UK Valproate Restrictions in Men Justified? New Data

A large Danish cohort study showed no significant increase in neurodevelopmental disorders (NDDs) among children fathered by men taking valproate during spermatogenesis, challenging earlier safety concerns and current UK restrictions on valproate use in men.

As previously reported by Medscape Medical News, the decision to restrict the drug in women and in men younger than 55 years was made in January 2024, after the UK Medicines and Healthcare products Regulatory Agency issued new guidance on the drug’s use.

“Paternal exposure to antiseizure medication in association with conception is unlikely to pose any major risk for the offspring,” the investigators led by Jakob Christensen, DrMedSci, consultant neurologist at Aarhus University Hospital and professor at Aarhus University, Aarhus, Denmark, noted.

The study was published online on May 22 in JAMA Network Open.

Unnecessary Precaution?

In the US and Europe, there is strong guidance about avoiding valproate in pregnant women and women of childbearing age due to an elevated risk for birth defects and other developmental problems.

In January 2024, the European Medicines Agency’s (EMA’s) safety committee (Pharmacovigilance Risk Assessment Committee [PRAC]) expanded precautionary measures on valproate use to men considering fatherhood. The advisory was fueled largely by an observational study by the contract research organization IQVIA.

The study showed that about 5 out of 100 children had an NDD when born to fathers taking valproate during the 3 months before conception compared with about 3 out of 100 when born to fathers treated with lamotrigine or levetiracetam.

Last summer, Christensen and colleagues were unable to replicate the IQVIA results in a study using a subset of the same IQVIA data. However, at the time, only limited information about the IQVIA study was publicly available.

Once additional information from the IQVIA study became available, the researchers tried again to replicate the findings, aligning their methods more closely with the IQVIA study.

Despite using the same methodology and incorporating additional data, they were still unable to replicate the IQVIA findings. Their conclusion remained unchanged — there was no statistically significant increased risk for NDDs.

Specifically, among 961 children exposed to paternal valproate monotherapy and 1401 exposed to lamotrigine or levetiracetam, there was no significant increase in risk for NDDs (adjusted hazard ratio [aHR], 1.02; 95% CI, 0.67-1.54).

“This finding remained robust across analyses of specific NDDs, analyses of valproate dose, analyses accounting for time trends, analyses allowing for polytherapy, analyses expanding the definition of NDDs, analyses restricted to fathers with epilepsy, and analyses with a restricted exposure window,” Christensen and colleagues reported.

Restricting analyses to fathers with epilepsy of unknown cause yielded a higher risk (aHR, 2.48; 95% CI, 1.13-5.44), but this association was no longer significant in analyses matched on birth year (aHR, 2.33; 95% CI, 1.00-5.44).

Additional sensitivity analyses (restricting exposure window, excluding children with epilepsy or maternal epilepsy, and accounting for polytherapy) consistently showed no elevated risk for NDDs associated with paternal valproate exposure.

“We’ve examined this issue from many angles and still find no evidence supporting the concern behind EMA’s recommendations,” Christensen said in a news release.

Will the EMA Reconsider?

Reached for comment, Aatif Husain, MD, epileptologist, neurologist, and sleep medicine specialist at DukeHealth, Durham, North Carolina, said, “There seems to be a fair amount of literature” suggesting no increased risk for NDDs in children whose fathers use valproate.

“A recent systematic review that included 10 other studies came to this same conclusion,” said Husain, who wasn’t involved in the Danish study.

Taken together, the data “would probably move EMA to relook at their guidance to see if it needs to be modified,” he said.

Medscape Medical News reached out to the EMA press office for comment and received the following response.

“As with every medicine authorized in the EU, EMA continues monitoring and supervising the safety of these medicines. This includes monitoring information from various sources, such as spontaneous reports, clinical studies, scientific literature, and management of safety signals, which consists of a set of activities to determine whether there are new risks associated with an active substance or a medicine or whether known risks have changed. Should there be any updates, EMA will communicate them via the PRAC Highlights.”

Husain told Medscape Medical News that neither the FDA nor the American Epilepsy Society has issued guidance on valproate use in men “because the data has not been strong enough.”

Funding for the study was provided by the Independent Research Fund Denmark, Novo Nordisk Foundation, Lundbeck Foundation, Danish Epilepsy Association, and Central Denmark Region. Christensen received speaking fees and travel support from UCB Nordic and Eisai AB. Husain reported having no relevant disclosures.