The background for the study is growing concern in recent years about whether fathers’ use of medications during the period when sperm cells are produced might affect the child’s development. A previous Scandinavian registry study reported an increased risk of neurodevelopmental disorders, including autism and ADHD, in children of fathers who used valproate during the three months before conception. This led the European Medicines Agency (EMA) in 2024 to recommend precautionary measures. Among the recommendations were that men using valproate should be informed about possible risks, consider changing treatment, and use contraception while treatment is ongoing.
The new study brings together available results from several countries and compares children of fathers who used valproate with children of fathers who used other anti-seizure medications before conception. The results show no significantly increased risk of neurodevelopmental disorders, either overall or for specific outcomes such as autism, ADHD, or intellectual disability.
- “When we combine data from several countries, we get a larger data set and, in this case, a clearer and more consistent picture, with no evidence of increased risk. This provides important knowledge for clinicians, patients and, not least, the medicines authorities, who are responsible for monitoring the safety of medicines in society,” says pharmacoepidemiologist and professor Hedvig Nordeng at the University of Oslo.
- “Valproate is an important medication for people with difficult‑to‑control epilepsy, in the treatment of bipolar disorder, and some headache disorders. This study supports that treatment of men in the period before their partner becomes pregnant most likely does not increase the risk of long‑term cognitive or behavioral consequences in the children of men who have used the drug,” says neurologist and professor Marte Helene Bjørk at the University of Bergen and Haukeland University Hospital.
The study helps shed light on a controversial research field, where the precautionary warning from the medicines authorities has been criticized by clinical communities as premature, and where previous studies have produced conflicting results. The researchers point out that weaknesses and methodological differences between studies may be an important explanation.
At the same time, the researchers emphasize that treatment choices must always be based on an overall assessment of benefits and risks. For many patients, valproate is the most effective medication, and discontinuation may have consequences such as increased seizure activity, injuries, and reduced quality of life.
- “For people with epilepsy, stable treatment can be crucial. Uncertainty about medicines can create concern, and that is why solid knowledge and well‑justified treatment guidelines are important,” says Bjørk.
Secretary‑General Espen Lahnstein of the Norwegian Epilepsy Association believes the study is important for patients:
- “Many have been worried after the warnings of recent years. This study provides a more nuanced picture and can contribute to more confident decision‑making in dialogue with physicians. It is important that patients receive balanced information about both the risks and benefits of treatment.”
The researchers call for further analyses to understand why earlier studies have shown differing results, and point out that ongoing international studies will provide additional knowledge in the years to come.
Facts about the article
The study is an international collaborative project between research groups in Norway, Denmark, Sweden, and Taiwan, with key contributions from the University of Bergen (the research groups BergenBrain and the Norwegian Centre for Headache Research, NorHead), the University of Oslo (the research group PharmaSafe), as well as Aarhus University in Denmark, Karolinska Institutet in Sweden, and the National University of Taiwan. The work is based on large national health registries and has been published as a “living” meta-analysis that will be continuously updated as new evidence becomes available.
Razaz N, Soderling J, Tomson T, Werenberg Dreier J, Christensen J, Bjørk MH, Igland J. Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis. J Neurol Neurosurg Psychiatry. 2026 Mar 4:jnnp-2025-337441. doi: 10.1136/jnnp-2025-337441. Epub ahead of print. PMID: 41781215.