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June 7, 2021

Association of Fetal Exposure to Newer Antiseizure Medications With Neurodevelopment: A Step Toward a Better Understanding

Author Affiliations
  • 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • 2Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
  • 3Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
JAMA Neurol. Published online June 7, 2021. doi:10.1001/jamaneurol.2021.1217

The teratogenic risks of antiseizure medications (ASMs) have been a concern since the first reports more than 50 years ago of an association between maternal use of ASMs and occurrence of birth defects in offspring.1 The risks and possible differences in risks between ASMs have become a major factor in treatment decision and in particular drug selection for girls and young women with epilepsy.2 Although the initial focus was on anatomical teratogenicity (ie, malformations), more attention has been given during the last 2 decades to the possibility that exposure to ASMs during fetal life may adversely affect the neurodevelopment of the offspring. A landmark study by Meador et al3 showed that exposure to high doses of valproate was associated with lower IQ in children at 6 years of age compared with children whose mothers had been treated with phenytoin, carbamazepine, or lamotrigine. The results of this carefully designed cohort study have been confirmed in other similar studies.4 Large population health care register–based studies have subsequently expanded our understanding of the adverse effects of maternal use of valproate on the neurodevelopment of the exposed child. Hence, in nationwide population-based studies, valproate exposure has been associated with a 2- to 5-fold increased risk of autism and autism spectrum disorders,5,6 a 1.5- to 1.7-fold increased risk of attention-deficit/hyperactivity disorder,6,7 a 4- to 5-fold increased risk of intellectual disabilities,8 and a 3- to 5-fold increased risk of early neurodevelopmental disorders.9

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