The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has announced it is assessing new data on the potential risk of neurodevelopmental disorders (NDDs) in children born to men treated with valproate during spermatogenesis. The announcement comes after controversial new precautionary measures for the treatment of male patients with valproate medicines were imposed in January 2024.
The cautionary approach to valproate — a medicine used to treat epilepsybipolar disorders, and in some countries migraine — came about as a result of a post-authorization safety study (PASS) funded by a consortium of marketing authorization holders for valproate and related substances. After examining the results, PRAC recommended that valproate treatment in male patients be started and supervised by a specialist in the management of epilepsy, bipolar disorderor migraine. It also said that valproate treatment of male patients should be reviewed regularly to consider whether it remains the most suitable treatment, particularly if the patient is planning to conceive a child.
Original Study Suggests Risk
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PASS was a population-based retrospective study that used data from multiple Scandinavian registry databases in Denmark, Norway, and Sweden, together with other available information, to evaluate the association between paternal exposure to valproate and the risk of NDDs in offspring, including autism spectrum disorders, intellectual disability, communication disordersattention deficit/hyperactivity, and movement disorders, as well as congenital abnormalities.
The results suggested a potential increased risk to children born to men treated with valproate during the 3 months before conception. This led PRAC , and later the UK’s Medicines and Healthcare products Regulatory Agencyto recommend precautionary measures for the treatment of male patients with valproate medicines. These measures were in addition to restrictions already in place since 2018 to avoid valproate exposure in pregnancy due to evidence of an increased risk of malformations and developmental problems.
Second Study Casts Doubt
At that time, the committee acknowledged that the PASS data had limitations but concluded that the potential risk warranted informing patients and healthcare professionals.
However, a study published in JAMA in June 2024 using a subset of the same data cast doubt on the PASS findings.
That study aimed to replicate the PASS results using the nationwide Danish data sources that had been used in PASS. In this later study, 1336 children among the total cohort of 1,235,353 children had been born to fathers who filled prescriptions for valproate during spermatogenesis. No association was found between paternal valproate use and risk of major congenital malformations or NDDs, the researchers said.
The researchers highlighted that the PASS results stemmed from an observational study report prepared by contract research organization IQVIA. “We were unable to replicate the IQVIA study results,” they said.
Latest Study Shows No Risk
The same research team subsequently published a research letter in JAMA in May 2025, in which they said that they had access to only limited information about the IQVIA study at the time of their 2024 report. Following publication of the detailed IQVIA report, the team conducted analyses to explore the impact of methodological choices and definitions used in that study.
“Paternal valproate exposure was not associated with an increased risk of NDDs,” they concluded. This was the case for the composite endpoint of all NDDs and “remained robust” across analyses of specific NDDs, expanded definitions of NDDs, valproate dose, time trends, polytherapy, and analyses restricted to fathers with epilepsy.
PRAC said that, in the light of this latest study’s inability to replicate the signal for NDDs in children with paternal valproate exposure and a more recent systematic review from Australia that also showed “no clear evidence for an adverse impact of paternal antiseizure medication use on offspring outcomes,” the committee has initiated a signal procedure to understand the difference in the findings across the studies.
It has also requested further information and analysis from valproate marketing authorization holders. The EMA will communicate further when more information becomes available, it said.