Study of more than four million pregnant women and their offspring links exposure to antiseizure medication in pregnancy with increased risk of autism and intellectual disability

Women with epilepsy often need medication to prevent seizures during pregnancy. Previous studies have found an association between exposure to the antiseizure medication valproate during pregnancy and risk of autism and low IQ in the offspring. The current study which is the largest to date includes more than 4 million pregnancies and not only confirms this risk, but also shows that pregnancy use of the drug topiramate is connected to similar risks of autism and intellectual disability in the child. Valproate and topiramate are frequently used for epilepsy and migraine, and valproate is also used for bipolar disorder.

The Nordic register-based study of antiepileptic drugs in Pregnancy (SCAN AED) is 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. With the large dataset, it has also for the first time 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.

– We found that children of women with epilepsy exposed to topiramate or valproate during pregnancy had a two-to-four-fold increased risk of autism and intellectual disability compared to children not exposed to any antiseizure medications says lead investigator of SCAN AED, Marte-Helene Bjørk. She is an associate professor at University of Bergen and a consultant neurologist at Haukeland University Hospital. She is also the chair of Bergen Epilepsy Research Group initiating the study.

– Epilepsy, migraine, and bipolar disorder are common disorders in women of childbearing age. It is important that women having these disorders are offered information on which treatment is safest in pregnancy so that they together with their doctor can take informed decisions on the best treatment, Bjørk says.

Together with researchers from Denmark, Finland, Iceland, and Sweden, the Norwegian 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 used antiseizure drug in pregnancy (lamotrigine) is not associated with risk of autism and intellectual disability in the offspring. Neither levetiracetam, another much used drug in people with epilepsy were associated with increased risk of these disorders. 

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 as in children exposed to valproate and topiramate. 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 the last author of the study Jakob Christensen. Jakob Christensen is a specialist in both neurology and clinical pharmacology a consultant at Aarhus University Hospital and Associate Professor at Aarhus University. 

Behind the research result:

Type of study: Registry-based study using Nordic health registries

Collaborators: Researchers at hospitals, universities and public health institutions 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:

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.

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.

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. (doi:10.1001/jamaneurol.2022.1269, Published online May 31, 2022). 

Further information:

Marte-Helene Bjørk

Lead investigator, SCAN AED study, www.scanaed.org

Associate professor, University of Bergen, Norway

Consultant, Department of Neurology, Haukeland University Hospital

Chair, Bergen Epilepsy Research Group. 

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