In a large population-based cohort study, first-trimester exposure to dual therapy with lamotrigine and levetiracetam was associated with a 60% lower risk for major congenital malformations than exposure to valproate monotherapy in offspring of pregnant people with epilepsy.

Valproate is an effective treatment for seizures in people with epilepsy, particularly generalised epilepsy. However, valproate use during pregnancy is associated with increased risk for major congenital malformations (MCMs) and adverse effects on fetal neurodevelopment. In a large population-based cohort study of nearly eight million total pregnancies in Denmark, Finland, Iceland, Norway, Sweden, the USA and Australia between 2000 and 2020, investigators sought to (1) describe rates of first-trimester use of antiseizure medications (ASMs) that are potential alternatives to valproate and (2) determine whether certain ASM combinations resulted in lower risk for MCMs compared with valproate monotherapy.

The main ASMs included in the study were valproate, lamotrigine, levetiracetam, topiramate and zonisamide. Among 50,905 pregnancies in people with epilepsy, the most prevalent first-trimester combination was lamotrigine with levetiracetam (788 pregnancies), followed by lamotrigine with topiramate (291 pregnancies) and then levetiracetam with topiramate (208 pregnancies). Few pregnancies involved combinations with zonisamide. Use of combination therapies increased over time while use of valproate monotherapy decreased. Compared with valproate monotherapy, dual therapy with lamotrigine and levetiracetam during the first trimester was associated with an approximately 60% lower risk for MCM than valproate monotherapy after adjustments for confounders, whereas dual therapy with lamotrigine and topiramate did not show reduced risk for MCM. Other ASM combinations were too rarely used for MCM risk comparisons. Similarly, estimates of risk comparing high-dose valproate monotherapy to combinations of lamotrigine or levetiracetam with low-dose valproate in secondary analyses were inconclusive.

Comment: Strengths of this study include rigorous exposure and outcome definitions, confounder adjustment and the combination of data and databases to allow sufficient sample size to evaluate safety of specific ASM combinations. Infrequent combinations of ASM use limited comprehensive risk-assessment comparisons for zonisamide and between high and low valproate dosing. However, the findings support favouring the combination of lamotrigine and levetiracetam over valproate monotherapy in pregnant people with epilepsy.

Tanya J.W. McDonald, MD, PhD, Assistant Professor of Neurology, Department of Neurology, Division of Epilepsy, Johns Hopkins University School of Medicine, Baltimore USA.

Cohen JM, et al. Comparative risk of major congenital malformations with antiseizure medication combinations vs valproate monotherapy in pregnancy. Neurology 2023 Dec 26; e-pub (https://doi.org/10.1212/ WNL.0000000000207996).

This summary is taken from the following Journal Watch title: Neurology.