A new study from researchers at Aarhus University and Aarhus University Hospital found no increased risk of neurodevelopmental disorders in children whose fathers were treated with valproate during spermatogenesis. The results have just been published in JAMA Network Open and cast new light on the European Medicines Agency's (EMA's) recent recommendation for precautionary measures.
In January 2024, EMA recommended precautionary measures for treating male patients with valproate, based on a report by the contract research organization IQVIA. Last summer, the same research group from Aarhus published findings that failed to replicate the IQVIA results, but only limited information about the IQVIA study was available at that time.
In the new article, the authors present additional analyses of their extensive register-based dataset, aligning their methods more closely with the IQVIA definitions. Yet the conclusion remains unchanged: no statistically significant increased risk of neurodevelopmental disorders was found. Based on the conflicting results, the researchers strongly urge for full transparency, including publication of the analytical code and full peer-review of the IQVIA study as soon as possible.
- Precautionary measures, like the ones issued by EMA, have significant implications for both patients and healthcare professionals. It is therefore problematic if such measures are not based on solid scientific evidence, as they may cause unnecessary uncertainty and concern among patients, says Julie Werenberg Dreier, Senior Researcher at the National Centre for Register-based Research at Aarhus University.
- We've examined this issue from many angles and still find no evidence supporting the concern behind EMA's recommendations, says Jakob Christensen, consultant neurologist at Aarhus University hospital and professor at Aarhus University.
Study type: Population-based cohort study of 1,235,350 children born in Denmark 1997-2017, identified in the Danish Medical Birth Register. Children of fathers treated with valproate monotherapy were compared to those exposed to lamotrigine or levetiracetam monotherapy.
Collaborating institutions: Department of Neurology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, and the National Centre for Register-based Research (NCRR), Department of Public Health at Aarhus University.
External funding: Independent Research Fund Denmark, Novo Nordisk Foundation, Lundbeck Foundation, Danish Epilepsy Association, Central Denmark Region
Conflicts of interest: Yes – Jakob Christensen has received speaking fees and travel support from UCB Nordic and Eisai AB
Read the scientific article: Christensen J, Trabjerg BB, Dreier JW. The risks of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis. JAMA Network Open. May 22, 2025. DOI: 10.1001/jamanetworkopen.2025.12139
