Prenatal exposure to combination therapy for epilepsy linked to neurodevelopmental risk

Children born to mothers who are taking combination therapy for epilepsy during pregnancy are at increased risk of neurodevelopmental disorders, according to a new study published in JAMA Network Open.

In a population-based cohort study, researchers used the health and social registers of the Nordic countries to identify close to 4.5 million mother-child participants, including 24,825 children who were prenatally exposed to antiepileptic drugs, of whom approximately 16,000 were born to mothers with epilepsy.

The researchers estimated the cumulative incidence of the neurodevelopmental disorders, autism spectrum disorder (ASD) and intellectual disability (ID) at the age of 8 years in exposed and unexposed children of mothers with epilepsy. From their findings, topiramate and valproate monotherapy were associated with a two- to four-fold increase in ASD and ID compared with unexposed children. The adjusted hazard ratios for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7) after valproate exposure.

Furthermore, combination therapy as levetiracetam and carbamazepine, and lamotrigine and topiramate, were associated with a similar increased risk of neurodevelopmental disorders as valproate in children born to mothers with epilepsy (3.5 [95% CI, 1.5-8.2] and 2.4 [95% CI, 1.1-4.9], respectively). 

Children exposed to levetiracetam and lamotrigine as monotherapy or combination therapy, had similar risks for neurodevelopmental disorders as unexposed children  when comparing risks among children of mothers with epilepsy.

Safer recommendations

The research above reinforces recommendations made by the MHRA in January 2021. Following a review of the risks of major congenital malformations and neurodevelopmental outcomes associated with antiepileptics, the MHRA published a drug safety update confirming lamotrigine and levetiracetam are safer options to consider in pregnancy, compared to valproate and other antiepileptic drugs.

Daniel Jennings, senior policy and campaigns officer at Epilepsy Action, said the research 'also provides valuable new information around the increased risks associated with topiramate use in pregnancy, and it is now important that these findings are properly communicated to women with epilepsy so they are aware of these risks and can make an informed choice about their treatment during pregnancy.'