05.06.2024

In contrast to EMA warnings, Danish researchers found no association between paternal use of valproate during spermatogenesis and the risk of congenital malformations and neurodevelopmental disorders in the offspring.

That is the conclusion of a comprehensive nationwide study published by researchers from Aarhus University Hospital and Aarhus University. In the study, the researchers found that men's use of the drug valproate (an antiseizure medication used to treat epilepsy and other neurological conditions) while sperm cells were being formed was not associated with increased risk of malformations and neurodevelopmental disorders in their children.

The background for the study is a recent warning from the European Medicines Agency (EMA) about the potential risk of neurodevelopmental disorders in children born to men treated with valproate.

The warning was issued even though EMAs Pharmacovigilance Risk Assessment Committee (PRAC) was not able to show a definite link between valproate use in men and the risk of congenital malformations and neurodevelopmental disorders in their children.

The Danish study is the largest study published so far and is based on data from 1,235,350 Danish children born between 1997 and 2017. The study, published in JAMA Network Open, does not support the warnings from EMA about men's use of valproate.

In the study, 1,340 children whose fathers had redeemed prescriptions for valproate during spermatogenesis were compared to children whose fathers had not redeemed prescriptions for valproate during spermatogenesis. In an average follow-up period of more than 10 years, no difference in risk of congenital malformations and neurodevelopmental disorders, including autism was found between the two groups of children.

"In Denmark, we can compare data from large health registers, and this has given us the opportunity to compare the risk of malformations and neurodevelopmental disorders in children of fathers who have used valproate with children of fathers who have not used valproate. Our results show no association between fathers' use of valproate during spermatogenesis and children's risk of congenital malformations or developmental disorders," says Jakob Christensen, senior physician at Aarhus University Hospital and professor at Aarhus University.

The researchers have carried out a large number of supplementary analyses of the data they use in the study, but none of these analyses suggested that treatment of men with valproate prior to pregnancy was associated with a significant risk. Julie Werenberg Dreier, co-author of the study and Senior Researcher at the National Centre for Register-based Research at Aarhus University, explains:

"It can be a challenging task to investigate the effects and side effects of medications in register-based studies. Ideally, we would like to compare children of fathers who used valproate during spermatogenesis with children of fathers who could have used valproate during spermatogenesis but happened not to - but unfortunately, we do not know who they are. Therefore, we have looked at a number of different comparison groups – e.g. compared siblings where the father used valproate in relation to one pregnancy but not in the second pregnancy, or compared children where the father used valproate in the past but did not during spermatogenesis, or where the father used another form of epilepsy medication while the sperm was formed. But no matter which comparison we made, we could see no difference in the risk of congenital malformations or neurodevelopmental disorders."

Because the findings of the Danish study do not support the conclusions reached by EMA, the researchers point out that further research is needed to understand the potential risks of using valproate more fully in fertile men.

Study type: Population-based cohort study of 1,235,350 children born in Denmark between 1 January 1997 and 31 December 2017, identified in the  Danish Medical Birth Register.

Collaborators: Department of Neurology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, and the National Centre for Register-based Research (NCRR) and Center for Integrated Register-based Research (CIRRAU) at Aarhus University.

External funding: The study is supported by the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, Central Region Denmark, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033) and the Lundbeck Foundation (R400-2022-1205).

Conflicts of interest: Jakob Christensen has received fees for being a member of UCB Nordics and Eisai AB's Scientific Advisory Board, as well as fees for giving lectures for UCB Nordic and Eisai AB and funds for a trip from UCB Nordic.

Read the scientific article
Christensen J, Trabjerg BB, Dreier JW. Valproate Use During Spermatogenesis and Risk to Offspring. JAMA Netw Open. 2024;7(6):e2414709. doi:10.1001/jamanetworkopen.2024.14709

More information

Jakob Christensen
Senior physician at Neurology, Aarhus University Hospital.
Professor at the Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Tel. +45 6086 5899, e-mail: jakob@farm.au.dk

Julie Werenberg Dreier
Senior researcher at the Center for Register Research at Aarhus University, Aarhus, Denmark
Tel: +45 2562 1178, e-mail: jwdreier.ncrr@au.dk