SSRIs and autism: interpreting an umbrella review – Authors' reply

Michael Bracken raised concerns about our umbrella review and meta-analysis,1Kim JY Son MJ Son CY et al.Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence.Lancet Psychiatry. 2019; 6: 590-600Summary Full Text Full Text PDF PubMed Scopus (103) Google Scholar regarding two of the included studies: Andalib and colleagues2Andalib S Emamhadi MR Yousefzadeh-Chabok S et al.Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review.Eur Psychiatry. 2017; 45: 161-166Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar and Morales and colleagues.3Morales DR Slattery J Evans S Kurz X Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations.BMC Med. 2018; 16: 6Crossref PubMed Scopus (69) Google Scholar Both meta-analyses tested the association of antidepressant use versus unexposed groups and autism spectrum disorder, but Morales and colleagues3Morales DR Slattery J Evans S Kurz X Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations.BMC Med. 2018; 16: 6Crossref PubMed Scopus (69) Google Scholar addressed the overall association of antidepressant use (including SSRIs but without providing a subset of analysis of SSRIs) versus unexposed, whereas Andalib and colleagues2Andalib S Emamhadi MR Yousefzadeh-Chabok S et al.Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review.Eur Psychiatry. 2017; 45: 161-166Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar addressed the specific association of SSRI use (not the other antidepressants) versus unexposed. To ensure that all the exposures analysed in our umbrella review were as specific as possible, we included Andalib and colleagues2Andalib S Emamhadi MR Yousefzadeh-Chabok S et al.Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review.Eur Psychiatry. 2017; 45: 161-166Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar and not Morales and colleagues.3Morales DR Slattery J Evans S Kurz X Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations.BMC Med. 2018; 16: 6Crossref PubMed Scopus (69) Google Scholar Morales and colleagues' study was included to assess the association between prepregnancy exposure to antidepressant use and autism spectrum disorder. Bracken highlighted potential intrinsic errors within the meta-analysis of Andalib and colleagues.2Andalib S Emamhadi MR Yousefzadeh-Chabok S et al.Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review.Eur Psychiatry. 2017; 45: 161-166Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar As we have acknowledged in the limitation paragraph of our study,1Kim JY Son MJ Son CY et al.Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence.Lancet Psychiatry. 2019; 6: 590-600Summary Full Text Full Text PDF PubMed Scopus (103) Google Scholar reassessing primary errors in meta-analyses and their individual studies is out of the scope of umbrella reviews.4Fusar-Poli P Radua J Ten simple rules for conducting umbrella reviews.Evid Based Ment Health. 2018; 21: 95-100Crossref PubMed Scopus (168) Google Scholar However, we have reanalysed the results from Andalib and colleagues2Andalib S Emamhadi MR Yousefzadeh-Chabok S et al.Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review.Eur Psychiatry. 2017; 45: 161-166Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar after correcting for the biases highlighted by Bracken and found that the summary estimate was still significant (odds ratio [OR] 1·57, 95% CI 1·19–2·07). We have also reanalysed the association of antidepressant use versus unexposed and autism spectrum disorder reported by Morales and colleagues3Morales DR Slattery J Evans S Kurz X Antidepressant use during pregnancy and risk of autism spectrum disorder and attention deficit hyperactivity disorder: systematic review of observational studies and methodological considerations.BMC Med. 2018; 16: 6Crossref PubMed Scopus (69) Google Scholar (digitally extracting data from their figure 2—a procedure that was not originally planned in our protocol). The results were similarly graded as convincing evidence according to the established criteria (n of studies=11, OR 1·53 [95% CI 1·31–1·78], p<0·0001, I2=33, 95% prediction interval 1·07–2·19, Egger p=0·82, no signs of biases). Therefore, there are no changes in the direction of our results. Certainly, the association of SSRI use versus unexposed and autism spectrum disorder is probably due to confounding, as we have previously acknowledged.1Kim JY Son MJ Son CY et al.Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence.Lancet Psychiatry. 2019; 6: 590-600Summary Full Text Full Text PDF PubMed Scopus (103) Google Scholar We concluded that overall, our findings suggest that maternal psychiatric disorder might act as an independent risk factor for autism spectrum disorder.1Kim JY Son MJ Son CY et al.Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence.Lancet Psychiatry. 2019; 6: 590-600Summary Full Text Full Text PDF PubMed Scopus (103) Google Scholar Therefore, there are no errors in the interpretation of our results. We declare no competing interests. Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidenceConvincing evidence suggests that maternal factors, such as age and features of metabolic syndrome, are associated with risk of autism spectrum disorder. Although SSRI use during pregnancy was also associated with such risk when exposed and non-exposed groups were compared, this association could be affected by other confounding factors, considering that prepregnancy maternal antidepressant use was also convincingly associated with higher risk of autism spectrum disorder. Findings from previous studies suggest that one possible confounding factor is underlying maternal psychiatric disorders. Full-Text PDF SSRIs and autism: interpreting an umbrella reviewJong Yeob Kim and colleagues1 published an ambitious umbrella review of 119 risk factors for autism, one of which is the use of SSRIs by mothers during pregnancy. This risk was reported as an odds ratio (OR) of 1·84 (95%CI 1·60–2·11) that was not meaningfully influenced by sensitivity analysis. The methodology for this umbrella review involved identifying “the most recent meta-analysis with the largest number of studies” as of Oct 17, 2018. For SSRI exposure, the authors selected a meta-analysis by Andalib and colleagues2 published in 2017. Full-Text PDF