A NEW Nordic study reports that valproate use in fathers during the months before conception is associated with increased risk of neurodevelopmental disorders in their children, although no rise in congenital malformations was detected.
Assessing Paternal Valproate Use in Reproductive Contexts
Growing concerns about valproate, a medication primarily used to treat epilepsy , have largely centred on maternal exposure, but evidence regarding paternal effects has been sparse. This study examined whether antiseizure medications taken by men during the 3-month spermatogenic window may influence early development. Fathers treated with valproate were compared with those using lamotrigine or levetiracetam, providing a clearer view of potential drug specific risks during male reproductive years.
Nordic Cohort Data Reveal Elevated NDD Risk
Using nationwide registries from Denmark, Norway and Sweden, researchers followed 5721 offspring born between 1997 and 2019. The analysis compared paternal valproate use with lamotrigine or levetiracetam exposure. In Denmark, neurodevelopmental disorder occurrence was recorded in 38 of 678 offspring, compared with 36 of 1118. In Norway, 13 of 325 versus 21 of 910 were affected, and in Sweden 47 of 841 versus 34 of 1334. Propensity score weighting showed a significantly higher risk for valproate exposed offspring, with a pooled adjusted hazard ratio of 1.50 (95% confidence interval:1.09-2.07; p value = .01. Congenital malformation analyses, involving 1161 offspring, showed no increased risk, with an unadjusted pooled odds ratio of 0.8 (95% confidence interval: 0.48-1.36). However, heterogeneity in congenital malformation estimates limits certainty.
Clinical Implications and Future Directions
These findings raise important considerations for clinical practice. Clinicians should discuss reproductive planning with male patients and assess whether alternative antiseizure therapies may reduce potential offspring risks linked to valproate use. Further research is needed to clarify biological mechanisms, reduce methodological uncertainties and determine how best to integrate paternal exposure assessment into routine preconception counselling and long term epilepsy management.
Reference
Colas S et al. Paternal valproate use and neurodevelopmental disorder and congenital malformation risk in offspring. JAMA Netw Open. 2025;8(11):e2542581.
