Research shows there are no major concerns about the risks to the offspring of expectant fathers taking epilepsy drugs

Prospective fathers taking drugs to stop their seizures – and valproate in particular – should be largely reassured that the available evidence on the developmental risks to their offspring does not warrant major concerns, concludes a systematic review of relevant studies published online in the Journal of Neurology Neurosurgery and psychiatry.

The available evidence is scant and inconsistent, but most studies do not indicate an increased risk, the findings show, casting doubt on the position of the UK drugs regulator in particular, the MHRA, the authors say.

The use of valproate during pregnancy has already been restricted due to strong evidence that it is harmful to the developing fetus. And experimental animal studies have linked antiepileptic drugs to male infertility and congenital and behavioral abnormalities in their offspring, raising concerns that these findings could also apply to men.

To investigate this further, the authors searched research databases for studies published in English that reported on neurodevelopmental disorders, major birth defects, low birth weight, or smaller-than-expected body size at birth, among the infants of fathers who used antiepileptic drugs at the time the child was conceived.

From an initial set of 923 articles, 26 underwent full-text review for eligibility, yielding 10 for inclusion in the final review.

This showed that although the data was limited, there was no clear evidence of a harmful effect of these drugs on the outcomes studied in men taking them. A few isolated adverse side effects were not replicated in other studies.

Several methodological limitations prevented pooled data analysis of the individual study results, including the inability to report outcomes separately for each drug, the wide variations in measurements and outcome reporting, and the small number of men taking only one drug.

The European medicines regulator, the EMA, has commissioned a retrospective observational study based on Scandinavian registry data. This has yet to be peer-reviewed and suggests that there is an estimated 5% increased risk of neurodevelopmental disorders in children born to men who have used valproate in the three months before conception, compared to around 3% for two other antiepileptic drugs: lamotrigine and levetiracetam.

However, the EMA concluded that it was not possible to determine whether the increased risks were due to valproate, due to several important methodological limitations.

And in January 2024, it was recommended to prescribe valproate to men with epilepsy, bipolar disorder or migraine, provided that treatment is supervised and patients are informed about the possible risks and use contraception. And it recommended regular evaluations to assess the appropriateness of treatment when planning to conceive a child.

But the UK drugs regulator, the MHRA, took a more restrictive stance, banning anyone under the age of 55 from starting valproate unless there was no other effective and well-tolerated alternative or there was absolutely no opportunity for new parenthood.

And this month the MHRA has updated its safety guidelines for men it is advised that they should be aware of the potential increased risk and use contraception while taking the medicine and for three months after stopping treatment.

“The wisdom of the UK regulatory changes has been questioned,” the authors of the reviews point out, adding that not prescribing valproate “is likely to lead to an increased risk of morbidity and mortality, including increased risk to sudden unexpected death in epilepsy (SUDEP). ).”

They acknowledge that the quality of the studies included in their review was variable and that the potential reproductive consequences of antiepileptic drug use in men have not been adequately investigated. This must be clearly addressed, they emphasize.

But they suggest: “Given the findings of this systematic review, in particular the reassuring results of the recent large population-based study from Denmark, the MHRA restrictions on the use of valproate in men should be reassessed and possibly revised.”

In a linked editorial, Professor Torbjörn Tomson of the Karolinska Institutet agrees. “These peer-reviewed data, highlighted in the current systematic review, contradict the observations of the EMA-initiated study, with its limitations, and call for a reconsideration of, in particular, the MHRA restrictions,” he says.

“It is questionable to consider the restriction as a precaution when male patients with generalized epilepsy are at risk of inadequate seizure control with potentially fatal consequences,” he continues.

“Potential risks from paternal exposure will remain a hot topic, but it is difficult to see how more compelling evidence regarding valproate could be generated in the coming years,” he concludes.