A retrospective cohort study of valproate and infertility in men with epilepsy or bipolar disorder using international health data
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. Valproate prescribing is being restricted in men due to animal studies linking it to infertility. Results in humans are conflicting. In this large study, men with epilepsy or bipolar disorder on valproate did not show a clear increase in infertility.
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 91,917 participants or records.
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