Environmental Toxicology and Risk Assessment for Autism Phenotypes: A Prospective Study of Children Exposed In Utero to Antiepileptic Drugs

Background: Despite the momentum of the environmental factor hypothesis, the role of toxins in the pathogenesis of autism is poorly understood. Data from experimental animals with in utero and postnatal exposure to certain GABA agonists, including ethanol and some antiepileptic drugs (AEDs), show altered neurodevelopment for CNS substrates including cell differentiation, neuronal apoptosis, and neuronal migration. Human outcomes from well-controlled studies, however, are needed to identify the risk this class of environmental factors may pose to the development of autism. Objectives: In a prospective teratology study of neurobehavioral outcomes in a pediatric population, we report the incidence of traits associated with autism in preschool children who were exposed in utero to four commonly used antiepileptic drugs. Methods: Subjects are prospectively-enrolled preschool children between 3.5 and 5 years of age (n=54) from mother-child pairs who met stringent inclusionary criteria and are characterized by in utero exposure to carbamazepine, lamotrigine, phenytoin, or valproate monotherapy for the treatment of maternal epilepsy. Neuropsychological assessment, play observation, and clinical reports of traits associated with autism spectrum diagnoses are reported as observation data. Results: Across monotherapy groups, we observed traits associated with autism spectrum disorders, including developmental delay diagnoses (19%; n=10), expressive language deficits (20%; n=11), referral for occupational therapy services (11%; n=6), and extreme perseveration during cognitive tasks (24%; n=13). 17% of the subjects show 3 or more traits (valproate n=3; lamotrigine n=2; carbamazepine n=2; phenytoin n=1). Hand flapping, head banging, non-nutritive chewing, and contamination obsessions are reported as case reports. Conclusions: These outcomes exhibit increased incidence of traits associated with autism spectrum disorders. In humans, antiepileptic drugs may be in utero environmental factors that increase the risk of autism pathogenesis.