Abstract

Importance

Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring.

Objective

To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time.

Design, Setting, and Participants

This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023.

Exposure

Maternal use of ASMs at conception.

Main Outcomes and Measures

MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors.

Results

A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern.

Conclusions and Relevance

Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Key Points

Question  What is the comparative risk of major congenital malformations (MCMs) associated with antiseizure medication (ASM) monotherapy in the offspring of mothers with epilepsy taking ASMs during pregnancy?

Findings In this cohort study including 9840 pregnancies, offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine had the lowest prevalence of MCMs, compared with other ASMs. An increased risk of MCMs was associated with increasing doses of carbamazepine, phenobarbital, and valproate; the overall prevalence of MCMs decreased by 39% over time, in parallel with declining use of valproate and carbamazepine and greater use of levetiracetam and lamotrigine.

Meaning  Results of this study suggest essential information for safer treatment selection in women of childbearing potential requiring ASM therapy.

요약

소개

여성 간질 환자는 임신 중 항경련제(Antiseizure medications, ASMs) 치료가 필요하며, 이는 자녀의 주요 선천적 기형(Major congenital malformations, MCMs) 위험 증가와 연관될 수 있다.

이 연구는 일반적으로 사용되는 8가지 항경련제 단독 요법에 대한 임신 전 노출 후 MCM의 유병률과 시간에 따른 MCM 유병률 변화를 조사했다.

방법

이 연구는 1999년 6월부터 2022년 10월까지 진행된 전향적 관찰 연구로, 40개 이상의 국가에서 임신 결과가 알려지기 전 항경련제 치료를 받은 여성 환자를 등록하고 해당 환자에게서 출생한 자녀를 출생 1년 후까지 추적 관찰했다. 연구 참여자는 임신 중 자주 사용되는 8가지 항경련제에 노출된 14세에서 55세 사이의 여성들이다. 이 코호트 연구에는 9840건의 임신이 포함되었다.

결과

1. 레베티라세탐(levetiracetam), 옥스카바제핀(oxcarbazepine), 라모트리진(lamotrigine)에 노출된 자녀들은 다른 항경련제에 비해 MCM의 유병률이 가장 낮았다.

2. 카바마제핀(carbamazepine), 페노바르비탈(phenobarbital), 발프로에이트(valproate)의 용량이 증가함에 따라 MCM의 위험이 증가했다.

3. 전반적으로 MCM의 유병률은 시간이 지남에 따라 39% 감소했으며, 이는 발프로에이트와 카바마제핀의 사용이 줄어들고 레베티라세탐과 라모트리진의 사용이 증가한 것과 관련이 있다.

결론 및 의의

이 연구의 결과는 항경련제 치료가 필요한 가임기 여성들에게 안전한 치료 선택에 대한 중요한 정보를 제공한다는 의의가 있다.