Registration:
This study was registered prospectively with the PROSPERO database of systematic reviews (registration no. CRD42020152051) and will be completed in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P). Information regarding registration can be accessed from http://www.crd.york.ac.uk/PROSPERO.
Search Strategy:
The search strategy will be developed focusing on identifying the relevant intervention with no population related keywords. EMBASE and MEDLINE electronic databases will be searched for eligible, peer-reviewed literature with the following search terms: preterm birth OR premature birth AND progesterone. We will place no restriction on the length of study follow-up time, or on country, year, or language of publication. However, the search will be limited to studies on humans. Medical subject headings (MeSH) will be used when relevant.
Eligibility Criteria:
The eligibility of studies included will be based on inclusion and exclusion criteria applied to the domains of participant, exposure, comparator, study type, and outcome.
Participants:
This review will consider all studies that include asymptomatic pregnant women being treated with vaginal progesterone. We will exclude studies that include women with a short cervix or who were symptomatic. Studies that exclusively studied women with multi-gestation were will be excluded.
Intervention:
Studies comparing vaginal progesterone either compared to placebo or no treatment will be included. Studies that involved other methods of progesterone administration such as intramuscular injection will be excluded.
Vaginal Progesterone
Vaginal progesterone is available as a gel, suppository, or pessary(9). It is the most bioavailable form of progesterone for uterine and cervical effects with the fewest side effects. Its micronization decreases particle size and increases surface area. This results in improved absorption with less metabolic and vascular side effects(16). The vaginal route also allows rapid absorption and avoids first pass hepatic metabolism, resulting in high bioavailability in the uterus(17).
Outcomes:
The primary outcome is sPTB before < 37 weeks. The secondary outcome will be sPTB before < 34 weeks.
Types of studies:
The review will include randomised controlled trials. All included papers must vaginal progesterone to either placebo or no treatment. Those studies which also present a control group will be included.
Data collection and analysis
Study Selection
Titles and abstracts identified through all sources will be downloaded to Endnote(18) and duplicates will be removed. Studies will then be screened using the specified eligibility criteria above and studies that do not meet the criteria will be excluded. Full texts of remaining studies will be screened before undergoing critical appraisal and data extraction. All levels of screening will be conducted by two independent reviewers and any disputes between reviewers will be resolved by an independent moderator. None of these reviewers will be blinded to titles, authors, journals or institutions.
Data management
The search will be uploaded to an Endnote(18) library, which allows collaboration between multiple reviewers during the study selection process.
Data collection
Two reviewers will extract data through Endnote(18) using a standardised electronic data extraction sheet. Any discrepancies will be moderated by a third senior research reviewer. Once extracted, upon reviewer agreement, data will be transferred into Review Manager version 5.3 data-analysis software(19).
The following data will be extracted:
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Study characteristics: authors; publication date; study design; country of study; sample size; confounding factors of participants; publication status; trial size; funding; and risk of bias information.
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Intervention characteristics: type of intervention used; reason for intervention; patient characteristics (maternal age, gravity, parity, cervical length), and any co-interventions received.
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Outcomes: maternal, fetal and neonatal outcome data and definitions of each of the outcomes as described below.
Outcomes and prioritisation:
Primary outcome
The primary outcome is sPTB before < 37 weeks gestation.
Preterm birth will be defined as live or stillbirth with a gestational age between 20 and 37 weeks.
Secondary outcome
The secondary outcome is sPTB before < 34 weeks gestation.
Assessment of risk of bias
Risk of bias for each paper will be assessed using the Joanna Briggs Institute critical appraisal method for randomised control trials(20). Studies which are deemed to have not addressed the possibility of bias in the design, conduct or analysis will then be excluded.
Study quality will be assessed using the Cochrane GRADE tool(21). Evidence will be assessed in terms of risk of bias, consistency, directness, precision and publication bias. With regard to GRADE, quality will be assessed as being one of 4 grades: (i) high - we are very confident that the true effect is close to that of the estimate of the effect; (ii) moderate - we are moderately confident in the effect estimate, and the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; (iii) low - our confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect, and (iv) very low-we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect. Two independent reviewers will conduct the assessment, with discrepancies resolved through discussion and consensus between the two reviewers, or consultation with a third reviewer.
Review Manager version 5.3(19) will be used to compute graphic representations of potential bias within and across studies.
Data synthesis
Extracted data will be manually entered into Review Manager version 5.3(19). Forest plots and I² values will be used to explore the heterogeneity of data. Heterogeneity of data will be examined using forest plots and quantified using the calculation of the I² value. Sensitivity analyses will be performed if there is significant heterogeneity between included studies which will be defined as I² of greater than or equal to 50%. The meta-analysis will be performed using the Mantel-Haenszel statistical method and random effects analysis model to produce treatment effect ratios and corresponding 95% confidence intervals.
Missing data
For studies which present missing data we will attempt to contact authors. However, if this is not possible we will conduct sensitivity analysis which will exclude trials with > 30% missing data.
Meta-bias(es)
To determine reporting bias we will attempt to investigate if protocols for included studies where published prior to those studies being started.
Sensitivity analysis
Sensitivity analysis will be conducted on the primary outcome for sPTB < 37weeks gestation for vaginal progesterone versus either placebo or no treatment. This will be done by removing studies which are judged to have an overall high risk of bias, allowing us to examine their impact on the effect estimate of the primary outcome.