News release

From: BMJ Group

Further evidence of developmental risks linked to epilepsy drugs in pregnancyStudy adds weight to previously reported risks and calls for monitoring of new antiseizure drugs

Findings published by The BMJ today reinforce previous research linking use of the antiseizure drug valproate during pregnancy to neurodevelopmental disorders such as ADHD and autism in children, and indicate no substantial risk for several other antiseizure drugs including levetiracetam and lamotrigine.

However, the researchers say continued monitoring of the few signals - possible associations between a medicine and an unintended side effect - that emerged (eg, for zonisamide) will be important.

Antiseizure drugs are commonly and increasingly used by women of childbearing age for conditions like epilepsy, bipolar disorders, and migraine prevention. Women with epilepsy are advised to continue taking these during pregnancy, as uncontrolled seizures pose risks to both mother and child.

Yet, while valproate use during pregnancy has been linked to impaired neurodevelopment in children, information on other antiseizure drugs is limited.

To address this gap, researchers analysed claims data for pregnancies with diagnosed epilepsy from two large US public and commercial insurance databases, spanning the period from 2000 to 2021.

They compared 14,993 children exposed to at least one antiseizure medication during the second half of pregnancy with 8,887 unexposed children. Of these, 5,505 were followed for at least 5 years and 2,516 for at least 8 years after birth.

Potentially influential factors including mother’s age, ethnicity, mental health, substance use, other medication use and underlying conditions were also taken into account.

Valproate and zonisamide showed associations with several neurodevelopmental disorders, whereas levetiracetam and phenytoin were not associated with an increased risk of any of the studied outcomes.

Although no meaningful associations were found for topiramate and lamotrigine across most outcomes, there was a potential signal for intellectual disability (both drugs) and learning difficulty (topiramate only). However, the authors note that  these findings are based on small numbers and require confirmation in follow-up studies.

Several other drugs were also associated with a risk increase for intellectual disability. However, the authors note that these estimates are based on small numbers and therefore should be interpreted with caution.

Carbamazepine and oxcarbazepine also showed a modest risk increase for ADHD and behavioral disorders.

This is an observational study, so no definitive conclusions can be drawn about cause and effect, and the authors point to several limitations including relying on insurance claims data and the potential influence of other unmeasured factors such as underlying epilepsy type and severity.

However, the use of two large nationwide databases of insured pregnant women linked to their children enhanced the generalisability of their findings and enabled them to assess the risk of specific neurodevelopmental disorders associated with individual antiseizure medications. Results were also consistent after additional analyses, suggesting that they are robust.

As such, they conclude: “Our study reinforces the substantial risks of neurodevelopmental disorders associated with prenatal valproate exposure and suggests the need to further evaluate the safety of zonisamide during pregnancy.”

“Continued monitoring of newer antiseizure drugs and the few potential signals that emerged (ie, the moderate increased risk of ADHD and behavioral disorder after carbamazepine and oxcarbazepine exposure, and the association of several antiseizure drugs with intellectual disability) will be important,” they add.