Aim: this study aims to determine the pooled risk of congenital malformations in offsprings of pregnant women placed on SSRIs during pregnancy compared to the offsprings of pregnant women not on SSRIs. It secondarily aims to assess if significant increase in risk of congenital malformations occurs across the different trimesters and to determine if the trend has been on the increase or decline.
Objectives:
The specific objectives of the study are:
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to determine the pooled risk of congenital malformations in offsprings of women placed on SSRIs during pregnancy.
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to assess the level of risk of congenital malformations across trimesters.
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to assess the trend of risk, if any, of congenital malformations over the years.
Review Questions:
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What is the risk of congenital malformations in the offspring of women placed on SSRIs during pregnancy compared to offspring of women not placed on SSRIs during pregnancy?
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Does the risk of teratogenicity if any, with SSRI use in pregnancy increase across the different trimesters?
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Is there a trend of teratogenicity with SSRIs use in pregnancy over the years, 2009–2020?
Design:
This is a protocol for systematic review and meta-analysis on observational studies from 2009 to 2020, focussing on the use of SSRIs in pregnancy and risk of congenital malformations. This review will look at the proportion of pregnancies in women on SSRIs that resulted in congenital malformations. It will also assess if the risk of congenital malformations occurs at the different trimesters and if there is an increase or a decrease in the trend of teratogenicity with SSRI use in pregnancy over the years.
INCLUSION CRITERIA:
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Observational studies: Cohort studies, case control studies, cross sectional studies, historic cohort studies.
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Studies must be published between 2009–2020.
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Studies must be published and retrievable in English.
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Studies reporting occurrence or risk of teratogenicity with SSRI use in pregnancy
Exclusion criteria:
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Reviews, commentaries, letters to editors and editorials.
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Studies reporting in- vitro and animal studies.
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Interventional studies including randomized clinical trials and quasi-clinical trials.
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Duplicates or replicates of studies.
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Studies not retrievable in English.
This review will be reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2015 Statement).
Information sources
The search will employ sensitive topic-based strategies designed for each database. The search will be carried out in the following databases: PUBMED, EMBASE, CINAHL, RESEARCHGATE, AJOL, GOOGLE SCHOLAR, WEB OF SCIENCE, SCOPUS and COCHRANE LIBRARY. Only observational studies retrievable in the English Language will be included.
Search strategy
This will include MESH terms, Text words and Entry terms. Table 1 illustrates the search strategies to be used in the databases.
S/No
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Database
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Search strategy
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1
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PubMed
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((("Pregnancy"[Mesh] OR Pregnancies OR Gestation) AND ((5-Hydroxytryptamine Uptake Inhibitors OR 5 Hydroxytryptamine Uptake Inhibitors OR Selective Serotonin Reuptake Inhibitors OR 5-HT Uptake Inhibitors OR 5 HT Uptake Inhibitors) OR "Serotonin Uptake Inhibitors"[Mesh])) AND ((Congenital Abnormality OR Congenital Defects OR Congenital Defects OR Birth Defects OR Birth Defect) OR "Congenital Abnormalities"[Mesh]). Filters: From 2009 to 2020
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The same search strategy will be used in other databases with slight modifications. |
PICOs:
Participants: In this study, the participants are pregnant women placed on SSRIs.
Intervention: SSRI,
Comparator: The Comparator is pregnant women not on SSRI.
Outcomes: the primary outcome is proportion of live births with congenital malformations. Secondary outcomes include risk of congenital malformation across the different trimesters.
Data Extraction and Management
a. Data Extraction:
Studies will be searched using the search strategy in Table 1. There are four levels of data screening in this study:
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Level 1 is based on the study design: only observational studies, published and/ or retrievable in the English Language will be included; other study designs will be excluded;
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Level 2: selected studies will first be screened by titles and abstracts using entry terms, keywords, and MeSh terms;
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level 3: selected studies will be further screened by full-text reading using the same strategy;
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level 4: snowballing of literature from included studies.
Eleven reviewers are involved in this study. A pair of reviewers will independently screen studies from each database. Conflicts will be resolved by a third independent reviewer. The review will not be blinded. All screened and retrieved items will be exported to Endnote version 9. After screening, data will be exported to Microsoft Excel. All relevant studies that meet the inclusion criteria and are exported to Microsoft Excel will also have full texts retrieved and read to enable snowballing search on references. Authors of eligible studies with missing data will be contacted by email or telephone. Grey literature will not be included; only data available in electronic databases.
b. Selection process:
Two independent reviewers will screen full texts of all eligible observational studies and snowballed articles and conflicts will be resolved by a third reviewer.
c. Data collection process:
De-duplication of the studies will then be done in the EndNote version 9. Eligible studies will be exported and screened in Microsoft Excel. The following data will be extracted from the Microsoft Excel file:
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First author's surname and year of publication;
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prevalence or proportion of congenital malformations in women on SSRIs;
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prevalence or proportion of congenital malformations in women not on SSRIs
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sample size,
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trimester and f) time of initiation of drug use and g) duration of drug use
Data from Excel will be exported to CMA Software for meta-analysis.
Data items/Measurable outcomes
Data items for statistical synthesis include the following:
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proportion of pregnancies in women on SSRIs that resulted in congenital malformations (primary outcome). This is interpreted as a success event. It can also be reported as a relative risk. The effect size to be used for analysis is relative risk (RR). Other effect sizes from similar design and report will be converted to RR in the CMA Software.
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Proportion of pregnancies in women not on SSRI who had babies with congenital malformations. This is interpreted as a failure event. It will be considered in reporting of relative risk (RR) as effect size.
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Trimester of pregnancy that has teratogenicity.
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Time of initiation of drug use during pregnancy.
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Duration of SSRI use in pregnancy.
Risk of bias
The risk of bias will be accessed for the individual studies using the National Institute of Health (NIH) Quality assessment tool for observational cohort and cross-sectional studies. This will be cross-checked with the Cochrane tool of risk of bias assessment for the strength of the body of evidence; i.e. using specific relevant items from this tool to assess the strength of the body of evidence.
The following areas shall be assessed and any study with extreme bias will be excluded following consensus decision.
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Method of reporting: this will be done at the outcome level.
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Reporting of study: Studies that were reported in different units but similar in outcome and design will be converted based on individual case evaluation. This will be evaluated for individual studies by assessing unit of reporting of studies, for example, whether prevalence with confidence intervals, OR or RR was reported. This will be done at the study level
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Heterogeneity will be assessed at the study level
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Publication bias will be assessed at the study level
Data synthesis
a. Studies that passed the methodological quality assessment using the NIH quality assessment tool will be extracted. The results will be presented in tabular format in addition to a narrative synthesis.
b. The following will be included into the meta-analysis;
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Proportion of pregnant women on SSRIs and had babies with congenital malformation and proportion of pregnant women not on SSRIs who had babies with congenital abnormalities. Effect size is relative risk.
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Quantitative analysis
Pooled RR of congenital malformations will be calculated with 95% CI. This is the primary measurable outcome.
Sub-group analysis using the different trimesters and time of initiation of drug use, as categorical data and moderators, will be performed.
Meta-regression on relative risk of congenital malformations using duration of drug use as a moderator (quantitative) will also be performed.
Cumulative meta-analysis be performed to check for trend in the RR of congenital malformation from 2009 to 2020.