Lamotrigine-Topiramate Duotherapy Increases Congenital Malformation Risk Fourfold

Navigating the Teratogenic Risks of Multidrug Epilepsy Management

Managing epilepsy during pregnancy requires a delicate titration between maintaining maternal seizure control and minimizing the risk of major congenital malformations. While the teratogenic profile of valproic acid is well established, showing a significantly higher risk for neural tube defects and cleft lip compared to other agents, the safety of newer generation medications remains a subject of active investigation [1, 2]. Current clinical guidelines generally favor monotherapy with lamotrigine or levetiracetam due to their lower observed risk profiles [3]. However, many patients require polytherapy to prevent convulsive seizures, which themselves pose substantial risks to both the mother and the fetus [4, 3]. Despite the increasing clinical use of multidrug regimens, evidence regarding the comparative safety of specific antiseizure medication combinations has remained limited [5, 6]. Recent registry data now provide a detailed analysis of malformation risks across common polytherapy pairings to help clinicians optimize treatment plans prior to conception.

Registry Analysis of First Trimester Polytherapy Exposure

To evaluate the safety of multidrug regimens, researchers analyzed data from the North American AED Pregnancy Registry collected between 1997 and 2024. Data collection involved structured phone interviews conducted at enrollment, at seven months of gestation, and during the postpartum period to capture precise details on maternal characteristics and antiseizure medication use. Exposure was defined as the use of either antiseizure medication monotherapy or polytherapy during the first 12 weeks of pregnancy, the critical window for fetal organogenesis. To ensure diagnostic accuracy, all major congenital malformations were confirmed via medical records and adjudicated by a blinded teratologist (a specialist who evaluates the causes and patterns of abnormal fetal development). The total study population included 15,318 pregnant women taking antiseizure medications at the time of conception. Among this group, 2,348 women (15.3%) used two or more antiseizure medications during the first trimester. The researchers identified 796 polytherapy-exposed pregnancies that met all eligibility criteria for the final analysis, with a mean maternal age of 30 years. This cohort was compared against a reference group of 2,582 women receiving lamotrigine monotherapy, who had a mean maternal age of 31 years. Epilepsy was the primary indication for treatment in 98.5% of the analyzed polytherapy cases, providing a focused look at the risks associated with seizure management rather than psychiatric or off-label indications.

Comparative Safety Profiles of Common Drug Pairings

The lamotrigine monotherapy group served as the baseline for comparison, demonstrating a major congenital malformation prevalence of 2.0%. Among the polytherapy cohorts, the levetiracetam-lamotrigine combination was the most frequently prescribed, representing 38.4% of all analyzed cases. This specific pairing was associated with an adjusted relative risk of 1.63 (95% CI 0.69-3.40) compared to lamotrigine monotherapy. Because the confidence interval crosses the null value, this finding did not reach statistical significance, suggesting that adding levetiracetam to lamotrigine does not drastically alter the baseline teratogenic risk. Other levetiracetam-based duotherapies showed varying risk profiles, though none reached statistical significance due to wide confidence intervals. The adjusted relative risk for levetiracetam-carbamazepine was 0.78 (95% CI 0.04-3.78), while levetiracetam-lacosamide showed an adjusted relative risk of 0.99 (95% CI 0.05-5.29). For combinations involving other agents, the adjusted relative risk for levetiracetam-topiramate was 1.40 (95% CI 0.22-4.97) and the adjusted relative risk for levetiracetam-zonisamide was 1.21 (95% CI 0.07-6.22). In contrast, combinations involving lamotrigine paired with certain other antiseizure medications showed more pronounced risk elevations. Most notably, the study identified a statistically significant 4.5-fold increase in risk for the lamotrigine-topiramate combination, which yielded an adjusted relative risk of 4.54 (95% CI 1.61-11.07). Other lamotrigine-based pairings also showed elevated point estimates, though they lacked statistical precision. Specifically, the adjusted relative risk for lamotrigine-carbamazepine was 3.25 (95% CI 0.74-9.98) and the adjusted relative risk for lamotrigine-zonisamide was 3.22 (95% CI 0.74-9.79). While these estimates are high, the wide confidence intervals reflect a limited number of cases, meaning clinicians should interpret these specific pairings with caution until larger datasets become available.

Specific Malformation Patterns and Clinical Guidance

Beyond overall risk calculations, the researchers identified specific patterns of major congenital malformations among infants exposed to any antiseizure medication polytherapy during the first trimester. The most frequently observed anomalies were hypospadias (5 cases), a condition where the urethral opening is located on the underside of the penis, and ventricular septal defect (5 cases), a structural opening in the wall separating the lower chambers of the heart. These findings highlight the importance of targeted anatomical screening, such as fetal echocardiography, during prenatal care for women requiring multiple medications for seizure control. Craniofacial abnormalities also emerged as a significant concern. The study documented 4 cases of cleft lip or palate among infants exposed to polytherapy. Notably, all 4 cases of cleft lip or palate occurred in infants exposed to drug combinations involving either topiramate or zonisamide. This specific association suggests that these agents may contribute to a higher risk of midline facial defects when used as part of a multidrug regimen during the first 12 weeks of pregnancy, providing obstetricians and maternal-fetal medicine specialists with specific markers to monitor during routine ultrasound examinations. For practicing neurologists and primary care physicians, these data underscore the necessity of rigorous pre-pregnancy counseling and medication optimization. Given the statistically significant 4.5-fold increase in malformation risk associated with lamotrigine-topiramate duotherapy, physicians should consider alternative regimens or dose adjustments prior to conception whenever clinically feasible. While the study population was largely composed of women with epilepsy, the findings provide a practical framework for managing any patient of childbearing age on these specific antiseizure medication combinations to minimize teratogenic outcomes.

References

1. Yang X, Sun Y, Hua Z, Li T, Li X, Du P. Safety of Valproic Acid Use in Pregnant Women: A Systematic Review and Meta-Analysis.. The journal of obstetrics and gynaecology research. 2025. doi:10.1111/jog.70121

2. Heneghan C, Aronson J. Sodium valproate: who knew what and when? Cumulative meta-analysis gives extra insights. BMJ evidence-based medicine. 2018. doi:10.1136/bmjebm-2018-111068

3. Pack AM, Oskoui M, Roberson SW, et al. Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM.. Neurology. 2024. doi:10.1212/WNL.0000000000209279

4. Veroniki AA, Cogo E, Rios P, et al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Medicine. 2017. doi:10.1186/s12916-017-0845-1

5. Lavu A, Vaccaro CM, Zusman EZ, et al. Antiseizure medication use during pregnancy and neonatal growth outcomes: A systematic review and meta‐analysis. British Journal of Clinical Pharmacology. 2023. doi:10.1111/bcp.15752

6. Goubran J, Okunnu O, Lavu A, Eltonsy S. Third generation antiseizure medications exposure during pregnancy and neonatal adverse birth outcomes: A systematic review. Science Progress. 2024. doi:10.1177/00368504241234781