A large-scale international study led by the University of Liverpool and funded by the Epilepsy Research Institute UK has found little evidence that sodium valproate significantly impairs male fertility in men with epilepsy or bipolar disorder.
Sodium valproate is a widely used and highly effective treatment for both conditions, which affect millions of people worldwide. However, in the UK and several other countries, recent regulations limit its use in men unless alternative treatments have failed.
These restrictions stem partly from the drug’s well-documented risks during pregnancy: about 1 in 10 babies exposed develop birth defects, and up to 4 in 10 experience developmental problems. Because of these established effects, prescribing rules for women of childbearing potential are already very strict. Concerns have also been raised about possible risks for men, such as reduced fertility or effects on future children. But Liverpool researchers note that these concerns are based mainly on animal studies using much higher doses than those given to patients, and on small, inconsistent human studies.
The new research, published in Nature Communications, analysed data from TriNetX – the world’s largest healthcare database, covering more than 200 healthcare organisations across 19 countries. The retrospective study – the largest of its kind – compared almost 92,000 men with epilepsy or bipolar disorder who had taken sodium valproate with almost 536,000 men with the same conditions who had not.
Using an advanced statistical method called propensity score matching, the researchers ensured the two groups were similar in age, health, use of other antiseizure medications, lifestyle, and other factors that might affect the results. Differences in infertility diagnoses, sperm counts and testicular atrophy (shrinkage of the testicles) between the two groups were minimal (less than 1%), and hormone levels in men taking valproate remained within normal ranges.
Lead author Dr Gashirai 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.”
Epilepsy affects more than 70 million people worldwide, and bipolar disorder affects over 40 million. Valproate remains a first-line treatment for men with newly diagnosed generalised epilepsy in most countries and is still widely used for bipolar disorder. In the UK, regulators have highlighted possible fertility risks and potential transgenerational effects (harm to children of men taking valproate) seen in animal studies, while acknowledging that human data are limited. The current study addresses concerns about fertility risks, but further research is still needed to determine whether transgenerational effects occur.
The authors note that the study relied on indirect measures of fertility such as diagnostic codes, hormone levels, and semen parameters, rather than direct conception outcomes. Birth rates and partner fertility data were not available. Further research is now needed, particularly into real-world conception outcomes, to build on these findings. However, it is hoped the evidence will help inform future clinical guidelines and provide a more balanced basis for counselling men on valproate’s potential risks and benefits. Anyone with questions or concerns about their treatment should always seek advice from a medical professional.
This study forms part of the work being done at the University’s Liverpool Centre for Cardiovascular Science and the Liverpool Interdisciplinary Neuroscience Centre, as part of Dr Mbizvo’s Emerging Leader Fellowship investigating valproate prescribing safety.
The paper, ‘A retrospective cohort study of valproate and infertility in men with epilepsy or bipolar disorder using international health data’, was published in Nature Communications (DOI: 10.1038/s41467-025-63469-0)