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Sexual health
Protocol
Mifepristone as a non-emergency contraceptive among women of reproductive age: a protocol for systematic review and meta-analysis
  1. Miriam Nkangu1,2,
  2. Caroline Frisendahl3,4,
  3. Chelsea Polis2,
  4. Tracy Chen5,
  5. Evan Sterling6,
  6. Rebecca Gomperts7,8,
  7. Marlena Plagianos2,
  8. Lisa Haddad2,
  9. Kristina Gemzell-Danielsson3,4
  1. 1 University of Ottawa, Ottawa, Ontario, Canada
  2. 2 Population Council Center for Biomedical Research, New York City, New York, USA
  3. 3 WHO Collaborating Centre, Division of Neonatology, Obstetrics, Gynecology, and Reproductive Health, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
  4. 4 Division of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden
  5. 5 University of Hawai'i at Mnoa John A Burns School of Medicine, Honolulu, Hawaii, USA
  6. 6 University of Ottawa Library, University of Ottawa, Ottawa, Ontario, Canada
  7. 7 Women on Waves, Zuid-Holland, Netherlands
  8. 8 Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands
  1. Correspondence to Dr Miriam Nkangu; mngui058{at}uottawa.ca

Abstract

Background Mifepristone is a selective progesterone receptor modulator with decades of data demonstrating its potential as a highly effective emergency as well as non-emergency contraceptive. Despite considerable evidence pointing to the potential effectiveness of mifepristone as a non-emergency contraceptive, no systematic review has been conducted to synthesise the available evidence. This systematic review aims to synthesise the current evidence on the use of mifepristone as a non-emergency contraceptive to prevent pregnancy among cisgender girls and women of reproductive age.

Methods We developed an electronic search strategy in collaboration with the research librarian. We will search five databases (Ovid Medline, CINAHL, EMBASE, Cochrane-Central Trials and Global Health) from inception and identify additional studies using several grey literature search strategies. All databases will be searched from inception, and we planned to complete the search by 30 June 2024. An Ovid Medline search strategy conducted on 24 May 2024 is provided as an example. We will include all studies that involve cisgender girls and/or women of reproductive age (defined as 54 years or younger), which assessed mifepristone as a non-emergency contraceptive to prevent pregnancy. The primary outcome is contraceptive effectiveness. Two independent reviewers will screen studies for eligibility through title, abstract, and full-text review. We will extract data with Covidence software using a Cochrane Effective Practice and Organisation of Care (EPOC)-adapted data-extraction tool and will assess risk of bias using the EPOC risk of bias tool and the Newcastle–Ottawa Scale. If sufficient data are available, we will conduct a meta-analysis using fixed and/or random effect models. However, if we are unable to conduct a meta-analysis, we will present the results narratively using the synthesis without meta-analysis guidelines and the EPOC table recommended for presenting findings without meta-analysis. Grades of Recommendation, Assessment, Development and Evaluation will be used to assess the quality of the evidence. We will report this review according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines.

Ethics and dissemination This review is focused on secondary data and does not require any ethical approval. We aim to publish the review in a peer-reviewed scientific journal to promote knowledge transfer and present results using other knowledge translation mediums.

PROSPERO registration number CRD42024554720.

  • Systematic Review
  • Pregnancy
  • Reproductive medicine
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2024-090402

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • The protocol has been designed according to the Cochrane Collaboration’s standard for conducting a systematic review.

    • No language restrictions will be applied in the selection of the studies.

    • Our search strategy was carefully designed in consultation with an experienced research librarian, and a second librarian peer reviewed the search strategy for quality control.

    • This review may face potential heterogeneity in study designs and dosages studied that may limit our ability to statistically assess the effectiveness of a specific dose.

    Introduction

    Globally, approximately 121 million unintended pregnancies occur every year with a significant portion occurring in low- and middle-income countries.1 In 2019, there were 190 million women worldwide who wished to avoid pregnancy but did not use any contraceptive method.1 Addressing this unmet need for contraceptives could avert 79 000 maternal deaths and 1.1 million infant deaths annually, resulting in enhanced health and socioeconomic outcomes.2

    While existing contraceptive methods have improved the well-being of many women by effectively preventing unwanted pregnancies, there is still a significant gap in meeting the diverse needs of women. This gap is evident by high levels of contraceptive failure with typical use across various methods alongside issues such as method non-use, frequent switching and discontinuation.3 4 In addition, the majority of the most highly effective contraceptive options are hormonal and may be associated with undesirable side effects for some women such as irregular bleeding and mood changes.3 Also, some women either cannot use or opt against oestrogen-containing hormonal methods due to an increased risk of cardiovascular complications (including arterial and venous thromboembolism) and breast cancer.5 Investigation into novel contraceptive options, including non-hormonal options, may help to broaden the menu of acceptable contraceptive options available to the variety of people who need them.

