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

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  • Gashirai K. Mbizvo

    (Liverpool John Moores University and Liverpool Heart & Chest Hospital
    University of Liverpool
    University of Liverpool
    The Walton Centre NHS Foundation Trust)

  • Susan E. Duncan

    (The University of Edinburgh)

  • Lewis Nancarrow

    (Member of Liverpool Health Partners
    Liverpool Women’s NHS Foundation Trust)

  • Tessa Sagarino

    (TriNetX LLC)

  • Lance V. Watkins

    (University of South Wales
    Swansea Bay University Health Board
    University of Plymouth Peninsula School of Medicine)

  • Michael T. Mbizvo

    (Population Council)

  • Gregory Y. H. Lip

    (Liverpool John Moores University and Liverpool Heart & Chest Hospital
    Aalborg University)

  • Anthony G. Marson

    (University of Liverpool
    University of Liverpool
    The Walton Centre NHS Foundation Trust)

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.

Suggested Citation

  • Gashirai K. Mbizvo & Susan E. Duncan & Lewis Nancarrow & Tessa Sagarino & Lance V. Watkins & Michael T. Mbizvo & Gregory Y. H. Lip & Anthony G. Marson, 2025. "A retrospective cohort study of valproate and infertility in men with epilepsy or bipolar disorder using international health data," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63469-0
    DOI: 10.1038/s41467-025-63469-0
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