International research led by University of Liverpool provides reassurance on sodium valproate and male fertility risks

International research led by University of Liverpool provides reassurance on sodium valproate and male fertility risks

(IN BRIEF) A major international study led by the University of Liverpool and funded by the Epilepsy Research Institute UK found little evidence that sodium valproate significantly affects male fertility in men with epilepsy or bipolar disorder. Analysing health records from nearly 92,000 men on valproate and more than 536,000 men not using the drug, researchers observed minimal differences in infertility rates, sperm counts, and hormone levels. The study, published in Nature Communications, provides reassurance against fears that valproate uniquely harms male fertility, although questions remain about possible transgenerational effects. Researchers emphasise that epilepsy itself is strongly linked to reduced fertility, highlighting the importance of balancing risks when prescribing treatments.

(PRESS RELEASE) LIVERPOOL, 15-Sep-2025 — /EuropaWire/ — A landmark international study led by the University of Liverpool, with support from the Epilepsy Research Institute UK, has found minimal evidence that sodium valproate significantly harms male fertility in patients with epilepsy or bipolar disorder.

Sodium valproate remains one of the most effective treatments for both conditions, which together affect more than 100 million people worldwide. Yet, in the UK and elsewhere, regulators have imposed restrictions on prescribing it to men unless other therapies have proven unsuccessful. These rules were influenced by long-standing concerns about the drug’s impact during pregnancy, where it is known to cause birth defects and developmental problems in children, and by uncertainty over potential risks for men.

Fertility-related concerns in men have largely stemmed from high-dose animal experiments and small human studies with mixed findings. To address this gap, Liverpool scientists conducted the largest human analysis to date, published in Nature Communications. Using the TriNetX global healthcare database, which includes records from over 200 healthcare organisations in 19 countries, the team assessed nearly 92,000 men who had taken sodium valproate against more than 536,000 men with the same conditions who had not.

The retrospective study applied advanced statistical matching to account for age, health status, use of other medications, and lifestyle differences. Findings showed only minimal differences—less than 1%—in infertility diagnoses, sperm counts, and testicular atrophy between the two groups. Hormone levels in valproate users also remained within normal ranges.

Lead author Dr Gashirai Mbizvo, NIHR Academic Clinical Lecturer and Deputy Director for Epilepsy Research at the Liverpool Interdisciplinary Neuroscience Centre, emphasised the significance of the results: “This large-scale analysis shows little evidence that valproate adds to fertility problems beyond those already associated with epilepsy, bipolar disorder, or other antiseizure medicines. Fear of fertility side effects often leads men to abandon valproate, exposing them to uncontrolled seizures or mental health decline. It’s important to recognise that epilepsy itself significantly lowers fertility rates in men.”

While valproate continues to be a first-line therapy for generalised epilepsy and is widely used for bipolar disorder, regulators in the UK have cited possible fertility risks and transgenerational effects seen in animals. The Liverpool-led study provides strong reassurance regarding direct male fertility but highlights the need for further research into whether effects may extend to future generations.

The authors acknowledge that their study relied on indirect measures such as diagnostic codes, hormone levels, and semen analysis, rather than direct conception outcomes. Data on birth rates and partner fertility were unavailable. Future studies focusing on real-world conception results are needed to confirm these findings.

This research forms part of Dr Mbizvo’s Emerging Leader Fellowship on valproate safety, conducted within the University of Liverpool’s Centre for Cardiovascular Science and the Liverpool Interdisciplinary Neuroscience Centre. The published paper, A retrospective cohort study of valproate and infertility in men with epilepsy or bipolar disorder using international health data, is available in Nature Communications.

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SOURCE: University of Liverpool