Anticonvulsant medications (ASMs), used to treat epilepsy and stabilize mood, pose risks during pregnancy, including fetal malformations and neurodevelopmental problems. Valproate is one of the most dangerous, associated with lower IQs and increased incidence of autism, ADHD, and intellectual disability.
Anticonvulsant medications (ASMs) are widely used to treat seizures in epilepsy and to stabilize mood in psychiatric conditions such as bipolar disorder.
Despite their effectiveness, the use of these medications during pregnancy raises serious concerns due to the risk they pose to the developing fetus. These risks include physical malformations and long-term impacts on the child's neurodevelopment.
One of the best-known ASMs, Valproate, is proven to be teratogenic, that is, it causes birth defects and damage to fetal development, and is contraindicated for pregnant women regardless of the indication.
Robust studies, such as the Neurodevelopmental Effects of Antiepileptic Drugs, have shown that children exposed to Valproate in the womb have a lower IQ at age six, as well as a greater likelihood of developing autism, intellectual disability and ADHD (Attention Deficit Hyperactivity Disorder).
However, the risks associated with other newer or less widely used anticonvulsants, such as Topiramate, are still less understood.
Research, such as a large Nordic study, suggests that the use of Topiramate during pregnancy may double the risk of neurodevelopmental conditions, such as intellectual disability in children.
On the other hand, a North American study was unable to confirm these associations conclusively, highlighting the need for further investigation.
Assessing the causal effects of ASMs is a complex task, as it is not feasible to conduct randomized clinical trials for ethical and practical reasons. In addition, genetic factors that influence both the indication for ASMs and neurodevelopmental disorders can confound the results.
This means that the risks associated with the drugs may be mixed with the underlying genetic characteristics of the mother or fetus. To address these limitations, researchers at the University of Bristol conducted a study combining data from primary care in the United Kingdom and national registers in Sweden.
This analysis, involving more than 3.18 million children, of whom 17,495 were exposed to ASMs during pregnancy, assessed the relationship between exposure to drugs and neurodevelopmental diagnoses, such as autism and intellectual disability. The methodology included comparisons between siblings exposed and not exposed to the drugs, allowing the interference of genetic and environmental factors to be minimized.
The results showed that children exposed to Valproate were more likely to be diagnosed with autism, intellectual disability, and ADHD.
As for Topiramate, exposure was associated with a 2.5-fold increased risk of intellectual disability. Carbamazepine was associated with a 1.25-fold increased risk of autism and a 1.3-fold increased risk of intellectual disability. Meanwhile, there was little evidence of increased neurodevelopmental risk with Lamotrigine, suggesting a more favorable safety profile.
The pooled absolute adjusted risk (%) of offspring neurodevelopmental conditions from ASM exposure during pregnancy at ages 4, 8, and 12 years. All estimates are adjusted for maternal age, region, diagnosis of neurodevelopmental conditions before pregnancy, evidence of hazardous drinking and illicit drug use during pregnancy, pregnancy, healthcare utilization, seizure events, use of antipsychotics and antidepressants in the year before pregnancy, vomiting or antiemetic prescriptions during pregnancy, and socioeconomic status. Note that the pooled estimates of ADHD risk among those not exposed to an ASM are heavily weighted toward the United Kingdom (age at risk 12), where a lower risk was estimated than in Sweden (age at risk 12). Sample size for figure: Total cohort = 3,182,771, No ASM = 3,165,276, Carbamazepine = 3,030, Gabapentin = 1,428, Lamotrigine = 5,974, Levetiracetam = 806, Phenytoin = 240, Pregabalin = 1,715, Topiramate = 418, Valproate = 1,601, Other ASM = 543, Polytherapy = 1,740. Source data are provided as a source data file. ADHD, Attention deficit hyperactivity disorder, Anticonvulsant medication ASM.
These findings highlight the need to carefully plan anticonvulsant use before conception whenever possible and to consider safer alternatives such as Lamotrigine when clinically appropriate.
While risks should be discussed on a case-by-case basis, the research provides valuable information to guide physicians and patients in making informed decisions, especially in review by regulatory agencies such as the European Medicines Agency (EMA).
More research, especially with larger cohorts and long-term follow-up, is essential to better understand the risks and benefits of each ASM during pregnancy. In the meantime, collaboration between physicians, scientists, and regulators is crucial to improving care for women who need ASMs and want to become pregnant.
READ MORE:
Antiseizure medication use during pregnancy and children’s neurodevelopmental outcomes.
Madley-Dowd P, Ahlqvist VH, Forbes H. et al.
Nat Commun 15, 9640 (2024).
Abstract:
The teratogenic potential of valproate in pregnancy is well established; however, evidence regarding the long-term safety of other antiseizure medications (ASMs) during pregnancy remains limited. Using routinely collected primary care data from the UK and nationwide Swedish registries to create a cohort of 3,182,773 children, of which 17,495 were exposed to ASMs in pregnancy, we show that those exposed to valproate were more likely to receive a diagnosis of autism, intellectual disability, and ADHD when compared to children not exposed to ASMs. Additionally, children exposed to topiramate were 2.5 times more likely to be diagnosed with intellectual disability (95% CI: 1.23–4.98), and those exposed to carbamazepine were 1.25 times more likely to be diagnosed with autism (95% CI: 1.05–1.48) and 1.30 times more likely to be diagnosed with intellectual disability (95% CI: 1.01–1.69). There was little evidence that children exposed to lamotrigine in pregnancy were more likely to receive neurodevelopmental diagnoses. While further research is needed, these findings may support considering safer treatment alternatives well before conception when clinically appropriate.
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