Valproate has “minimal” effect on male fertility, international study says

Sodium valproate has a “minimal” effect on male fertility, according to large-scale, international research by the University of Liverpool and funded by the Epilepsy Research Institute UK, published in Nature Communications.

The Medicines and Healthcare Regulatory Agency (MHRA) last year released a guideline advising men taking sodium valproate and any female partners to use contraception to prevent unplanned pregnancies.

The MHRA warned of a “potential small increased risk” of neurodevelopmental disorders in children born to fathers taking the medication.

Earlier this year, the MHRA confirmed that any new prescriptions of valproate for men under the age of 55 will need to be independently signed off by two specialists. This doesn’t affect men currently prescribed valproate or men over the age of 55.

Significant results and the wider picture

The new research covered 19 countries and more than 200 healthcare organisations. It compared almost 92,000 men with epilepsy or bipolar disorder who had taken sodium valproate with 536,000 men with the same conditions who had not taken the medication.

They found that differences in infertility diagnoses, sperm counts and testicular atrophy (shrinkage of the testicles) were less than 1% between the two groups. Hormone levels in men taking valproate were also found to be within normal ranges.

Dr Gashirai Mbizvo, NIHR academic clinical lecturer and deputy director for Epilepsy Research at the Liverpool Interdisciplinary Neuroscience Centre, who carried out the research, 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.”

Providing reassurance

Alison Fuller, director of health improvement and influencing at Epilepsy Action, said: “Many men have expressed their concerns about the impact of sodium valproate on their fertility, and our helpline team receives inquiries relating to this issue.

“We hope that this study provides reassurance for men prescribed this medication, but we know that current MHRA guidance still means that doctors are required to warn patients about the risks of potential infertility.

“This is concerning, as incorrectly telling male patients that they may not be able to have children could prompt them to stop taking their medication, which puts them in danger.

“Epilepsy Action has been consistently raising this issue with the MHRA and asking them to reconsider the published regulations. Given this new study, it is time for them to revisit the evidence and give it consideration.”

Future research

The researchers advise that more research is now needed to build on this study which looked at diagnoses, hormone levels and semen parameters to establish fertility levels. They said it should focus on whether men taking sodium valproate are successfully able to have children.

The study authors say they hope the evidence will help inform future clinical guidance.

The rules around prescribing sodium valproate in women are already much stricter.

Women under the age of 55 should only be prescribed sodium valproate if two specialists agree that there are no other effective treatments for them. They also must be on the Pregnancy Prevention Programme if they are able to become pregnant.

This is because sodium valproate has been known to increase the risk of birth defects (1 in 10 babies) and developmental disorders (4 in 10 babies) if taken during pregnancy.

There is more information on the risks and rules around sodium valproate in men, women and transgender and nonbinary people on the Epilepsy Action website.

No one should stop taking their medication without speaking to their doctor first, as this could result in more or worse seizures.