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 SCQ (Social Communication Questionnaire), ADI-R (Autism Diagnostic Interview-Revised) and ADOS (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 WISC-III (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 documented additional findings including an increased cephalic index, decreased head circumference/height index, and increased intercanthal distance. There were no differences between the craniofacial features of VPA-exposed children with and without ASD. CONCLUSIONS 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.

Macrocephaly Phenotype and Psychiatric Comorbidity in Autism Spectrum Disorder

“…In the same lines, a recent study showed that valproic acid-exposed children during the first trimester of pregnancy compared to the unexposed children had a large cephalic index. The large cephalic index was present in valproic acid-exposed children both with and without ASD (Stadelmaier et al 2017).…”

SAVER: sodium valproate for the epigenetic reprogramming of high-risk oral epithelial dysplasia—a phase II randomised control trial study protocol

“…Due to the significant risk of birth defects and developmental disorders in babies born to mothers taking VPA during pregnancy, the MHRA have issued guidance advising: ‘Valproate medicines must no longer be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place’. Women of childbearing potential (WOCBP) will not be recruited to the trial, due to known teratogenic effects of VPA [ 22 ]. All women will require a follicular stimulating hormone (FSH) test prior to randomisation, to confirm post-menopausal status.…”

Editorial In Bed with The Devil: Recognizing Human Teratogenic Exposures

“…To be useful for exposure cohort studies, pregnancy registries and teratogen information services must collect Reference: Hill, 1965. data from unexposed control pregnancies in the same manner as exposed pregnancies (Chambers et al, 1996(Chambers et al, , 2016. A few pregnancy registries and teratogen information services also collect data on the children in sufficient detail and with sufficient rigor to permit recognition of recurrent patterns of congenital anomalies (Cassina et al, 2012;Stadelmaier et al, 2017), something that is rarely possible in other kinds of epidemiology studies.…”