indicating no significant difference compared to children whose fathers did not use valproate. Similarly, the AHR for autism spectrum disorder was 0.92, further supporting the lack of association. The study also included rigorous analyses to confirm the robustness of these findings. This included dose-response analyses, sibling comparisons, and examinations of children of fathers with epilepsy and those exposed to other antiepileptic drugs, such as lamotrigine. Across all these measures, there was no increased risk of congenital malformations or neurodevelopmental disorders linked to paternal valproate use.
These findings underscore that valproate use in men during spermatogenesis does not pose additional risks to their children. Thus, this medication can be continued in managing epilepsy without undue concern for future offspring health. The study offers robust evidence supporting the safety of paternal valproate use, contributing valuable data to the field of neurodevelopmental research and clinical decision-making.
Reference: Christensen J et al. Valproate use during spermatogenesis and risk to offspring. JAMA Netw Open. 2024;7(6):e2414709
