Would-be dads taking drugs to stop their epilepsy seizures—and valproate in particular—should be largely reassured that the available evidence on the developmental risks to their offspring doesn't justify any major concerns, concludes a systematic review of relevant studies published online in the Journal of Neurology Neurosurgery & Psychiatry.
The available evidence is scarce and inconsistent, but most studies indicate no heightened risk, the findings show, casting doubt on the stance taken by the UK drugs regulator, the MHRA, in particular, say the authors.
The use of valproate during pregnancy is already restricted because of strong evidence showing that it's harmful to the developing fetus. And experimental animal studies have linked antiseizure drugs to male infertility and congenital and behavioural abnormalities in their offspring, sparking concerns that these findings might also apply to men.
To explore this further, the authors trawled research databases for studies published in English that reported on neurodevelopmental disorders, major congenital abnormalities, low birthweight or smaller than expected size at birth, among the babies of fathers taking antiseizure drugs when the child was conceived.
Out of an initial haul of 923 articles, 26 underwent full-text review for eligibility, yielding 10 for inclusion in the final review.
This showed that although the data were limited, there was no clear evidence of a detrimental impact of these drugs on the studied outcomes in men taking them. A few isolated harmful side effects weren't replicated in other investigations.
Several methodological limitations prevented pooled data analysis of the individual study results, including the failure to report outcomes separately for each drug, wide variations in measurement and outcome reporting, and the small numbers of men taking just one drug.
The European drugs regulator, the EMA, commissioned a retrospective observational study drawing on Scandinavian registry data. Yet to be peer reviewed, this suggests that there may be an estimated 5% increased risk of neurodevelopmental disorders in children born to men taking valproate in the 3 months before conception compared with around 3% for two other antiseizure drugs—lamotrigine and levetiracetam.
The EMA, however, concluded that it wasn't possible to establish whether the increased risks were due to valproate, because of various important methodological limitations.
And in January 2024 it recommended that valproate could be prescribed for men with epilepsy, bipolar disorder, or migraine, provided treatment is supervised and patients are advised of the possible risks and use contraception. And it recommended regular reviews to assess the suitability of the treatment when planning to father a child.
But the UK drugs regulator, the MHRA, took a more restrictive stance, prohibiting starting anyone under the age of 55 on valproate unless there was no other effective and well tolerated alternative or where there was absolutely no possibility of new parenthood.
And this month, the MHRA updated its safety guidance for men, advising that they should be aware of the potentially increased risk and should use contraception while taking the drug and for 3 months after stopping treatment.
"The wisdom of the UK regulatory changes has been questioned," point out the review authors, adding that not prescribing valproate "is likely to lead to an increased risk of morbidity and mortality, including an increased risk of 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 implications of taking antiseizure drugs in men have not been sufficiently studied. This clearly needs to be addressed, they emphasise.
But they suggest: "In view of the findings of this systematic review, particularly the reassuring results from the recent large population-based study from Denmark, the MHRA restrictions regarding the use of valproate in men should be reappraised and potentially 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 reported from the EMA-initiated study, with its limitations, and call for a reconsideration of, in particular, the MHRA restrictions," he says.
"It is questionable to refer to the restriction as a precautionary measure when they place male patients with generalised epilepsies at risk of inadequate seizure control with potentially fatal consequences," he continues.
"Potential risks with paternal exposure will remain a hot topic, but it is difficult to see how more conclusive evidence regarding valproate could be generated within the next few years." he concludes.
