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Original Investigation
June 2017

Risk for Autism Spectrum Disorders According to Period of Prenatal Antidepressant ExposureA Systematic Review and Meta-analysis

Author Affiliations
  • 1Department of Psychiatry, Assistance Publique–Hôpitaux de Paris, Bicêtre University Hospital, Le Kremlin Bicêtre, France
  • 2EPIMED Research Centre–Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
  • 3Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
  • 4Université Paris-Saclay, Univ Paris-Sud, UVSQ, CESP, INSERM U1178, Bicêtre University Hospital, Le Kremlin Bicêtre, France
  • 5Université Paris-Saclay, Univ Paris-Sud, UVSQ, CESP, INSERM U1178, Department of Biostatistics, Maison de Solenn, Paris, France
  • 6Research Center INSERM 1219, Bordeaux Population Health Bordeaux University, University Department of Adult Psychiatry, Charles-Perrens Hospital, Bordeaux, France
JAMA Pediatr. 2017;171(6):555-563. doi:10.1001/jamapediatrics.2017.0124
Key Points

Question  Does prenatal antidepressant exposure increase the risk for autism spectrum disorders?

Findings  This systematic review and meta-analysis suggests an association between increased autism spectrum disorder risk and maternal use of antidepressants during pregnancy; however, it appears to be more consistent during the preconception period than during each trimester. The association was weaker when controlled for past maternal mental illness.

Meaning  Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for autism spectrum disorders.

Abstract

Importance  Several studies have examined the links between prenatal exposure to antidepressants and autism spectrum disorders (ASDs) in children, with inconsistent results, especially regarding the impact of the trimester of exposure.

Objective  To perform a systematic review of the literature and a meta-analysis of published studies to assess the association between ASDs and fetal exposure to antidepressants during pregnancy for each trimester of pregnancy and preconception.

Data Sources  PubMed, EMBASE, and PsycINFO databases up to May 2016 were searched in June 2016 for observational studies. For the meta-analyses, data were analyzed on RevMan version 5.2 using a random-effect model. For the review, studies were included if they had been published and were cohort or case-control studies, and for the meta-analysis, studies were included if they were published studies and the data were not derived from the same cohorts.

Study Selection  We included all the studies that examined the association between ASDs and antenatal exposure to antidepressants.

Data Extraction and Synthesis  Three reviewers independently screened titles and abstracts, read full-text articles, and extracted data. The quality of the studies was also assessed.

Main Outcomes and Measures  Primary outcome was the association between antidepressants during pregnancy and ASDs. Secondary outcomes were the associations between antidepressants in each individual trimester or before pregnancy and ASDs.

Results  Our literature search identified 10 relevant studies with inconsistent results. For prenatal exposure, the meta-analysis on the 6 case-control studies (117 737 patients) evidenced a positive association between antidepressant exposure and ASDs (odds ratio [OR], 1.81; 95% CI, 1.49-2.20). The association was weaker when controlled for past maternal mental illness (OR, 1.52; 95% CI, 1.09-2.12). A similar pattern was found whatever the trimester of exposure considered (first trimester: OR, 2.09, 95% CI,1.66-2.64; second: OR, 2.00, 95% CI, 1.55-2.59; and third: OR, 1.90, 95% CI, 1.20-3.02. Controlled for past maternal mental illness: first trimester: OR, 1.79; 95% CI, 1.27-2.52, second: OR, 1.67, 95% CI, 1.14-2.45; and third: OR, 1.54, 95% CI, 0.82-2.90). No association was found when the 2 cohort studies were pooled (772 331 patients) for the whole pregnancy (hazard ratio, 1.26; 95% CI, 0.91-1.74) or for the first trimester. In addition, preconception exposure to antidepressants was significantly associated with an increased risk for ASDs (OR controlled for past maternal illness, 1.77; 95% CI, 1.49-2.09).

Conclusions and Relevance  There is a significant association between increased ASD risk and maternal use of antidepressants during pregnancy; however, it appears to be more consistent during the preconception period than during each trimester. Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for ASDs. Future studies should address the problem of this potential confounder.

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