Hidden Risks of Antiepileptic Drugs in Pregnancy

The teratogenic risk of antiepileptic drugs (AEDs) has been a major concern in pharmacovigilance over the past several decades. However, neurodevelopmental and autism-related risks associated with these medications have gradually emerged. Although international registries provide information, they are not sufficiently comprehensive to fully assess the risks posed by many AEDs introduced in the past 20 years.

This dual challenge concerning parents and limited information provided to them by the clinicians was discussed by neurologist Sophie Dupont, MD, PhD, head of the Department of Neurological Rehabilitation at the Pitie-Salpetriere Hospital, Paris, France, during the French Language Neurology Days Congress held in Clermont-Ferrand, France, from 15-18 April 2025.

“Future parents are worried, and physicians are perplexed about the nature of the information they should provide, given its highly fluctuating nature,” said Dupont. She also reviewed the current robust knowledge and uncertainties.

Medication Risk

The teratogenic risks of first- and second-generation AEDs were identified in the 1970s. Since then, the number of new drugs has increased significantly. Registries such as the EURAP, which tracks pregnant women treated with AEDs, have advanced our understanding.

The registry has recently clarified the dose-dependent relationships between teratogenicity and some molecules.

For instance, sodium valproate exhibits progressive dose-dependent teratogenicity, whereas carbamazepine exhibits toxicity above a threshold dose. However, the risks associated with the use of topiramate and pregabalin remain unknown. Levetiracetam and lamotrigine appear to lack teratogenic risks; however, data on newer drugs, such as lacosamide, zonisamide, and cenobamate, are insufficient.

The risks for neurodevelopmental and autism spectrum disorders associated with AEDs are complex.

Concerns about sodium valproate and topiramate emerged in 2009, with in utero exposure linked to a twofold to fourfold increased risk of developing autism. However, recent registry data have challenged the risk for autism associated with topiramate use, suggesting that epilepsy may be an underlying factor. However, data on other AEDs are limited and inconclusive.

Data Discrepancies

“Folate deficiency has been suspected as a factor in the teratogenicity of these drugs, but conflicting data on preconception folate supplementation remains unresolved,” Dupont noted. It is unclear whether folate supplementation prevents neural tube defects, although it may improve cognitive outcomes in fetuses. This issue may be due to dosage such as dose above 0.4 mg/day; however, methodological biases in studies prevent definitive conclusions.

Another uncertainty is the neurodevelopmental risk associated with paternal AED use during conception. Some studies have suggested a higher risk among children born to fathers treated with sodium valproate. “However, this study did not account for the indication of the prescription, which could introduce a bias. Another study that avoided this bias did not find the same risk.”

The European Medicines Agency is still awaiting the results of major studies.

Data Gaps

Dupont stated that “the biggest challenge ahead was the complete lack of data on third-generation AEDs, with the exception of lamotrigine, levetiracetam, and oxcarbazepine. We may never have this data because we know that third-generation drugs are free of teratogenicity.”

This could pose challenges for women whose epilepsy is not effectively treated with these medications.

“The best approach would be to understand the mechanisms underlying teratogenicity,” she added. These mechanisms have been extensively studied in sodium valproate, including folate metabolism disorders that reduce embryonic folic acid, disrupt gene expression, increase embryonic oxidative stress, epigenetic modifications, histone acetylation, and hypomethylation, and with topiramate, including GABAergic signaling and DNA methylation. The fact that “the teratogenicity of certain drugs only manifests in some children also suggests a genetic susceptibility in certain mothers,” she noted.

Future Directions

To better understand these risks, it is essential to structure information so that it can be updated in real time and continue enrolling women in registries. “Given the uncertainty surrounding robust data for the most recent drugs, it is imperative to develop reliable and predictive animal models for the potential teratogenicity and neurodevelopmental or autism-related risks of these medications,” concluded Dupont.

This story was translated from Univadis France.