    Mifepristone is a selective progesterone receptor modulator with decades of data demonstrating its potential as a highly effective emergency6 and a potential non-emergency contraceptive.7–17 As there are few medical conditions for which the use of mifepristone is contraindicated, it presents as an optimal option for individuals seeking a non-oestrogenogenic contraceptive approach. Its contraceptive mechanism varies depending on the dosage and timing of administration within the menstrual cycle,11–17 potentially involving delay or inhibition of follicular development and ovulation, prevention of endometrial receptivity, prevention of embryo implantation or a combination of the above.10–17 Besides its use for abortions,18–22 there is evidence supporting its role in management of early pregnancy loss23 and cervical priming prior to surgical abortion.24 Mifepristone has also been evaluated for the purpose of managing ectopic pregnancy, inducing labour and treating uterine leiomyoma, endometriosis, adenomyosis, Cushing syndrome and hormone-responsive malignancies.9 10 12 23 25

    In this review, we focus on the use of mifepristone as a ‘non-emergency contraceptive’, meaning use of mifepristone as an ongoing contraceptive method. This definition is intended to exclude studies that assess the use of mifepristone as an emergency contraceptive (including peri-coital and post-coital use), missed period pills or as an abortifacient.

    Studies assessing the contraceptive efficacy of mifepristone have evaluated dosages between 0.5 mg and 200 mg, with dosing frequencies ranging from daily to monthly administration, and all of these studies have demonstrated minimal side effects.8 10 26 27 Contraceptive effectiveness has been shown to be dependent on dose and timing of treatment with the highest efficacy achieved when both ovulation and endometrial development are inhibited.9–11 However, some of the lower-dosed studies were terminated early due to reaching a pre-prescribed incidence of pregnancy.26 27

    Despite considerable evidence pointing to the potential effectiveness of mifepristone as a non-emergency contraceptive,7–17 26–29 we have been unable to identify a systematic review on this topic. Specifically, on 10 April 2024, we searched the Joanna Briggs Institute Evidence Synthesis, Cochrane Database of Systematic Reviews, PROSPERO, PubMed, Google and the Open Science Framework registry for systematic review protocols or publications on this topic. We also reviewed potentially relevant resources shared by colleagues. While one narrative review is available which summarises evidence on a variety of uses of mifepristone, including a section on its contraceptive potential, this paper was published nearly 15 years ago, did not include a systematic search of the literature and did not provide an in-depth assessment of studies on this topic.30 A recent systematic review discussed mifepristone’s effectiveness in treating various conditions but did not report its effect as a contraceptive.31 Thus, our systematic review aims to collect and synthesise the evidence that is currently available on the use of mifepristone non-emergency contraception.

    Objective

    The objective of this review is to assess the use of mifepristone as a non-emergency contraceptive to prevent pregnancy among cisgender girls and women of reproductive age. The following questions will guide the review:

    1. What dosage and frequency of administration of mifepristone have been used as a non-emergency contraceptive to prevent pregnancy?

    2. What is the contraceptive efficacy of various dosage regimens of mifepristone?

    3. What are the reported side effects of various dosage regimens of mifepristone when used as a non-emergency contraceptive?

    4. What are the reported acceptability components of mifepristone when used as a non-emergency contraceptive?

    Methods

    Reporting and registration

    This protocol is a systematic review and meta-analysis of published and unpublished studies that assess the use of mifepristone as a non-emergency contraceptive to prevent pregnancy among cisgender girls and women of reproductive age. This protocol is developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocol (PRISMA-P) checklist32 (see attached online supplemental file 1). The protocol is registered with PROSPERO, the International Prospective Register of Systematic Reviews. The registration number CRD42024554720. Any amendments or deviations to this protocol will be documented and reported in the final review. We began work on this systematic review in March 2024 and anticipate completing the review by December 2024.

    Supplemental material

    Eligibility criteria

    Inclusion and exclusion criteria

    The following PICO (Population, Intervention, Comparator and Outcome) elements will guide the search strategy and review protocol.

    Types of population

    All studies that involve cisgender girls and women of reproductive age (defined as 54 years or younger), who are fertile, sexually active and who use mifepristone as a non-emergency contraceptive to prevent pregnancy.

    Types of intervention(s)

    All studies that have assessed the effect of mifepristone as a non-emergency contraceptive, regardless of dosage or dosing frequency used. As stated above, a non-emergency contraceptive in the context of this review is defined as use of an ongoing contraceptive, excluding studies that assessed mifepristone for use as an emergency contraceptive, missed period pills and/or for use in abortion.

