Levetiracetam, Oxcarbazepine, and Lamotrigine Among Safest Antiseizure Medications for Pregnant Women With Epilepsy


A recent study indicated that certain antiseizure medications used in pregnant women with epilepsy had a lower risk of major congenital malformations.

Dina Battino, MD, staff member, Epilepsy Center, Department of Neurophysiology and Experimental Epileptology, Fondazione IRCCS Istituto Neurologico Carlo Besta

Dina Battino, MD

Credit: International League Against Epilepsy

Recently published in JAMA Neurology, a longitudinal cohort study showed that offspring of women with epilepsy exposed to levetiracetam, oxcarbazepine, and lamotrigine had the lowest prevalence of major congenital malformations (MCMs) compared with other antiseizure medications (ASMs).1 These findings may help guide clinicians for safer treatment selection in women of childbearing who potentially require the use of ASM therapy.

Among 10,121 prospective pregnancies exposed to ASM monotherapy, 9840 pregnancies in 8483 women (mean age in years, 30.1; range, 14.1-55.2) were exposed to 8 of the most frequently used ASMs. Notably, researchers observed that 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%), and 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%). In addition, MCMs occurred at a lower rate for other studied medications, including in 10 of 204 pregnancies 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%).

Top Clinical Takeaways

  • Levetiracetam, oxcarbazepine, and lamotrigine showed the lowest prevalence of major congenital malformations compared with other antiseizure medications.
  • The study revealed a significant decrease in the prevalence of major congenital malformations over time.
  • Limitations of the study included its non-population-based nature, potential bias in patient enrollment, and the absence of a control group of untreated pregnancies.

Lead author Dina Battino, MD, staff member, Epilepsy Center, Department of Neurophysiology and Experimental Epileptology, Fondazione IRCCS Istituto Neurologico Carlo Besta, in Milan, Italy, and colleagues conducted the study between June 1999 and October 2022 using data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP).2 Since 1999, clinicians from over 40 countries enrolled ASM-treated women with epilepsy prior to the known pregnancy outcome and followed up their offspring until 1 year after birth. Patients included in the study were aged 14 to 55 years.

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Investigators analyzed the data on the maternal use of ASMs at conception from April to September 2023. In addition, MCMs were analyzed 1 year following birth by a committee blinded to type of exposure. Researchers also compared teratogenic outcomes across exposures by random-effects logistic regression, which was adjusted for potential confounders and prognostic factors.

Authors noted a significant increase in the prevalence of MCMs associated with increasing dose for valproate, phenobarbital, and carbamazepine among the participants. Overall, researchers observed that the prevalence of MCMs reduced from 6.1% (153 out of 2505) during between 1998 and 2004 to 3.7% (76 out of 2054) in the time between 2015 and 2022. Authors noted that this reduction over time was significant in univariable logistic analysis but not following the adjustment for changes in ASM exposure pattern. Additional findings showed that a shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine was associated with a 39% decline in the prevalence of MCMs.

All told, this cohort study was not population based compared with studies based on national health databases. Also, authors noted that pregnancies were probably enrolled by clinicians who had an interest in epilepsy and pregnancy and possibly include those with more severe epilepsies with more specialized management. Furthermore, investigators acknowledged that parental race was not included as a covariate in the analysis and the lack of a control group of pregnancies in women with untreated epilepsy included in the study.

1. Battino D, Tomson T, Bonizzoni E, et al. Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy. JAMA Neurol. Published online March 18, 2024. doi:10.1001/jamaneurol.2024.0258
2. Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17(6):530-538. doi:10.1016/S1474-4422(18)30107-8
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