Prenatal Antidepressant Exposure and the Risk of Autism Spectrum Disorder and Attention-Deficit Hyperactivity Disorder

Abstract

Background: Recent studies suggested that prenatal exposure of Selective Serotonin Reuptake Inhibitors (SSRIs) may be associated with increased risk of Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). However, confounding has not been comprehensively excluded. Objectives: To investigate the association between SSRIs and ASD and ADHD in a large health-care system. Methods: 429,645 children who were delivered in public hospital were identified using the Hong Kong Population-based electronic medical records on the Clinical Data Analysis & Reporting System (2001-2014). Using a case-control study design, we evaluated the association between ASD or ADHD and prenatal exposure of SSRIs. Further analyses using disease risk score (DRS) matching (1:10) and within-patient study design, case-time-control (CTC) were conducted to address residual confounding. The Risks of ASD and ADHD were estimated using odds ratios (ORs) from logistic regression. Results: Among 429,645 children identified, 299,672 were included in the analysis. 4,208 and 2,706 children were diagnosed with ASD and ADHD respectively. 0.88% of ASD and 1.22% of ADHD children were having prenatal SSRIs exposure compared with 0.6% in controls. The adjusted OR of ASD and ADHD are 1.35 (95%CI 0.94-1.93) and 2.12 (95%CI 1.44-3.11) respectively. The findings were similar in DRS matched model. In contrasts, no association was found in CTC analysis (OR=1.12, 95%CI 0.83-1.53 for ASD; OR=0.81, 95%CI 0.58-1.12 for ADHD). Alternative analyses using non-SSRI antidepressant as exposure showed similar results. The CTC OR for ASD and ADHD were 1.08 (95%CI 0.81-1.44) and 1.02 (95%CI 0.75-1.39) respectively. In validation analysis using insulin as negative control, no association was found in CTC analyses (OR=1.13, 95%CI 0.31-4.04 for ASD; OR=1.15, 95%CI 0.25-5.28 for ADHD). Conclusions: This study does not support the hypothesis that prenatal SSRIs exposure increased the risk of ASD or ADHD in children. These results suggest that the risk of ASD and ADHD observed with prenatal SSRI exposure is likely confounded by maternal underlying medical conditions and genetic factors.