Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy

Abstract

Summary Purpose The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well‐characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug‐exposure status. Methods Participants were 105 Australian children aged 6–8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). Results Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. Significance Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low‐dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.

Autism and epilepsy

“…Studies have shown that use of valproic acid during pregnancy is associated with increased risk of ASD in offspring. 16,17 In contrast to our results, a Danish case-control study reported that epilepsy was not more common in parents of individuals with ASD than in control parents. 18 In our study, parents of individuals with epilepsy had no increased risk of ASD.…”

Sensitivity of the UK Clinical Practice Research Datalink to Detect Neurodevelopmental Effects of Medicine Exposure in Utero: Comparative Analysis of an Antiepileptic Drug-Exposed Cohort

“…The overall prevalence of all three NDDs combined in the CPRD cohort for women without epilepsy was 0.96% and this is lower than the background population prevalence of ASD alone, which is estimated to be between 1.16 and 1.57% in the UK general population [12, 13]. The rate of NDDs within the CPRD study cohort was also lower than other prospective observational cohort studies where rates following valproate monotherapy exposure ranged from 3.8 to 8.9% [2–4]. Finally, the rate of NDDs in the CPRD was also lower than those reported by the only other electronic healthcare record study assessing specific neurodevelopmental outcomes for AEDs [5].…”

“…Observational studies have in the past ascertained relatively small cohorts from specialist clinics and may therefore have included mother–child participants at higher risk of adverse outcome on the basis of both disease severity and higher exposure dose. The dose-related effects of valproate on the fetus have been documented in relation to major congenital malformations [16], reduced IQ [17] and in the parental ratings of autistic behaviours [4]. It is thus possible that ascertainment bias may account for some of the differences and that the prevalence rates from observational studies are higher than those generated by population-based electronic health record studies as a consequence of different methodological approaches to data collection.…”

“…Christensen et al [5] reported an increased prevalence of autism following exposure to valproate using Danish electronic healthcare data, but these rates were lower than those reported by an earlier UK-based prospective study by Bromley et al [2] and in other prospective cohort studies [3, 4]. This raises questions about the utility of using electronic healthcare databases for neurobehavioural teratogen signal detection, or to quantify risk, given the subtle and varying patterns with which neurodevelopmental disorders (NDDs) may present.…”

Valproate: life-saving, life-changing

“…9 Well-designed prospective studies have delineated the autistic traits in children. 10 What is less clear -but potentially sobering -is the experimental work from rats which identify autism-like behaviours, induced by valproate, being transmitted to a third generation of pups, that themselves were not directly exposed to valproate. This finding has led some to speculate whether there are epigenetic processes that can lead to autism being passed on to the grandchildren of the mother who originally took the drug in pregnancy.…”