Fathers on Valproate Carry Higher Epilepsy Genetic Risk That May Explain Child NDD Findings

Valproate is a highly effective anti-seizure medication, but its well-known teratogenic effects when used by pregnant women have prompted growing concern about paternal exposure during spermatogenesis. In 2024, the European Medicines Agency's PRAC recommended precautionary measures for men using valproate after a Scandinavian study reported a 50% higher incidence of neurodevelopmental disorders (NDDs) in their children compared to children of men on lamotrigine or levetiracetam (adjusted HR 1.50, 95% CI 1.09–2.08). However, a Danish study found no such risk, and the biological mechanism remained unclear. This Norwegian study set out to determine whether shared genetic susceptibility — rather than drug exposure itself — could explain the reported associations.

The researchers drew on the Norwegian Mother, Father, and Child Cohort Study (MoBa), a prospective population-based birth cohort of over 114,500 children. After restricting to fathers with genotype data, live births, and self-reported epilepsy, four groups were defined: paternal valproate use (n=41), lamotrigine/levetiracetam use (n=37), other anti-seizure medications (n=80), and healthy population controls (n=54,752). Polygenic risk scores (PRSs) for epilepsy, ADHD, and ASD were computed using the LDpred2-auto method applied to large GWAS summary statistics, with standardized scores enabling direct group comparisons.

The central finding was striking: fathers using valproate had significantly higher epilepsy PRSs than those using lamotrigine or levetiracetam (mean difference: 0.66, 95% CI: 0.21–1.11, p≈0.005), other ASMs (mean difference: 0.41, 95% CI: 0.02–0.81, p≈0.04), and healthy controls (mean difference: 0.85, 95% CI: 0.54–1.15, p=5.8×10⁻⁸). This indicates that men prescribed valproate carry a substantially greater inherited genetic burden for epilepsy — likely because valproate is preferentially used for more severe or treatment-resistant epilepsy phenotypes that themselves carry higher polygenic load.

Despite this genetic difference, no robust associations were found between paternal ASM use group and child neurodevelopmental outcomes across six traits measured from 6 months to 8 years of age: hyperactivity, inattention, language difficulties, motor difficulties, repetitive behaviors, and social communication. After correction for multiple testing (25 tests, FDR<0.05), no significant differences survived. Similarly, paternal epilepsy PRS was not significantly associated with child neurodevelopmental outcomes, though the study was likely underpowered for this analysis given the small ASM exposure group sizes.

A particularly compelling secondary finding was the significant genetic overlap among the top 1% weighted SNPs across the three PRSs. A permutation test (10,000 iterations) identified 428 genes shared among the epilepsy, ADHD, and ASD PRSs (p≈0.0001), enriched for neurodevelopmental pathways including synaptic signaling and neuronal development. This genomic overlap provides a mechanistic rationale for why fathers with severe epilepsy — who are more likely to be prescribed valproate — may have children at elevated NDD risk regardless of medication exposure, simply due to inherited genetic architecture.

The study's key implication is that previous observational studies comparing valproate-exposed children to those of fathers on lamotrigine/levetiracetam may have been confounded by the differential genetic burden of the fathers themselves. Clinicians and regulators should weigh this genetic confounding carefully before restricting valproate access for men, particularly given its clinical importance for drug-resistant epilepsy. The authors call for larger studies with genetic data to properly disentangle drug effects from inherited susceptibility.