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KSR Number: KSRA73405

Use of selective serotonin-reuptake inhibitors in the first trimester and risk of cardiovascular-related malformations: a meta-analysis of cohort studies

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

The evidence indicates that the use of selective serotonin-reuptake inhibitors (SSRIs) for depression in pregnant women during the first trimester may be associated with an increased risk of cardiovascular-related malformations of infants including septal defects. The authors recommend that further studies are carried out into every selective serotonin-reuptake inhibitor and that the results are stratified by the different kinds of cardiovascular-related congenital defects. Better adjustment for any potential confounders is also highly desirable. At the same time, any future systematic reviews must pay special consideration to enable to reproduce searches and allow the reader a more informed interpretation of the given results.

Risk of Bias Assessment

Overall summary High risk of bias in the review


Whilst the review appears exempt from important bias and the potential limitations are well described, there is residual uncertainty regarding the sensitiveness of the searches and the individual study characteristics.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? No
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review High

Details of Review

Number of studies 18
Number of participants 7,280,932
Last search date 31 December 2015
Review type Aetiological
Objective To assess the relationship between selective serotonin-reuptake inhibitors use during the first trimester and cardiovascular-related malformations of infants.
Population Pregnant women with and without the use of any antidepressant drug during the first trimester.

Studies with pregnant women who were exposed to two kinds of anti-depressants or more at the same time were excluded.
Outcome Risk of any cardiovascular-related malformations at birth.
Study design Cohort study.

Review articles, systemic review and meta-analysis, non-cohort study designs (e.g. case-control study, descriptive study, randomised controlled trial, etc.), commentaries, editorials were excluded.
Exposure Selective serotonin-reuptake inhibitors.


The pooled analyses reported that statistically significant increased risk of infant cardiovascular-related malformations were associated with pregnant women who were exposed to selective serotonin-reuptake inhibitors (SSRIs) at any point during the first trimester (risk ratio [RR]: 1.26, 95% confidence interval [CI] 1.13 to 1.39, 18 studies).

The pooled estimate of seven studies reported that statistically significant increased risk of cardiac malformations in infants were associate with mothers who used SSRIs in the trimester (RR 1.17, 95% CI 1.06 to 1.28). The pooled analyses reported a significant increased risk of atrial septal defect (ASD) (RR 2.06, 95% CI 1.40 to 3.03, 6 studies), ventricular septal defect (VSD) (RR 1.15, 95% CI 0.97 to 1.36, 7 studies) and ASD and/or VSD (RR 1.27, 95%CI 1.14 to 1.42, 14 studies).

Full Risk of Bias Assessment

The review was judged to be at low risk of bias for this domain.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably yes
Concerns regarding specification of study eligibility criteria Low

PubMed and Web of Science databases were searched. Reference lists of identified articles were checked but no further searches for unpublished material or grey literature were undertaken. Search terms were provided, but a full search strategy was not reported so it is not possible to judge whether the search strategy was adequate. There were no date restrictions and no reported restrictions for publication format or language. Studies were independently selected by two reviewers.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably no
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably no
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies High

The study characteristics described in this review for included studies are very basic. Critically, it would have been highly desirable to report on the type of exposure, the definition of the outcome (e.g. diagnostic code) and the types of birth that were included, i.e. live births, still births or both. Quality was assessed using the Newcastle-Ottawa Scale for cohort studies, which was considered appropriate.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably no
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Unclear

The synthesis appeared to include all eligible studies. The method of analysis was explained and appeared appropriate. There was low to high evidence of heterogeneity among studies. Subgroup analysis, meta regression and sensitivity analysis were performed to explore the causes of heterogeneity among the included studies. No evidence of significant publication bias was found using Egger's test and Begg’s funnel plot. Sensitivity analysis was performed to test the robustness of findings. The quality of individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low