Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism

Abstract

Background: Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of autism spectrum disorder (ASD). An increased cephalic index (the ratio of the cranial lateral width to the cranial anterior-posterior length) has been observed in children with ASD.

Methods: Forty-seven children exposed to VPA during the first trimester of pregnancy were evaluated for dysmorphic facial features, identified subjectively and by measurements. Each VPA-exposed child was evaluated for ASD using the Social Communication Questionnaire, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. The same physical examination was carried out on an unexposed comparison group of 126 children. The unexposed children also had testing for cognitive performance by the Wechsler Intelligence Scale for Children.

Results: Several dysmorphic craniofacial features, including telecanthus, wide philtrum, and increased length of the upper lip were identified subjectively. Anthropometric measurements confirmed the increased intercanthal distance and documented additional findings, including an increased cephalic index and decreased head circumference/height index. There were no differences between the craniofacial features of VPA-exposed children with and without ASD.

Conclusion: An increased frequency of dysmorphic craniofacial features was identified in children exposed to VPA during the first trimester of pregnancy. The most consistent finding was a larger cephalic index, which indicates a disproportion of increased width of the skull relative to the shortened anterior-posterior length. Birth Defects Research 109:1134-1143, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: autism spectrum disorder; cephalic index; valproic acid; “VPA embryopathy”.