Women with epilepsy often need anti-epileptic medicine to prevent seizures during pregnancy. Previous studies of Danish data, for example, have demonstrated a link between exposure to the anti-epileptic medicine valproate during pregnancy and the risk of autism and other developmental disorders in children. This link has now been confirmed in the largest study in this area to date, including more than four million pregnancies. This new study also enabled the researchers to find out whether there was a risk associated with other types of anti-epileptic medicine and combinations of anti-epileptic medicines commonly used by pregnant women with epilepsy.

Together with researchers from Norway, Sweden, Finland and Iceland, researchers at the Department of Neurology at Aarhus University Hospital and at Aarhus University are behind a comprehensive and unique study that has collected data on the use of anti-epileptic medicine by pregnant women throughout the Nordic region and has followed more than four million pregnant women and their children in order to determine whether children of mothers with epilepsy have a greater risk of autism and developmental disorders.

"In collaboration with researchers from the entire Nordic region, we collected and analysed data from health registers in all of the Nordic countries, and the results show that children who have been exposed to certain types of anti-epileptic medicine have a two-to-four times higher risk of autism than other children," says Jakob Christensen, a consultant at Aarhus University Hospital and associate professor at Aarhus University. Jakob Christensen is a medical specialist in neurology and clinical pharmacology, and for many years he has worked using Danish registers.

The researchers retrieved register data on 4,494,926 Nordic children born between 1996 and 2017, of whom 31,047 were born to mothers who had redeemed prescriptions for anti-epileptic medicine during their pregnancy. The researchers examined whether their children had been diagnosed with autism or a cognitive impairment.

The results show that exposure to the drugs topiramate and valproate was associated with a two-to-four-fold higher risk of autism and cognitive impairment. The study also confirms results from previous studies showing that the most commonly used drug for pregnant women with epilepsy (lamotrigine) is not associated with the risk of autism and cognitive impairment in children.

However, children of mothers who had used a combination of the anti-epileptic medicines levetiracetam and carbamazepine or lamotrigine and topiramate had the same increased risk, whereas this was not the case for children of mothers who had used a combination of levetiracetam and lamotrigine. This is one of the first studies large enough to examine the risks of exposure to combined therapy – something that may be necessary for some women with epilepsy to prevent seizures during pregnancy.

“The new knowledge confirms previous studies and is important for physicians and for women with epilepsy. Five in 1,000 pregnant women use anti-epileptic medicine. If women with epilepsy do not use medicine during their pregnancy, they risk having seizures. Previous studies have shown that pregnant women with epilepsy have a higher mortality rate than women without epilepsy. Therefore, it’s important to know the risks for the child, and which drugs to use instead so that we can make sure that both mother and child are healthy," says Jakob Christensen.

The research results - more information:

Type of study: Register-based study on Nordic health registers

Partners: Researchers at hospitals and universities in Norway, Iceland, Finland, Sweden, Denmark and Australia.

External funding: The study was supported by the NordForsk Nordic Program on Health and Welfare Scandinavian Multiregistry study of Antiepileptic Drug Teratogenecity (project no. 83796) and Nordic Pregnancy Drug Safety Studies (project no. 83539), by the Research Council of Norway (International Pregnancy Drug Safety Studies project no. 273366), and by the Research Council of Norway through its Centers of Excellence funding scheme (project no. 262700).

Conflicts of interest:

Jakob Christensen received fees for participating in the Scientific Advisory Board for UCB Nordic and Eisai AB, fees for lectures from UCB Nordic and Eisai AB, and funding for a trip from UCB Nordic. Jakob Christensen received funding from the Danish Epilepsy Association, the Central Denmark Region and the Novo Nordisk Foundation (NNF16OC0019126) during the conduct of the study.

Marte-Helene Bjørk received grants from the Research Council of Norway and from Nordforsk during the conduct of the study. In addition, Marte-Helene Bjørk's workplace received fees for contract work in connection with tasks for the market authorisation holder of valproate. She received an advisory board fee from Eisai, and pay for advisory services from Novartis Norway. Advisory board fee from Jazz Pharmaceuticals. Advisory board fee from Angelini Pharma. Fees from Teva and from Lilly for speaks on topics other than those included in the current study.

Marte-Helene Bjørk received funding from the Research Council of Norway and from Nordforsk during the conduct of the study.

Mika Gissler and Marit K. Leinonen received grants from the Innovative Medicines Initiative (Building an ecosystem for better monitoring and communicating the safety of medicines’ use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimized evidence generation, IMI ConcePTION, grant agreement number 821520) during the conduct of the study.

Torbjörn Tomas received fees for speaks at his workplace from Eisai, Sanofi, Sun Pharmaceutical Industries Ltd and UCB, as well as research support from Bial, Eisai, GlaxoSmithKline, Stockholm County Council, Teva, GW Pharma, Arvelle and UCB.

The other authors have not stated any conflicts of interest.

Read the scientific article:

Marte-Helene Bjørk et al. Association of Prenatal Exposure to Antiseizure Medication with Risk of Autism and Intellectual Disability. JAMA Neurology. Date: 31.05.2022, DOI: 10.1001/Jamaneurol. 2022.1269

Further information:

Jakob Christensen
Consultant, Department of Neurology, Aarhus University Hospital
Associate professor at the Department of Clinical Medicine, Aarhus University
Tel. (+45) 45 6086 5899,
Email: jakob@farm.au.dk