Men who are on a drug to prevent epileptic seizures at the time of conceiving a child are “unlikely to pose any major risk” to their babies, according to researchers.
It follows a warning from the UK’s medicines regulator that would-be fathers should use “effective contraception” while on valproate due to an increased risk of neurodevelopmental problems in children.
However, Australian academics argue there is “no clear evidence” of a risk to babies exposed to the drug by the father at conception.
The review of 10 studies by Australian academics assessed risks to babies whose fathers were taking anti-seizure medications (ASMs) at the time of conception.
The team from the University of Melbourne said: “There was limited evidence available, but there appeared to be no clear evidence for an adverse impact of paternal ASM use on offspring outcomes.
“Few isolated adverse findings were not replicated by other investigations.”
They added that the findings, published in the Journal of Neurology Neurosurgery & Psychiatry, “provides reassuring evidence that paternal exposure to ASMs at conception is unlikely to pose any major risk of adverse outcomes for the offspring”.
“Further research is needed to examine the relationship between preconception ASM use in males and offspring outcomes at birth and postnatally,” researchers said.
Earlier this month, the Medicines and Healthcare products Regulatory Agency (MHRA) advised men on valproate to use effective contraception and to not donate sperm while on the drug or for three months after stopping it.
The advice followed a Scandinavian study which suggested a potential link between valproate use in men and a small increased risk of a range of neurodevelopmental disorders in their children, from babies to age 11.
It found five out of 100 children had a neurodevelopmental disorder when born to fathers treated with valproate, compared to about three in 100 born to fathers on other epilepsy medications lamotrigine or levetiracetam.
The MHRA said while the research does not prove there is an increased risk, it is a safety issue that warrants precaution.
It advised patients to keep taking their medication and said clinicians should inform male patients of the risk at the their next treatment review.
Reacting to the study review, Dr Bassel Wattar, associate professor of reproductive medicine and medical director of the clinical trials unit at Anglia Ruskin University, called for caution.
He said: “The conclusion is slightly exaggerated, giving a sense of reassurance, while in fact, the studies’ summaries are simply not reporting harm. Therefore, caution is warranted when interpreting the findings of this review.”
Prof Reecha Sofat of the University of Liverpool, who is also associate director at the BHF Data Science Centre at Health Data Research UK, said any signal of harm associated with a risk of health problems in babies “had to be taken seriously” when it comes to medicine regulation.
“Such advice is taken with a great deal of consideration and consultation,” she added.
“The risks that might be associated with withdrawing valproate need to be monitored, and accompanying advice has built in safe guards that allow for the continuation of valproate in men where this is deemed to be appropriate.
“For men that never start valproate because of these concerns and their symptoms are well controlled on another drug, then there are no problems.”
Women and girls of a child-bearing age in the UK have been banned from taking valproate without a pregnancy prevention plan in place since 2018.
Babies born to women who take the medication during pregnancy are at a high risk of birth defects or developmental disorders.
New measures brought in in January 2024 state new patients – male or female – who are younger than 55 should not be started on valproate unless two specialists independently consider the case, conclude there is no other effective treatment or if reproductive risks do not apply.
Commenting, an MHRA spokesperson said: “All of our safety measures for patients taking valproate were implemented following a robust, thorough examination of evidence available to us in our capacity as regulator.
“Our precautionary advice issued earlier this month for male patients and their female partners to use effective contraception, is consistent with the approach taken by regulators in Ireland, Europe, Singapore and New Zealand.
“The results of a retrospective observational study using Scandinavian registry data from Norway, Denmark and Sweden, which is yet to be published, found a statistically significant association between paternal valproate use and neurodevelopmental disorders in offspring when the results from the three countries were pooled, but not when data from single countries were investigated alone.
“In contrast, the (latest) systematic review summarises previously published evidence, mainly from small underpowered studies, which looked at single countries – this data was considered by MHRA as part of our assessment.
“This latest advice builds on previous safety measures implemented in January 2024 which advised healthcare professionals that valproate use should not be newly started in any patient under 55 unless two specialists independently consider and document that there is no effective or tolerated treatment or that the risks don’t apply to this individual patient.”
