A comprehensive review of existing research shows no evidence that men's use of the anti-seizure medication valproate increases the risk of neurodevelopmental disorders – such as autism and ADHD – in their children.
This is the conclusion of a new living meta-analysis led by researchers from Aarhus University Hospital and Aarhus University, combining data from large population-based studies in Denmark, Norway, Sweden and Taiwan.
– We have brought together and analysed the best available data from several countries, and overall, we find no increased risk. This is an important contribution to a field where previous findings have been conflicting, says the lead author of the study Jakob Christensen, consultant neurologist at Aarhus University Hospital and professor at Aarhus University.
Challenges the basis for European recommendations
In 2024, the European Medicines Agency (EMA) introduced precautionary measures for men treated with valproate, following a study suggesting a potential increased risk of neurodevelopmental disorders in their children.
The new analysis combines results from independent studies based on large-scale population data – and does not find the same signal.
– Our results do not support the increased risk previously reported. When several large and independent studies point in a different direction, it is relevant to reconsider whether current recommendations reflect the totality of the available evidence, says Professor Julie Werenberg Dreier from the Department of Public Health at Aarhus University.
The researchers note that differences between earlier and more recent findings may be explained by methodological differences – including how the data were analysed and adjusted for other influencing factors.
The study is designed as a living meta-analysis, meaning it will be continuously updated as new research becomes available.
Robust evidence across countries
The analysis is based on nationwide registry data from multiple countries and includes several large cohort studies.
Overall, the findings show no increased risk of neurodevelopmental disorders – either overall or for specific conditions such as autism and ADHD.
Results are consistent across countries and analyses, with only minor variation between studies.
Important implications for patients
Valproate remains an effective treatment for many patients with epilepsy and, in some cases, the most effective option available.
At the same time, discontinuing or switching treatment may increase the risk of seizures, injuries and hospitalisation.
– Clinical recommendations must balance potential risks with the real consequences of changing effective treatment. Our findings contribute to a more nuanced evidence base for clinical decision-making, says Jakob Christensen.
The researchers emphasise that further studies are needed and that the analysis will be updated as new evidence emerges.
About the study
Study design:
Systematic review and meta-analysis (living meta-analysis) of registry-based cohort studies
Collaborators:
Aarhus University Hospital, Aarhus University, Karolinska Institutet, University of Oslo, University of Bergen, National Taiwan University and others
Funding:
Including Novo Nordisk Foundation, Lundbeck Foundation, Independent Research Fund Denmark, Central Denmark Region and international funding bodies
Conflicts of interest:
Yes – some authors have received honoraria or research funding from pharmaceutical companies (as disclosed in the article)
Scientific publication:
Christensen J. et al.: The risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis – a living meta-analysis. Journal of Neurology, Neurosurgery, and Psychiatry, 2026. doi:10.1136/jnnp-2026-338454
