Studies on link between prenatal antidepressant exposure, autism likely biased, researchers suggest

Psychiatric control and discordant-sibling design studies did not support an association between prenatal antidepressant exposure and autism, according to results of a meta-analysis published in American Journal of Psychiatry.

“A causal link between fetal antidepressant exposure and autism is biologically plausible and thereby merits rigorous investigation,” Monica L. Vega, MD, of the department of psychiatry and behavioral sciences at University of Miami Miller School of Medicine, and colleagues wrote. “Converging lines of preclinical and clinical evidence suggest a pivotal neurotropic role for serotonin in neurodevelopment and implicate aberrant serotonin signaling in the pathophysiology of autism spectrum disorder. Considering that antidepressants alter serotonin neurotransmission, readily cross the human placenta and have been shown in a rodent model to bind to the serotonin transporter in the fetal brain, it is reasonable to posit a role for fetal antidepressant exposure in the pathogenesis of autism.”

Since 2011, several observational studies that examined the potential link between autism and prenatal antidepressant exposure showed discrepant results. However, prior meta-analyses have reported a significant association between autism and antidepressant exposure, but researchers noted that the association was nonsignificant when limited to women with histories of mental illness and may thus be a by-product of residual confounding.

In the current study, Vega and colleagues sought to gain insight into this association by examining the utility of comparison group operationalization in reducing surveillance bias. They conducted a systematic database search through August 2017, selected controlled observational studies of the association between autism and prenatal antidepressant exposure and assessed study quality using the Newcastle-Ottawa Scale. They produced summary effect measures with 95% confidence intervals using random-effects meta-analysis, with results stratified by comparator group composition, antidepressant class and trimester of exposure.

The investigators included 14 studies, of which 13 reported results using a population-based comparison group, five using a psychiatric control group and four using a discordant-sibling control group. They rated eight studies as poor because of inadequate control for maternal ethnicity and prenatal depression.

Results showed that autism risk estimates following prenatal exposure to any antidepressant were significantly different for population-based designs (HR = 1.42; 95% CI, 1.18-1.7 and OR = 1.58; 95% CI, 1.25-1.99) compared with discordant-sibling (HR = 0.97; 95% CI, 0.68-1.37 and OR = 0.85; 95% CI, 0.54-1.35) and psychiatric control (HR = 1.14; 95% CI, 0.84-1.53 and OR = 1.24; 95% CI, 0.93-1.66) designs. Vega and colleagues reported similar findings for prenatal exposure to selective serotonin reuptake inhibitors. Further, they noted that meta-regression of population-based studies revealed ethnicity differences remained a significant source of study heterogeneity, despite statistical adjustment.

“These results lead us to recommend that pharmacovigilance reports of large-scale registry and database data more carefully consider sources of bias, particularly surveillance bias, and that they accordingly consider incorporating alternative designs, such as family-based discordant-sibling designs, in lieu of conventional population-based comparisons to more effectively address the potential for surveillance bias,” the researchers wrote. – by Joe Gramigna

Disclosures: Vega reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.