Prenatal exposure to antiseizure medication tied to psychiatric disorders during childhood: JAMA

Findings from the study strengthen the evidence for the warning against valproate use in pregnancy and raise concerns about the risks of specific psychiatric disorders associated with levetiracetam and topiramate. The researchers ensure that oxcarbazepine, lamotrigine, and carbamazepine are not associated with long-term developmental or behavioural disorders. Still, they say that risks with higher doses cannot be ruled out.

Exposure to prenatal antiseizure medication (ASM) has been linked with adverse early neurodevelopment, but there has been no study on the associations with a broader range of psychiatric endpoints. Considering this, Julie Werenberg Dreier, Aarhus University, Aarhus, Denmark, and colleagues investigated the association between prenatal exposure to antiseizure medication with a spectrum of psychiatric disorders in childhood and adolescence in children of mothers with epilepsy in a prospective, population-based register study.

For this purpose, the researchers assessed 4 546 605 singleton children born alive in Finland, Denmark, Sweden, and Norway from 1996 to 2017. Of the 4 546 605 children, 38 661 children of mothers with epilepsy were identified, after excluding 54 953 with chromosomal disorders or uncertain birth characteristics. Data analysis was done from 2021 to 2023.

Prenatal exposure to antiseizure medication was defined as maternal prescription fills from 30 days before the first day of the last menstrual period until birth. The study's primary outcome was a diagnosis of psychiatric disorders (a combined endpoint and 13 individual disorders). Estimated adjusted hazard ratios and cumulative incidences were reported.

The study led to the following findings:

• Among the 38 661 children of mothers with epilepsy (42.6% exposed to ASM; 51.3% were male; mean age at the study's end, 7.5 years), prenatal valproate exposure was associated with an increased risk of the combined psychiatric endpoint (aHR, 1.80; cumulative risk at 18 years in ASM-exposed children, 42.1%; cumulative risk at 18 years in unexposed children, 31.3%), which was driven mainly by disorders within the neurodevelopmental spectrum.
• Prenatal exposure to lamotrigine, carbamazepine, and oxcarbazepine was not associated with an increased risk of psychiatric disorders. In contrast, associations were found for prenatal exposure to topiramate with attention-deficit/hyperactivity disorder (aHR, 2.38) and exposure to levetiracetam with anxiety (aHR, 2.17) and attention-deficit/hyperactivity disorder (aHR, 1.78).

"Our findings strengthen the evidence for the warning against valproate use in pregnancy, support concerns about topiramate use, and provide a preliminary indication for caution with levetiracetam use in pregnancy," the authors conclude.

Reference:

Dreier JW, Bjørk M, Alvestad S, et al. Prenatal Exposure to Antiseizure Medication and Incidence of Childhood- and Adolescence-Onset Psychiatric Disorders. JAMA Neurol. Published online April 17, 2023. doi:10.1001/jamaneurol.2023.0674