Abstract
Sonia Hernández-Díaz, Loreen Straub, Brian T Bateman, Yanmin Zhu, Helen Mogun, Katherine L Wisner, Kathryn J Gray, Barry Lester, Christopher J McDougle, Elyse DiCesare, Page B Pennell, Krista F Huybrechts. N Engl J Med. 2024;390(12):1069–1079. PMID: 38507750. doi: 10.1056/NEJMoa2309359 Background: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. Methods: We identified a population-based cohort of pregnant women and their children within 2 healthcare utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. Results: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. Conclusions: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate.
Commentary
Over 1 million women with epilepsy (WWE) are of childbearing age in the USA, making it one of the most common neurological disorders that require medical management during pregnancy. 1 Children born to WWE with fetal antiseizure medication exposure are at a higher risk for adverse outcomes, including congenital malformations and impaired developmental outcomes such as reduced intelligence quotient and language functioning, developmental delay, attention deficit hyperactivity disorder, and autism spectrum disorders (ASD). 2 Previous literature consistently demonstrates an increased risk of ASD following fetal exposure to certain medications such as valproic acid. Studies from UK cohorts reveal that 6.3% of children exposed to valproic acid monotherapy in utero were diagnosed with ASD after neuropsychological evaluation up to 6 years old. 3 While the use of certain antiseizure medications during pregnancy has long been recognized to carry an elevated risk of adverse neurodevelopmental outcomes, including ASD, the majority of the ∼30 Food and Drug Administration (FDA)-approved antiseizure medications lack a clear understanding of their associated risks. 4
Topiramate is a medication approved by the FDA in 1996 to treat epilepsy as monotherapy or adjunctive therapy. It is also commonly used to treat migraine, as well as chronic weight management for individuals with a body mass index over 30. Previously, topiramate use during pregnancy has been linked to small gestational age, increased risk of low birth weight, and congenital malformation in particular oral clefts. Recently, the European Medicines Agency has introduced new measures to discourage the use of topiramate in women of childbearing age due to concern about the teratogenic effects and the emergence of evidence linking it to neurodevelopmental disorders in the case of prenatal exposure. 5 However, there have been conflicting findings regarding the neurodevelopmental risk associated with fetal exposure to topiramate. For example, in a blinded prospective cohort study, fetal exposure to topiramate was not observed to be linked with declines in children's cognitive abilities, and higher dosage did not correlate with adverse outcomes. 6 However, other research studies have shown a higher risk of neurodevelopmental disorders such as learning disabilities, poor adaptive behavior, and autism with fetal exposure to topiramate.7,8
Hernández-Díaz et al 9 investigated the association between fetal topiramate exposure and autism risk. They used valproate and lamotrigine as positive and negative controls, respectively. This study extracted pregnancy data for females ranging from 12 to 55 years old, from 2 population-based database cohorts in the United States: MAX-TAF from 2000 to 2018, which includes data on healthcare use for Medicaid beneficiaries nationwide, and MarketScan from 2003 to 2020, which includes data on commercial health insurance. The primary outcome was the estimated cumulative incidence of ASD at 8 years old based on having at least 2 ASD diagnoses recorded in the database. The study defined exposure to antiseizure medication as prescription refills from gestational week 19 until delivery, based on the hypothesis that the latter half of pregnancy is a critical period for synaptogenesis and neurodevelopment. Their study showed that the estimated cumulative incidence of ASD was 1.9% for the general population without antiseizure medication exposure, 4.2% in children of WWE unexposed to medication, 4.1% in children of WWE that prenatally exposed to lamotrigine (n = 4205, with 50 ASD diagnoses), 6.2% in those exposed to topiramate (n = 1030, with 17 ASD diagnoses), and 10.5% with valproate exposure (n = 800, with 32 ASD diagnoses). However, after controlling for confounding factors using propensity score matching, the hazard ratio for exposure to topiramate was 0.96, indicating no increased risk of ASD for topiramate-exposed children, while the increased risk remained evident for valproate.
The findings of this study diverged from those of a prior large-scale Nordic register-based population study between 1996 and 2017, which included over 4 million children participants. 10 In unexposed children of mothers with epilepsy, 1.5% were diagnosed with ASD, whereas 4.3% of topiramate-exposed children received ASD diagnoses. The adjusted hazard ratio for ASD after topiramate exposure was 2.8 (95% confidence interval [CI], 1.4 to 5.7), and after valproate exposure, it was 2.4 (95% CI, 1.7 to 3.3). Both studies were well-conducted with a large population cohort and controlled for multiple variables. Despite their similar attributes, differences between the 2 studies exist. The USA cohort had a higher prevalence of epilepsy diagnoses (2%) compared to the Nordic study (0.8%), as well as a greater incidence of anxiety and depression and increased usage of antidepressants and opioids. The frequency of topiramate exposures varied between these 2 studies. Disparities arose in the assessment of exposure periods: the Nordic study considered potential antiseizure medication exposure from the last menstrual period to birth, while the USA study focused on the second half of pregnancy. Dose exposure calculations also differed, with the Nordic study utilizing cumulative defined daily doses over 90 days before the last menstrual period to birth, whereas the USA study relied on the first drug dispensing during the assessment period.
The current study offers reassuring findings regarding the potential risk of autism following fetal exposure to topiramate. However, various teratogenic effects have been unequivocally demonstrated in several antiseizure medications, including topiramate, and the teratogenic profile of the majority of antiseizure medications remains uncertain, which further adds complexity to clinical care. In practice, WWE of childbearing age often express concerns about the long-term effects of fetal exposure to antiseizure medications. A significant number of pregnancies are unplanned, with over 50% of women unaware of their pregnancy until after embryogenesis has occurred. Counseling WWE about medication safety during pregnancy is challenging due to limited information on the nature and extent of teratogenic risks in humans. There is an urgent need for a more proactive approach through prospective, well-controlled studies to comprehensively understand both the anatomical and neurodevelopmental teratogenic effects.
