Title : Paternal use of valproate and risk of neurodevelopmental disorders in the offspring
Abstract:
BACKGROUND AND OBJECTIVES: Valproate, FDA-approved for mania and bipolar disorder, epilepsy, and migraines, has a black box warning given its teratogenicity. Recently, there has been concern over paternal valproate use and fetal neurodevelopmental disorders (NDD). The purpose of this review is to chronologically organize relevant findings to clear confusion, highlight gaps in knowledge, and suggest next steps for research.
MATERIALS AND METHODS: A literature review on paternal valproate use and risk of NDD in offspring was conducted using PubMed, Google Scholar, and OpenEvidence with no restrictions on country or publication date. Search terms included the following: paternal AND ("valproate" OR "depakote") AND "neurodevelopmental disorders." Relevant articles were also found by backward search.
RESULTS: In 2023, the European Medicines Agency (EMA) post-authorisation safety study (PASS) found significantly increased risk of NDD with preconceptual paternal valproate use using pooled and adjusted data from Denmark, Norway, and Sweden. Consequently, warnings were issued by the EMA and regulatory agencies from the UK, Australia, and Switzerland.
The PASS study is criticized for its weak findings, residual confounding, and unaccounted-for genetic and lifestyle factors. Its results have never been replicated, including in the 2024 Christensen et al. Danish cohort study; the 2026 Meng et al. study with over 1.6 million offspring from Norway and Taiwan; and the 2026 Razaz et al. study using Swedish and Norwegian data.
CONCLUSION: Providers should not hesitate to prescribe valproate to male patients without contraindications as unnecessary restriction defies the principle of beneficence. Paternal valproate use may not affect fetal development, but the intersection of psychiatry and OB/GYN is a growing field, and recent research has shown worse neuropsychiatric fetal outcomes associated with paternal alcohol consumption. Further research needs to be done on paternal influences on fetal development to provide evidence-backed recommendations to couples planning to conceive.
