A retrospective cohort study of valproate and infertility in men with epilepsy or bipolar disorder using international health data

Gashirai K. Mbizvo (), Susan E. Duncan, Lewis Nancarrow, Tessa Sagarino, Lance V. Watkins, Michael T. Mbizvo, Gregory Y. H. Lip and Anthony G. Marson
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Gashirai K. Mbizvo: Liverpool John Moores University and Liverpool Heart & Chest Hospital
Susan E. Duncan: The University of Edinburgh
Lewis Nancarrow: Member of Liverpool Health Partners
Tessa Sagarino: TriNetX LLC
Lance V. Watkins: University of South Wales
Michael T. Mbizvo: Population Council
Gregory Y. H. Lip: Liverpool John Moores University and Liverpool Heart & Chest Hospital
Anthony G. Marson: University of Liverpool

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Valproate is highly effective at treating epilepsy and bipolar disorder. It faces prescribing restrictions in men due to concerns it causes testicular dysfunction and infertility. These mostly stem from animal models – the human evidence is limited and conflicting. We report the largest ever retrospective cohort study of infertility in men with epilepsy or bipolar disorder, using real-world healthcare data from TriNetX. 91,917 of the men are exposed to valproate, and 535,803 unexposed. Cohorts are propensity score matched for a comprehensive set of baseline covariates, and survival analysis is undertaken using Cox-proportional hazards models. No significant difference is seen between valproate-exposed and unexposed men across lifetime risks of infertility, testicular hypofunction, testicular atrophy, and a composite of low sperm concentration, motility, vitality, normal forms, and semen volume (p > 0.05). Our findings do not support an association between valproate and infertility in men with epilepsy or bipolar disorder in real-world settings.

Date: 2025
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DOI: 10.1038/s41467-025-63469-0

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