BACKGROUND AND OBJECTIVES: The use of antiseizure medication (ASM) polytherapy has become increasingly common. However, it is known that there is an elevated risk of major congenital malformations (MCMs) in newborns after maternal use of select ASMs. This study characterizes the risk of MCMs in infants born to women using common ASM polytherapies during the first trimester. METHODS: The study population was pregnant women enrolled in the North American AED Pregnancy Registry between 1997 and 2024. Phone interviews at enrollment, 7 months' gestation, and postpartum collected data on ASM use and maternal characteristics. ASM monotherapy or polytherapy exposure is defined by ASM or ASM combination use during the first 12 weeks of pregnancy. MCMs were confirmed by medical records and adjudicated by a blinded teratologist. The risk of MCMs was calculated among infants exposed to a specific ASM polytherapy during the first trimester of pregnancy and those exposed to lamotrigine (LTG) monotherapy. RRs and 95% CIs were estimated using logistic regression. RESULTS: In a population of 15,318 pregnant women taking ASM at conception, 2,348 (15.3%) used 2 or more ASMs during the first trimester, with 796 polytherapy-exposed pregnancies eligible for analysis (mean age 30 years). The most common monotherapy was lamotrigine (LTG) (n = 2,582, mean age 31 years). The most common polytherapy combination was levetiracetam-lamotrigine (LEV-LTG) (38.4%). Indication of analyzed ASM polytherapy use was largely epilepsy (98.5%). The prevalence of MCMs was 2.0% for the reference LTG monotherapy group. Compared with LTG monotherapy, the adjusted RR of MCM was 1.63 (95% CI 0.69-3.40) for levetiracetam-LTG, 0.78 (0.04-3.78) for levetiracetam-carbamazepine, 0.99 (0.05-5.29) for levetiracetam-lacosamide, 1.40 (0.22-4.97) for levetiracetam-topiramate, 1.21 (0.07-6.22) for levetiracetam-zonisamide, 3.25 (0.74-9.98) for LTG-carbamazepine, 4.54 (1.61-11.07) for LTG-topiramate, and 3.22 (0.74-9.79) for LTG-zonisamide. Among infants exposed to any ASM polytherapy, the most common MCMs were hypospadias (5 cases), ventricular septal defect (5 cases), and cleft lip/palate (4 cases). All cleft lip/palate cases occurred in combinations with either topiramate or zonisamide. DISCUSSION: Our findings suggest an increased risk of MCM associated with LTG-topiramate duotherapy compared with LTG monotherapy. Relative risk estimates were too imprecise for us to conclude on the teratogenicity of other analyzed polytherapy combinations.
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