Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations

Abstract

Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring.

Antiepileptic treatment with levetiracetam during the first trimester and pregnancy outcome: An observational study

“…Large studies from international pregnancy registries or from analysis of national health register data report low rates of 2%-3% for major birth defects for levetiracetam monotherapy. 6,21,22 Birth defect rates in our study were higher, but not significantly increased, and comparable to the estimated rate of 4.9% in the levetiracetam register study by using EUROCAT criteria, 23 and the rate of 5.2% reported in the MONEAD study 24 for use of levetiracetam in monotherapy. Birth defect rates can vary widely depending on the definition and mode of ascertainment of major birth defects.…”

The pharmacological treatment of epilepsy in adults

“…Research during the last decades has revealed major differences between ASMs in teratogenic risks 51,52 . Although our understanding of the risks with many newer generation ASMs is insufficient, exposure to valproate is clearly associated with a higher prevalence of major congenital malformations (MCM) in the offspring than other ASMs such as lamotrigine, levetiracetam, carbamazepine, and oxcarbazepine 12,51–53 . A recent population‐based register study has indicated a level of risk for MCMs after exposure to topiramate similar to that with valproate 53 .…”

“…Although our understanding of the risks with many newer generation ASMs is insufficient, exposure to valproate is clearly associated with a higher prevalence of major congenital malformations (MCM) in the offspring than other ASMs such as lamotrigine, levetiracetam, carbamazepine, and oxcarbazepine 12,51–53 . A recent population‐based register study has indicated a level of risk for MCMs after exposure to topiramate similar to that with valproate 53 . In addition to the increased risk of birth defects, prenatal exposure to valproate has been associated with adverse neurodevelopmental and behavioral outcomes, including reduced IQ, increased risk of autism and autism spectrum disorders, as well as intellectual disabilities 13,54,55 .…”

“…12,51-53 A recent population-based register study has indicated a level of risk for MCMs after exposure to topiramate similar to that with valproate. 53 In addition to the increased risk of birth defects, prenatal exposure to valproate has been associated with adverse neurodevelopmental and behavioral outcomes, including reduced IQ, increased risk of autism and autism spectrum disorders, as well as intellectual disabilities. 13,54,55 Again, a recent population-based register study suggests a similar increased risk for autism spectrum disorders and intellectual disabilities with exposure to topiramate.…”

“…Although the regulatory bodies have not yet issued formal restrictions regarding the use of topiramate, the recent data 13,53 suggest that topiramate should be used with similar caution as valproate to female patients of childbearing potential.…”