Implementation of Advanced Methods for Reproductive Pharmacovigilance in Autism: A Meta-Analysis of the Effects of Prenatal Antidepressant Exposure
Publication: American Journal of Psychiatry
Abstract
Objective:
Observational studies of prenatal antidepressant safety are hindered by methodological concerns, including susceptibility to surveillance bias. Some studies address potential bias by using alternative strategies to operationalize study comparison groups. In a meta-analysis of the association between prenatal antidepressant exposure and autism risk, the authors examined the utility of comparison group operationalization in reducing surveillance bias.
Methods:
A systematic search of multiple databases through August 2017 was conducted, selecting controlled observational studies of the association of prenatal antidepressant exposure with autism. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis produced summary effect measures with 95% confidence intervals stratified by comparator group composition, antidepressant class, and trimester of exposure.
Results:
Fourteen studies were included, with 13 reporting results using a population-based comparison group, five using a psychiatric control group, and four using a discordant-sibling control group. Eight of the 14 studies were rated poor because of inadequate control for prenatal depression and maternal ethnicity. Autism risk estimates after prenatal exposure to any antidepressant were decidedly different for population-based designs (hazard ratio=1.42, 95% CI=1.18, 1.70; odds ratio=1.58, 95% CI=1.25, 1.99) compared with psychiatric control (hazard ratio=1.14, 95% CI=0.84, 1.53; odds ratio=1.24, 95% CI=0.93, 1.66) and discordant-sibling (hazard ratio=0.97, 95% CI=0.68, 1.37; odds ratio=0.85, 95% CI=0.54, 1.35) designs. Findings for prenatal exposure to selective serotonin reuptake inhibitors were similar. Meta-regression of population-based studies demonstrated that despite statistical adjustment, ethnicity differences remained a significant source of study heterogeneity.
Conclusions:
In this meta-analysis, neither psychiatric control nor discordant-sibling designs supported an association between prenatal antidepressant exposure and autism. Discordant-sibling designs effectively addressed surveillance bias in pharmacovigilance reports derived from national registries and other large databases.
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History
Received: 1 July 2018
Revision received: 28 June 2019
Revision received: 7 January 2020
Accepted: 23 January 2020
Published online: 7 May 2020
Published in print: June 01, 2020
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Competing Interests
Dr. Nemeroff has received research grant support from NIH; he has served on scientific advisory boards for the American Foundation for Suicide Prevention (AFSP), the Anxiety and Depression Association of America (ADAA), the Brain and Behavior Research Foundation, Skyland Trail, and Xhale; he has served on the board of directors for AFSP, ADAA, and Gratitude America; he has served as a consultant to Bracket, Janssen, Intra-Cellular Therapies, Magstim, Navitor, SK Pharma, Sunovion, Taisho, Takeda, TC-MSO, and Xhale; he is a shareholder in Abbure, Antares, Calgene, Corcept, EMA Wellness, Seattle Genetics, TC-MSO, Trends in Pharma Development, and Xhale; he has income sources or equity of $10,000 from American Psychiatric Association Publishing, Bracket, Intra-Cellular Therapies, and TC-MSO; and he holds patents for a method and devices for transdermal delivery of lithium (U.S. patent number 6,375,990B1) and for a method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (U.S. patent number 7,148,027B2). Dr. D.J. Newport has received research grant support from Eli Lilly, GlaxoSmithKline, Janssen, the National Alliance for Research on Schizophrenia and Depression, NIH, Sage Therapeutics, Takeda Pharmaceuticals, the Texas Health and Human Services Commission, and Wyeth; he has served on speakers bureaus for AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, and Wyeth; and he has served on the advisory board of GlaxoSmithKline. The other authors report no financial relationships with commercial interests.
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