Antiseizure medication use in pregnancy and the risk of poor fetal growth in the EURAP international registry: a prospective cohort study.

Authors

Piero Perucca, Charles B Malpas, Alexander Berry-Noronha, Susan P Walker, Tomas Kalincik, Bibiane Moche Kamga, Silje Alvestad, John Craig, Anne Sabers, Frank J E Vajda, Dina Battino, Emilio Perucca, Torbjörn Tomson, EURAP Collaborators

Published in

The Lancet. Neurology. Volume 25. Issue 9. Pages 840-851.

Abstract

Poor fetal growth is a major cause of perinatal morbidity and mortality and predisposes individuals to chronic diseases in adulthood. Antiseizure medication use in pregnancy has been linked with poor fetal growth, but this association has received little attention and its multifaceted aspects remain unclear. We investigated the risk of poor fetal growth in infants exposed prenatally to antiseizure monotherapy versus polytherapy, across different antiseizure monotherapies, and across common antiseizure medication combinations.
This prospective, observational, longitudinal cohort study was based on singleton livebirths of women (aged 14-55 years at conception) with epilepsy on antiseizure medication and enrolled at any point in pregnancy into the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) between June 20, 1999, and Nov 15, 2023. Follow-up data were acquired after each trimester and at delivery. Multivariable models were used to assess the association of antiseizure medication exposures with different fetal growth indicators: birthweight centile (primary outcome); small for gestational age (SGA; birthweight <10th centile for gestational age); severe SGA (birthweight <3rd centile); and low birthweight (<2500 g). Models were adjusted for a wide range of clinical and demographic factors that could influence the association between antiseizure medication exposure and poor fetal growth.
The primary outcome analysis included 15 893 offspring prenatally exposed to antiseizure medications (12 911 exposed to monotherapy and 2982 to polytherapy). The other analyses were limited to one offspring per mother and included 13 728 offspring (11 142 exposed to monotherapy and 2586 to polytherapy). Compared with offspring exposed to monotherapy, those exposed to polytherapy had a lower birthweight centile (adjusted unstandardised model coefficient [b] -2·74 [95% CI -4·22 to -1·26]) and an approximately 50% higher risk of SGA (adjusted odds ratio [OR] 1·48 [95% CI 1·29 to 1·70]), severe SGA (1·49 [1·22 to 1·83]), and low birthweight (1·50 [1·15 to 1·95]). Birthweight centile decreased with increasing number of concomitant antiseizure medications (adjusted b -14·18 [95% CI -24·07 to -4·29] with four antiseizure medications [n=48] relative to monotherapy). Among monotherapies, birthweight centile was lower (in decreasing order) with topiramate (adjusted b -11·93 [95% CI -16·72 to -7·15], n=248), phenobarbital (-8·08 [-11·89 to -4·26], n=431), oxcarbazepine (-5·10 [-8·24 to -1·96], n=557), carbamazepine (-3·15 [-5·01 to -1·28], n= 2797), valproic acid (-2·54 [-4·50 to -0·58], n=1829), and levetiracetam (-2·51 [-4·38 to -0·63], n=1809) compared with lamotrigine (n=4672). Offspring exposed to carbamazepine and levetiracetam in combination (n=173) had a lower birthweight centile (adjusted b -6·27 [95% CI -12·03 to -0·50]) than those exposed to lamotrigine monotherapy. No differences in birthweight centile were found between offspring exposed to lamotrigine monotherapy and those exposed to lamotrigine in combination with either levetiracetam (adjusted b 0·19 [95% CI -2·67 to 3·06], n=470) or valproic acid (0·11 [-3·59 to 3·82], n=258).
In addition to congenital malformations and neurodevelopmental effects, poor fetal growth should be regarded as an important adverse outcome of prenatal antiseizure medication exposure. Risk varies across individual antiseizure monotherapies and specific antiseizure combinations and increases with the number of concomitant antiseizure medications. These findings have important implications for preconception counselling and management, including risk prediction and individualised treatment selection.
Brain Australia, Neurological Foundation of New Zealand, Norman Beischer Medical Research Foundation, Weary Dunlop Medical Research Foundation.

PMID:
42586099
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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