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Levetiracetam, oxcarbazepine, and lamotrigine had the lowest prevalence of major congenital malformations (MCMs) compared with other monotherapy anti-seizure medications (ASMs) for pregnant women with epilepsy, a prospective observational study found.

The prevalence of MCMs was 2.5% (95% CI 1.8-3.5) with levetiracetam, 2.9% (95% CI 1.7-5.0) with oxcarbazepine, and 3.1% (95% CI 2.5-3.7) for lamotrigine, Dina Battino, MD, of the Fondazione IRCCS Istituto Neurologico Carlo Besta in Milan, and colleagues reported in .

The study also found a 39% drop in overall prevalence of MCMs in offspring exposed to ASMs over time, from 6.1% in the period from 1998 to 2004 to 3.7% from 2015 to 2022. This drop was significant in univariable analysis, but not after adjusting for changes in ASM exposure pattern.

"Considering that there are up to 12 million [women with epilepsy] of childbearing potential worldwide and that additional women are exposed to ASMs for other indications, a 39% decline in the prevalence of MCMs in their offspring has major public health implications," the authors wrote.

Women with epilepsy often need to continue their ASM through pregnancy, as do some women taking the same drugs for other conditions like psychiatric disorders, migraine, and neuropathic pain, Battino and colleagues noted.

An updated assessment of common ASMs and their risks is needed as more women have been added to the registry used in the study -- the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) -- and prescribing patterns have shifted away from drugs like valproate, which carries a boxed warning for fetal risks, the researchers added.

However, some women "require the use of the more dangerous anti-seizure medicines, because they are the only medications that control seizures for that woman," noted Jacqueline French, MD, of New York University in New York City, who wasn't involved in the study, in an email to MedPage Today. "Non-specialists would be advised to refer women who need medication such as valproate (the most dangerous ASM in pregnancy) to a specialty center for evaluation."

The rise in use of levetiracetam and lamotrigine coincided with the decrease in MCMs, observed Denise Li, MD, of the University of Pittsburgh Medical Center, who also wasn't involved in the study.

"This is a very positive development considering that the use of antiseizure medications ... is not uncommon during pregnancy," Li said in an email to MedPage Today. "Lamotrigine, levetiracetam, or oxcarbazepine should be strongly considered for patients of childbearing potential or those considering pregnancy who need to take antiseizure medications."

The study used data from EURAP, which spanned 47 countries. It included women with epilepsy exposed to monotherapy ASM treatment at conception and enrolled within the 16th week of pregnancy. MCMs were assessed 1 year after birth, along with risks across different dosages. Pregnancies were categorized based on four time periods of conception between 1998-2022, and follow-up data were collected after each trimester, at delivery, and 1 year after delivery.

Pregnancies were categorized based on the type and dosage of ASM at the time of conception. Anti-seizure medications included the eight most common monotherapies: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate. Seizures were classified as tonic-clonic or other types, and MCMs referred to structural abnormalities with medical, surgical, cosmetic, or functional significance.

Overall, 9,840 pregnancies from 8,483 women were included in the analysis. The mean maternal age was 30 years and 87% of the women were white.

Valproate, phenytoin, and phenobarbital were associated with the highest prevalence of MCMs, at 9.9%, 6.3%, and 6.2%, respectively. Cardiac malformations were the most common abnormality across ASMs. Valproate was associated with a number of MCMs, including hypospadias, neural tube defects, and multiple defects. Carbamazepine, phenobarbital, and valproate had the strongest dose-response effect.

Lamotrigine did not appear to cause a dose-related increase in MCMs, French noted. "This was a significant worry after previous analyses showed such a relationship, since the dose of lamotrigine needs to be increased substantially during pregnancy due to changes in the drug metabolism," she said.

She noted that the analysis addressed only fetal malformations and not autism or developmental delay, which are also concerns with ASMs.

The study was limited by a cohort that was not population-based, and pregnancies that were likely to be enrolled by physicians particularly interested in epilepsy and pregnancy, or pregnancies in women with more severe epilepsy. Parental race was not included as a covariate in the analysis, and there was no control group of pregnancies in women with untreated epilepsy.

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