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Observational Study
. 2024 May 1;81(5):481-489.
doi: 10.1001/jamaneurol.2024.0258.

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy

Dina Battino  1 , Torbjörn Tomson  2   3 , Erminio Bonizzoni  4 , John Craig  5 , Emilio Perucca  6   7 , Anne Sabers  8 , Sanjeev Thomas  9 , Silje Alvestad  10   11 , Piero Perucca  12   13   14   15   16 , Frank Vajda  6 ; EURAP Collaborators
Collaborators, Affiliations
Observational Study

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy

Dina Battino et al. JAMA Neurol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tomson reported receiving grants from Angelini, Accord, Glenmark, GlaxoSmithKline, UCB, Eisai, Ecu Pharma, Bial, Teva, Sanofi, SF Group, GW Pharma, and Zentiva during the conduct of the study and speaker honoraria from Eisai, Angelini, GlaxoSmithKline, and UCB outside the submitted work. Dr Bonizzoni reported receiving personal fees from Zambon Biotech and Helsinn outside the submitted work. Dr Craig reported receiving lecture fees from UCB Pharma, GlaxoSmithKline, Eisai, and Janssen Pharmaceuticals during the conduct of the study. Dr E. Perucca reported receiving funds from Accord, Angelini, Bial, EcuPharma, Eisai, Glenmark, GW Pharma, GlaxoSmithKline, Sanofi, SF Group, Teva, UCB, and Zentiva to the EURAP International Registry of Antiepileptic Drugs and Pregnancy; speaker/consultancy fees from Angelini, Eisai, Janssen, PMI Life Sciences, Sanofi, Shackelford Pharma, Sintetica, SKL Life Science, Takeda, UCB, and Xenon Pharma; and authorship royalties from Wiley, Elsevier, and Wolters Kluwer for publications outside the submitted work. Dr Sabers reported receiving consulting/lecture fees from Jazz Pharmaceutical, Angelini Pharma, and UCB Nordic A/B during the conduct of the study. Dr Alvestad reported receiving personal fees from Eisai AB (speaker honoraria) outside the submitted work. Dr P. Perucca reported receiving speaker/consultancy fees from Chiesi, Eisai, LivaNova, Sun Pharma, UCB Pharma, and The Limbic outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prevalence of Different Categories of Major Congenital Malformations (MCMs) After Prenatal Exposure to Monotherapy With 8 Antiseizure Medications (ASMs)
Prevalence (expressed as percentage of exposed offspring) of different categories of MCMs after prenatal exposure to monotherapy with the 8 most commonly used ASMs.
Figure 2.
Figure 2.. Proportion of Monotherapies per Year Groups (N = 9840)
Changes in exposure to different antiseizure medication (ASM) monotherapies over time in the population included in the study and corresponding prevalence (%) of major congenital malformations (MCMs).
See this image and copyright information in PMC

References

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