Researchers from Aarhus in Denmark in collaboration with Nordic researchers are behind a unique study to present individual data on use of antiseizure medication among more than four million pregnant women and their offspring in the Nordic countries. The study shows that exposure to antiseizure medication in pregnancy is linked to an increased risk of autism and intellectual ability.

Women with epilepsy often need medication to prevent seizures during pregnancy. Previous studies from Denmark, UK and USA have previously found an association between exposure to the antiseizure medication valproate during pregnancy and risk of autism and other neurodevelopmental disorders in the offspring. This association is now confirmed in the to date largest study including more than 4 million pregnancies. With the large dataset, it has also been possible to study if there is a risk in connection with other types of antiseizure drugs and combinations of antiseizure drugs, which are also widely used among pregnancy women with epilepsy.

Researchers at Department of Neurology, Aarhus University Hospital and Aarhus University in Denmark in collaboration with researchers from Norway, Sweden, Finland and Iceland are behind a large and unique study collecting data on the use of antiseizure medication among pregnant women across the Nordic countries. The researchers have followed the women and their offspring to investigate if children born to mothers with epilepsy have an increased risk of autism and neurodevelopmental disorders.

- In collaboration with researchers from the Nordic countries we have collected and analysed data from Nordic health registries. Our results show that children exposed to certain types of antiseizure medication have a two- to four-fold increased risk of autism compared with other children, says Jakob Christensen, Consultant at Aarhus University Hospital and Associate Professor at Aarhus University. Jakob Christensen is a specialist in both neurology and clinical pharmacology and has for many worked with data from Danish registries.

Researchers collected registry data on 4,494,926 Nordic children born between 1996 and 2017; of these, 31,047 children were born to mothers who had redeemed prescriptions for antiseizure medication during pregnancy. The researchers studied if the offspring had been diagnosed with autism or other neurodevelopmental disorders.

The results show that exposure to the drugs topiramate and valproate was associated with a two- to four-fold increased risk of autism and intellectual disability. The study further confirms previous results that the most commonly used antiseizure drug in pregnancy (lamotrigine) is not associated with risk of autism and intellectual disability in the offspring.

Children born to mothers who had used a combination of the antiseizure drug levetiracetam and carbamazepine as well as a combination of lamotrigine and topiramate had the same increased risk. However, this did not apply to children born to mothers who had used a combination of levetiracetam and lamotrigine. This study is one of the first studies large enough to investigate the risk of exposure to a combination treatment, which may be necessary in some women with epilepsy to ensure they are seizure-free during pregnancy.

- This new knowledge agrees with previous studies and is important to both doctors and women with epilepsy. Among pregnant women, five in 1000 take antiseizure medication and women with epilepsy who do not take the medicine during their pregnancy are at risk of seizures. Previous studies have shown that pregnant women with epilepsy have a higher mortality than women without epilepsy, and some of this risk may be attributed to seizures. Therefore, it is important to know the risk for the child and which drugs can be used to ensure the health of both mother and child, says Jakob Christensen.

Behind the research result:

Type of study: Registry-based study using Nordic health registries
Collaborators: Researchers at hospitals and universities in Norway, Iceland, Finland, Sweden, Denmark and Australia.
External funding: The study is supported by 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 Nordic Research Council (International Pregnancy Drug Safety Studies project no. 273366) and by the Nordic Research Council through its Centers of Excellence funding scheme (project no. 262700).
Conflicts of interest: Jakob Christensen has received a fee for participating in the Scientific Advisory Board for UCB Nordic and Eisai AB, received fee for lectures from UCB Nordic and Eisai AB, and support for travelling from UCB Nordic. Jakob Christensen has received support from the Epilepsy Association, Central Denmark Region and the Novo Nordisk Foundation (NNF16OC0019126) during his work with the study.
Marte-Helene Bjørk has received funding from the Norwegian Research Council and from Nordforsk during her work with the study. Moreover, the workplace of Marte-Helene Bjørk has received a fee in connection with a contractual obligation on assignments for the owner of the marketing permission for valproate. She has received an advisory board fee from Eisai, and payment for counselling from Novartis Norway. She has received an advisory board fee from Jazz Pharmaceuticals and Angelini Pharma. Moreover, fee for lectures from Teva and from Lilly on subjects other than those included in the current study.
Kari Furu has received funding from the Norwegian Research Council and from Nordforsk during the work with the study.
Mika Gissler and Marit K. Leinonen have received funding 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 their work with the study.
Torbjörn Tomson has received a fee for a presentation at his workplace from Eisai, Sanofi, Sun Pharmaceutical Industries Ltd og UCB as well as research support from Bial, Eisai, GlaxoSmithKline, Region Stockholm, Teva, GW Pharma, Arvelle and UCB.
Other authors report no 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, PhD, DrMedSci
Department of Neurology, Aarhus University Hospital
Associate Professor at Department of Clinical Medicine, Aarhus University, Denmark
Tel.: +45 6086 5899, e-mail: jakob@farm.au.dk