Largest study finds minimal male fertility impact from epilepsy drug valproate

A major international study funded by the Epilepsy Research Institute has found little evidence that sodium valproate significantly impairs male fertility in men with epilepsy or bipolar disorder.

The research, led by the University of Liverpool and published in Nature Communications, is the largest of its kind. It analysed records from almost 92,000 men with epilepsy or bipolar disorder who had taken sodium valproate, compared with nearly 536,000 men with the same conditions who had not.

This work forms part of lead researcher Dr Gashirai Mbizvo’s Emerging Leader Fellowship, investigating valproate prescribing safety at the University of Liverpool’s Liverpool Centre for Cardiovascular Science and the Liverpool Interdisciplinary Neuroscience Centre.

Why this research matters

Sodium valproate is a highly effective treatment for both conditions, which affect millions worldwide. In the UK and elsewhere, restrictions on prescribing the drug to men stem from concerns about possible fertility risks. Until now, evidence from large-scale human studies has been limited.

What the study found

Using advanced statistical matching to compare groups fairly, the researchers found only minimal differences (less than 1%) in infertility diagnoses, sperm counts and testicular atrophy. Hormone levels also remained within normal ranges.

Dr Mbizvo, NIHR Academic Clinical Lecturer and Deputy Director for Epilepsy Research at the newly launched Liverpool Interdisciplinary Neuroscience Centre, said:

“In the largest study of its kind, we found little evidence that valproate impairs male fertility over and above the epilepsy or bipolar disorder themselves or other antiseizure medications – all of which can impair male fertility. These results are significant because fear of fertility side effects specifically attributed to valproate can lead men to discontinue the medication, risking uncontrolled seizures, mental health deterioration, hospitalisation, or death in extreme cases. It is important to consider the wider picture of what else may be causing infertility. For example, epilepsy, in and of itself, can affect fertility rates, which are two-thirds lower in men with epilepsy than without.”

Next steps

The team notes that the study used indirect measures of fertility such as diagnostic codes, hormone levels and semen parameters, rather than direct conception outcomes. Birth rate and partner fertility data were not available. Further research into real-world outcomes is now needed, including whether the “transgenerational” effects seen in animal studies apply to humans.

A step forward in evidence

For the more than 70 million people living with epilepsy and 40 million with bipolar disorder worldwide, valproate remains an essential treatment. This study provides the strongest human evidence so far to guide clinical guidelines and patient counselling.

Anyone with questions about their treatment should always seek advice from their medical professional.

The 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 (DOI:10.1038/s41467-025-63469-0).

Source: https://epilepsy-institute.org.uk/eri/news/minimal-male-fertility-impact-valproate/