Paternal prescription of valproate during spermatogenesis may not increase risk of major congenital and neurodevelopmental disorders: JAMA

Concerns have been raised about the potential teratogenic effects and long-term neurodevelopmental outcomes of paternal valproate use during spermatogenesis. Valproate is a medication commonly used to treat epilepsy and other neurological conditions, but its impact when taken by men prior to conception has been less clear. This study aimed to evaluate these potential risks by examining a large cohort of births in Denmark.

The study included 1,235,353 singletons born in Denmark between January 1, 1997, and December 31, 2017. Of these, 1336 children had fathers who had filled prescriptions for valproate during the critical period of spermatogenesis (three months prior to conception). Congenital malformations were identified within the first year of life, while neurodevelopmental disorders were tracked from one year of age until the end of follow-up on December 31, 2018. Statistical analyses included log-binomial regression to estimate adjusted relative risks (ARRs) for congenital malformations and Cox proportional hazards regression to estimate adjusted hazard ratios (AHRs) for neurodevelopmental disorders, accounting for relevant confounders.

• The median follow-up period was 10.1 years for valproate-exposed children and 10.3 years for unexposed children.

• 43,903 children (3.6%) were diagnosed with major congenital malformations in the first year.

• 51,633 children (4.2%) were diagnosed with neurodevelopmental disorders during follow-up.

• The ARR of major congenital malformations in valproate-exposed children was 0.89 (95% CI, 0.67-1.18).

• The AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37).

• The AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30).

• Additional analyses, including dose-response, sibling comparisons, and assessments of children with paternal epilepsy or paternal lamotrigine exposure, supported the robustness of these findings.

The results suggest that paternal valproate use during spermatogenesis does not increase the risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder, in offspring. These findings provide important clinical guidance for the management of men requiring valproate for neurological conditions, reassuring them that their medication use is unlikely to harm their future children.

In this extensive Danish cohort study, paternal valproate use during the spermatogenesis period was not linked to an increased risk of congenital malformations or neurodevelopmental disorders in offspring. These findings are crucial for informing treatment decisions and providing peace of mind to prospective fathers on valproate therapy.

Reference:

Christensen, J., Trabjerg, B. B., & Dreier, J. W. (2024). Valproate use during spermatogenesis and risk to offspring. JAMA Network Open, 7(6), e2414709. https://doi.org/10.1001/jamanetworkopen.2024.14709