Investigators at Aarhus University Hospital, Denmark; and Centers for Disease Control, Atlanta, GA, conducted a population-based study of all children born alive in Denmark from 1996 to 2006 to determine the risk of autism spectrum disorders (ASD) and childhood autism (CA) in children exposed to valproate during pregnancy. [ASD includes CA, Asperger syndrome, atypical autism, and pervasive developmental disorders]. The Danish Psychiatric Central Register was used to identify children diagnosed for the first time with ASD and with CA. The National Hospital Register was used to identify children diagnosed with congenital malformations and parents diagnosed with epilepsy. Of 655,615 children born from 1996-2006, 5437 were identified with ASD, including 2067 with CA. The mean age of the children at end of follow-up was 8.84 years (range 4-14 years). The estimated absolute risk of ASD after 14 years of follow-up was 1.53% for ASD and 0.48% for CA. In the overall cohort, the 508 children exposed to valproate had an absolute risk of 4.42% for ASD and 2.50% for CA. In the 6584 children born to women with epilepsy, the absolute risk of ASD among 432 children exposed to valproate was 4.15%, and the risk of CA was 2.95%. In comparison, the risk among 6152 children not exposed to valproate was 2.44% for ASD and 1.02% for CA. [1]

COMMENT. Maternal exposure to valproate during pregnancy is associated with a small (<5%) but significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for effects of parental epilepsy and psychiatric disease. The risk of childhood autism following valproate use in women with epilepsy is lower compared with the overall risk. Exposures to carbamazepine, oxcarbazepine, lamotrigine and clonazepam monotherapy are not associated with increased risks of ASD and CA. The possible protective effects of folic acid ingestion during pregnancy are not evaluated. [2, 3]

The risks of valproate in women of childbearing potential (15-44 years) may outweigh the benefits. Given the evidence linking fetal valproate exposure to congenital malformations, cognitive impairments [4], and autism, the use of valproate in potentially parous women should be minimized, restricted to cases with no available alternative treatment, and only introduced (in low dosage) after potential risks are fully explained. [5]

Fetal Growth and Risk of Autism. Investigators at the University of Manchester, UK, and other centers studied the relationship between fetal growth and autistic spectrum disorder (ASD). Deviance in fetal growth at either extreme and preterm birth are strong independent risk factors for later ASD, especially with intellectual disabilities. Genetic and environmental factors might influence fetal growth and predispose to ASD. [6]