ORCID

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.

Publication Date

2025-09-15

Publication Title

Nature Communications

Volume

16

Issue

1

ISSN

2041-1723

Acceptance Date

2025-08-13

Deposit Date

2025-09-22

Funding

G.K.M. is supported by a National Institute for Health and Care Research (NIHR) Clinical Lectureship (CL-2022-07-002), Academy of Medical Sciences (AMS) Starter Grant for Clinical Lecturers (REF: SGL030\1029), and an Epilepsy Research Institute Emerging Leader Fellowship (F2401). A.G.M. is supported by the NIHR Applied Research Collaboration North West Coast (ARC NWC). The funders had no role in the study design, data collection, analysis and interpretation, or writing of this manuscript. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, AMS, the Epilepsy Research Institute, or the Department of Health and Social Care. We are also grateful to Iain Buchan, Glen Martin, and Matthew Sperrin for their assistance with our queries regarding causal inference. A.G.M. declares i) a UCB Pharma grant paid to University of Liverpool for the National Audit of Seizure Management in Hospitals (NASH) study, which is unrelated to the submitted work; ii) an Angelini grant to be paid to University of Liverpool as co-applicant for A multi-method PRoject to maximise efficient and equitable pathways tO suPport from a rEgional epiLepsy centre (PROPEL), which is unrelated to the submitted work; iii) Honoraria paid to University of Liverpool for lectures unrelated to the submitted work given at educational events sponsored by Sanofi, Eiasi, and GSK; iii) Support from Angelini for attendance unrelated to the submitted work at the 2024 International League Against Epilepsy (ILAE) congress. G.K.M. declares an Angelini grant paid to the University of Liverpool as co-applicant on the PROPEL study, which is unrelated to the submitted work; ii) Honoraria paid to the University of Liverpool for delivering a lecture at an educational event sponsored by Angelini, which was unrelated to the submitted work. G.Y.H.L. is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos, which is unrelated to the submitted work. No fees are received personally. G.Y.H.L. is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 899871, which is unrelated to the submitted work. T.S. is an employee of TriNetX, which routinely provides data for research studies, including the data used in this study. The involvement of T.S. as a co-author reflects her technical assistance as a data analyst and does not imply any compensation or influence from TriNetX on this study. The remaining authors declare no competing interests.

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