ASD Risk on Offspring With Prenatal Use of Medication Affecting Neurotransmitter System
The unadjusted model suggests that the number of maternal diagnoses was likely a confounding factor for several medication classes.
The majority of medications that affect neurotransmitter systems do not appear to increase the risk for autism spectrum disorder (ASD) in prenatally exposed offspring, according to study results published in JAMA Psychiatry,
Investigators conducted a case-control study comprised of children born between January 1, 1997 and December 31, 2007 who were subsequently followed for the development of ASD until January 26, 2015 through an Israeli health maintenance organization. A total of 55 groups of medications affecting the neurotransmitter system were identified; children prenatally exposed to these medications were compared with unexposed children. Cox proportional hazards regression was performed to identify the ASD risk associated with relevant medications. Analyses were adjusted for the relevant confounders, including birth year, maternal age, maternal history of psychiatric or neurologic disorders, and number of maternal medical diagnoses 1 year prior to pregnancy.
The analytic sample comprised of 96,249 individuals (48.8% girls) with a mean (SD) age of 11.6 (3.1) years by conclusion of follow-up. At follow-up, 1405 individuals had an ASD diagnosis; the remaining 94,844 individuals were classified as healthy controls. From the initial 55 medication groups, 16 were excluded following no observed ASD cases and 4 were excluded following no correlation with ASD per the Spearman rank correlation test (R=1.0). In the remaining 34 medication groups, 5 showed “nominally…significant” association with ASD in the fully adjusted model.
A statistically significant association was observed between the use of antagonists of neuronal nicotinic acetylcholine α receptor and ASD (hazard ratio [HR], 12.94; 95% CI, 1.35-124.25; P =.03). This association remained substantial in all sensitivity analyses. The risk for ASD associated with the use of GABA transaminase inhibitors (solely valproate sodium) was initially high but declined after adjustments for confounders. In the final model, the association was not significant (HR, 3.15; 95% CI, 0.82-12.06; P =.09). When the number of maternal diagnoses were included in the model, cannabinoid receptors agonists/fatty acid amide hydrolase inhibitors (solely paracetamol; HR, 0.72; 95% CI, 0.55-0.95; P =.02), muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24-0.98; P =.04), opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45-0.99; P =.045), and α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19-0.96; P =.04) were each correlated with a lower risk for ASD. These results suggest that the number of maternal diagnoses was likely a confounding factor for several medication classes in the unadjusted model. Antidepressant and antipsychotic medications were not associated with increased risk for ASD.
Only 2 medication classes appeared to be associated with higher estimates of ASD risk: valproate (inhibitors of GABA transaminase) and antagonists of neuronal nicotinic acetylcholine receptor α. Both of these medications are used in the treatment of epilepsy; the extent to which the observed effects are due to “shared mechanisms…[of] epilepsy” are unclear and warrant further research.
These data suggest that the majority of medications known to affect neurotransmitters are not associated with offspring risk for ASD when used prenatally.
Future research with alternative study designs must be performed to validate these results, and should account for the potential confounding effect of maternal number of diagnoses prior to pregnancy.
Janecka M, Kodesh A, Levine SZ, et al. Association of autism spectrum disorder with prenatal exposure to medication affecting neurotransmitter systems [published online October 31, 2018]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.2728