A recent population-based cohort study has shed light on the comparative safety of antiseizure medication combinations during the first trimester of pregnancy for women with epilepsy. According to the findings, using Lamotrigine and Levetiracetam together during the first trimester of pregnancy minimizes the risk of major congenital malformations by 60% compared to Valproate alone for epilepsy treatment.  However, combining Lamotrigine with Topiramate doesn't show the same risk reduction.

Led by researchers from various nations, including Iceland, the United States, Denmark, Finland, Norway, Sweden, New South Wales, and Australia, the study aimed to evaluate the risk of major congenital malformations associated with different antiseizure medication combinations as alternatives to Valproate monotherapy. Researchers examined the utilization of antiseizure medication combinations during the first trimester among pregnant women with epilepsy spanning from 2000 to 2020.

The analysis involved comparing the risk of major congenital malformations following first trimester exposure to antiseizure medication combinations against Valproate monotherapy. Additionally, investigators examined the risk linked with low-dose Valproate in combination with either Lamotrigine or Levetiracetam when compared to high-dose Valproate (≥1,000 mg/day).

To assess these risks, log-binomial regression with propensity score weights was employed to compute adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for each dataset. Subsequently, the results were consolidated utilizing fixed-effects meta-analysis techniques.

Out of a total of 50,905 pregnancies among those dealing with epilepsy identified from 7.8 million overall pregnancies, 788 involved the usage of Lamotrigine and Levetiracetam, 291 utilized Lamotrigine and Topiramate, 208 employed Levetiracetam and Topiramate, 80 combined Lamotrigine with Zonisamide, and 91 involved Levetiracetam alongside Zonisamide.  Following the exclusion of pregnancies involving other antiseizure medications, known teratogens, or children diagnosed with major congenital malformations of infectious or genetic origin, researchers compared 587 pregnancies exposed to Lamotrigine-Levetiracetam duotherapy and 186 exposed to Lamotrigine-Topiramate duotherapy with 1,959 pregnancies exposed to Valproate monotherapy.

The pooled aRRs were 0.41 (95% confidence interval [CI] 0.24–0.69) for Lamotrigine-Levetiracetam duotherapy and 1.26 (95% CI 0.71–2.23) for Lamotrigine-Topiramate duotherapy when compared to Valproate monotherapy. As found, certain antiseizure medication combinations offered a lower risk of major congenital malformations compared to Valproate monotherapy during the first trimester. Specifically, Lamotrigine-Levetiracetam duotherapy demonstrated a remarkable 60% reduction in the risk of major congenital malformations compared to Valproate monotherapy.

In contrast, Lamotrigine-Topiramate duotherapy did not show a vital drop in major congenital malformations risk compared to Valproate alone. The findings suggest that Lamotrigine-Levetiracetam duotherapy may be a preferable treatment option for epilepsy in individuals of childbearing potential due to its lower associated risk of birth defects. However, the study recognizes the necessity for additional research to determine the efficacy of this combination compared to Valproate.

The study's classification of evidence as Class II underscores the robustness of the findings, adding weight to the recommendation for Lamotrigine-Levetiracetam duotherapy as a safer alternative to Valproate monotherapy during pregnancy for individuals with epilepsy. These findings mark a pivotal advancement in maternal-fetal medicine, offering clearer guidance on the management of epilepsy during pregnancy.