Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) During Pregnancy and the Risk for Autism spectrum disorder (ASD) and Attention deficit hyperactivity disorder (ADHD) in the Offspring: A True Effect or a Bias? A Systematic Review & Meta-Analysis

Abstract

Background and objective: An inconsistent association between exposure to SSRIs and SNRIs and the risk for ASD and ADHD in the Offspring was observed in observational studies. Some suggest that the reported association might be due to unmeasured confounding. We aimed to study this association and to look for sources of bias by performing a systematic review and meta-analysis.

Methods: Medline, Embase, and the Cochrane Library were searched up to June 2019 for studies reporting on ASD and ADHD in the Offspring following exposure during pregnancy. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random- effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for each outcome using the adjusted point estimate of each study.

Results: Eighteen studies were included in the meta-analysis. We found an association between SSRIs/ SNRIs prenatal use and the risk for ASD and ADHD (OR=1.42, 95% CI: 1.23-1.65, I²=58%; OR=1.26, 95% CI: 1.07-1.49, I2=48%, respectively). Similar findings were obtained in women who were exposed to SSRIs/SNRIs before pregnancy, representing statistically significant association with ASD (OR=1.39, 95% CI: 1.24-1.56, I2=33%) and ADHD (OR=1.63, 95% CI: 1.50-1.78, I²=0%) in the Offspring, although they were not exposed to those medications in utero.

Conclusions: Although we found an association between exposure to SSRIs/SNRIs during pregnancy and the risk for ASD and ADHD, an association with those disorders was also present for exposure pre-pregnancy, suggesting that the association might be due to unmeasured confounding. We are aiming to further assess the role of potential unmeasured confounding in the estimation of the association and perform a network meta-analysis.

Keywords: ADHD; ASD; SNRI's; SSRI's; antidepressants; pregnancy.; prenatal exposure.

Fig. (1)

Flow diagram of studies through review process.

Fig. (2)

Association between maternal exposure to anti-depressant and the risk for ASD in offspring.Forest plot of OR for ASD in offspring. Black boxes represent point estimates for OR surrounded by 95% CI. *OR, odds ratio; ASD, autistic spectrum disorder; CI, confidence interval; AD, antidepressants; EXP, exposure. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Meta-analysis of all studies: Association between maternal exposure to anti-depressant and the risk for ADHD in offspring.Forest plot of OR for ADHD in offspring. Black boxes represent point estimates for OR surrounded by 95% CI. *OR, odds ratio; ADHD, attention-deficit hyperactivity disorder; CI, confidence interval; AD, antidepressants; EXP, exposure. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (4)

Pairwise network meta-analysis for different SSRI's and the risk for ASD.Blue boxes represent point estimates for OR surrounded by 95% CI. * SSRI's, selective serotonin reuptake inhibitors ASD, autistic spectrum disorder; OR, odds ratio; CI, confidence interval. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (5)

Funnel plot for publication bias assessment.* OR, odds ratio; SE, standard error. (A higher resolution / colour version of this figure is available in the electronic copy of the article).