Abstract
Perucca P, Anderson A, Jazayeri D, et al. Ann Neurol. 2020;87(6):897-906. doi: 10.1002/ana.25724 The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. Sixty-seven child–parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], P = .50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 (13%) of 67 children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. Our study indicates that prenatal AED exposure does not increase the burden of de novo variants and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling.Objective:
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Commentary
Epilepsy is one of the most common neurologic conditions in the population, so it should not be surprising that it is one of the most common disorders encountered in pregnant women, with a prevalence of 0.3% to 0.7%. 1 The management of women with epilepsy during pregnancy is complex for many reasons, 2 including changes in drug metabolism associated with hormonal changes during pregnancy. Importantly, taking one or more antiepileptic drugs (AEDs) during pregnancy can be associated with an increased risk of major congenital malformations (birth defects) including cardiac anomalies, neural tube defects, limb malformations, hypospadias, and craniofacial abnormalities. While the background rate of birth defects is 1% to 2%, prenatal exposure to AEDs can increase the risk up to nearly 10%, depending on the AED, combination of medications, and dose(s) that are being used. 3 Fetal exposure to valproate also increases the risk of neurodevelopmental effects, including learning deficits and autism spectrum disorder. 4
As is true for many teratogens, the mechanism through which AED exposure leads to abnormal fetal development is not known. Avoiding exposure is the most effective approach to preventing abnormal outcomes, but risks to the mother’s health must also be considered before changing medications. Understanding the underlying mechanism could provide opportunities for preventing abnormal pregnancy outcomes other than just avoiding exposure when necessary. For example, recognizing that folic acid deficiency increases the risk of neural tube defects led to the recommendation that pregnant women take folic acid supplementation, which greatly reduces the risk.
A recent study 5 explores the hypothesis that the teratogenic effects of AEDs may be due to an increased rate of de novo mutations. De novo pathogenic variants are the main cause of many “sporadic” genetic syndromes associated with a range of developmental delays and congenital malformations. 6 If the genome-wide de novo mutation rate is increased, the chance that one of the de novo variants lands in a critical gene, resulting in an abnormal outcome, would also be increased. This would be consistent with the observation that, although the risk of birth defects is increased with AED exposure, only a subset of pregnancies is affected, presumably those with a variant in a gene that is critical for development. The gene in which a pathogenic de novo variant occurs would vary across individuals, leading to both genetic and phenotypic heterogeneity, also consistent with observations of AED-related birth defects.
Perucca and colleagues studied a cohort of 56 families (parent–child trios) with children who were exposed to 1 or more AEDs in utero, 10 of which had 1 or more birth defects. A comparison group of 11 families with children who were not AED-exposed was also included. Using trio exome sequencing, they identified de novo sequence variants and de novo copy number variants in each trio. In short, there was no difference in de novo variant burden when comparing AED-exposed children to nonexposed children or when comparing AED-exposed affected to AED-exposed unaffected children. Valproate has long been associated with birth defects; there were no differences when comparing children exposed to valproate (alone or in combination) to those who were not.
Though the number of AED-exposed and affected individuals included in this study was small, the study was powered to detect differences of 2- to 3-fold between groups. And it should be highlighted that identifying large cohorts for a study associated with abnormal pregnancy outcomes can be difficult. The known association of some AEDs with birth defects means that fewer women will have taken those medications during pregnancy. For example, the most common drug exposure in this study for both monotherapy and polytherapy was levetiracetam, which is not associated with a significantly increased risk of congenital malformations. 7 Valproate, with a higher risk profile, was used in fewer pregnancies. An ideal study would include cohorts of women on monotherapy for each drug of interest, with both normal and abnormal outcomes. Though building such cohorts will take significant time and effort, they will be important for future studies to follow up on the de novo mutagenesis hypothesis tested here and to test additional possible mechanisms.
The hypothesis tested in this study is innovative and plausible for the reasons outlined above; however, the results suggest that increased generation of de novo variants in AED-exposed pregnancies is not a major factor in the increased risk of birth defects. Given the complexities of managing women with epilepsy during pregnancy and the risk associated with AED exposure, investigation into the underlying mechanisms of the teratogenic effects should continue.
