Existing precautionary measures for men taking valproate should remain in place, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has concluded, after finding that evidence on neurodevelopmental risks in their children remains inconsistent and the causal role of valproate uncertain.

The committee’s decision follows a review of conflicting evidence from multiple studies. While one study suggested a possible risk, most retrospective observational studies have not found an increased risk for neurodevelopmental disorders (NDDs) in children born to men treated with valproate — and PRAC determined that a causal role cannot be established. 

Background and Conflicting Study Evidence 

Valproate medicines are used to treat epilepsy and bipolar disorder, with some European Union member states also authorizing them for migraine prevention. NDDs include a range of developmental problems with onset in early childhood, such as autism spectrum disorder, intellectual disability, communication disorders, attention-deficit/hyperactivity disorder, and movement disorders.

Regulatory scrutiny of paternal valproate exposure intensified after a January 2024 assessment of a postauthorization safety study drawing on registry data from Denmark, Norway, and Sweden. The study suggested an increased risk for NDDs in children born to men treated with valproate in the 3 months before conception compared with men treated with lamotrigine or levetiracetam. PRAC concluded that NDDs represented a potential risk and recommended precautionary measures, while commissioning a larger follow-up study to address the limitations of the data.

Subsequent research has produced mixed results. A French study reported a 24% higher risk of NDDs in children of menwho used valproate compared with those using lamotrigine or levetiracetam. However, another study examining 883 children with paternal valproate exposure across Norwegian and Taiwanese cohorts found no significant association between valproate use within 90 days before conception and NDD risk after adjustment for confounders. Similarly, a Nordic study found no evidence of substantially increased risk among more than 2000 children whose fathers used valproate during spermatogenesis.

Unresolved Evidence Drives Continued Caution 

The most recent review was triggered in July 2025 after publication of a Danish nationwide registry-based study that found no increased NDD risk in children born to men treated with valproate. In reassessing the full evidence base, PRAC concluded that differences in study design — including patient selection criteria and approaches to controlling for underlying health conditions — probably account for much of the variation in findings.

PRAC could not determine whether a potential risk for NDDs in children of fathers treated with valproate before conception results from valproate or other factors, such as the fathers’ underlying medical condition. In light of remaining uncertainties and pending results of an ongoing study expected in 2028, PRAC agreed that precautionary measures introduced in 2024 should remain in place. 

Updated Guidance 

The updated risk minimization measures include updated educational materials for both healthcare providers and male patients. Clinicians will receive an updated guide with a dedicated section on valproate use in male patients, and male patients will receive an updated patient guide outlining potential risks and recommended actions. The medicines’ product information will also be updated to reflect the most recent available data.

The current guidance recommends that male patients discuss contraception with their doctors during treatment and for 3 months after stopping treatment. They should not donate sperm during this period. Patients currently taking valproate are advised not to discontinue treatment without medical consultation, as doing so may worsen their underlying condition. If a partner becomes pregnant while the patient was taking valproate in the 3 months before conception, both should seek medical advice promptly.

Marketing authorization holders must conduct further studies to investigate associations between paternal valproate exposure and risks of both congenital anomalies and NDDs. The full assessment report will be published on the EMA website in due course.