    Types of comparator(s)

    We will include non-comparative studies with a single arm assessing mifepristone as an ongoing contraceptive or studies that compare mifepristone as an ongoing contraceptive against any other ongoing contraceptive method.

    Types of outcomes

    Our primary outcome is contraceptive effectiveness (defined as: life table pregnancy probabilities, 12-month or 13-cycle Pearl pregnancy rates, survival analysis pregnancy rates (eg, Kaplan Meier) or studies reporting pregnancy incidence or person cycle observed with sufficient raw data to calculate a 12-month or 13-cycle Pearl pregnancy rate). Included studies must measure and report the mifepristone dose, frequency of administration, the number of pregnancies occurring while on treatment and the number of 28-day cycles during which participants used mifepristone.

    Secondary outcomes include side effects of mifepristone or reported adverse events, ovulation inhibition or dysfunctional ovulation. If acceptability is reported in the study, we will assess acceptability as a secondary outcome based on any acceptability measure or scale used by the study and present the outcome narratively.

    Types of study designs

    The review will focus only on quantitative study designs that enable calculation of contraceptive effectiveness including both single and multiarm (randomised or non-randomised) clinical trials and observational studies (cohort, case-control or cross-sectional) with prospectively collected pregnancy outcomes. We will exclude meta-analyses on this topic unless they incorporate novel data not reported elsewhere.

    Study eligibility criteria

    The review will include all studies that have assessed the contraceptive effectiveness of mifepristone as a non-emergency contraceptive for cisgender girls or women under the age of 54. There will be no restrictions on the frequency of administration or dosage used and no restrictions on the unit of measure of the outcome. This may include life table pregnancy probabilities, 12-month or 13-cycle Pearl pregnancy rates or survival analysis pregnancy rates (eg, Kaplan Meier). We will also include studies with sufficient raw data to calculate a 12-month or 13-cycle Pearl pregnancy rate. Studies that assess mifepristone for purposes other than ongoing use to prevent pregnancy (eg, emergency contraception, missed period pills, abortion or other uses) will be excluded. We will not have any restrictions based on study duration (number of cycles or months), scale used in reporting results or on comparison groups (or lack thereof). We will not impose restrictions on year of publication, region of study or language of publication. We will translate all non-English studies using professional translation services and/or team members who are fluent in other languages. Commentaries, perspectives, expert opinions, conference proceedings, editorials, thesis and book chapters will be excluded. Publications without full text (only abstracts) will be excluded.

    Search strategy

    The review will employ a three-step search strategy. The first step will involve an initial search of the literature through the Ovid Medline database. The search terms will be developed by an information specialist. This initial search will be used to identify keywords and index terms that will be used to further refine the search strategy. The second step will involve the translation of this search into each of the identified databases. The final step will be to hand-search the reference lists of included studies to identify additional studies not included in the searched databases and to conduct forward citation searching of included studies in Google Scholar. An Ovid Medline search strategy conducted on 24 May 2024 is provided as an example (attached as online supplemental file 2). The search will incorporate a minimum of five databases (Ovid Medline, CINAHL, EMBASE, Cochrane-Central Trials and Global Health) and grey literature from the following sources, but not limited to, the Centre for Disease Control (CDC), WHO, clinical trial registries for completed and/or in-progress clinical trial studies and preprint servers such as bioRxiv.org, medRxiv.org, SocArXiv, etc. All databases will be searched from inception, and we planned to complete the search by 30 June 2024. The review will consider studies in all languages, and there will be no limits imposed on the year or region of publication. We will translate all non-English studies that meet our PICO criteria. The search will be conducted with the help of a librarian specialised in systematic review and the studies will be exported into Covidence software for duplicate removal and screening.

    Supplemental material

    Data management

    We will export the search results into Zotero for data management and referencing. Data will be exported into Covidence software for systematic reviews33 for removal of duplicates, title and abstract screening, full-text and data extraction. Further analysis will be conducted using the JBI SUMARI software for meta-analysis34 or other software, if papers meet meta-analysis criteria.

    Screening and selection

    Studies will be screened for eligibility through title, abstract and full-text screening by at least two independent reviewers. Inclusion and exclusion criteria will be assessed by calibrating a small number of studies (about 5–10% of the papers), strictly adhering to the PICO criteria. Any disagreements will be resolved by consensus. If consensus is not achieved, then a third reviewer will be consulted. If a study has multiple publications, the most recent or the one reporting the highest number of participants will be retained as appropriate; if there is any degree of uncertainty in the title and abstract stage, the study in question will be retained for full-text screening. A full-text assessment will be performed in detail using the inclusion criteria. Any study that does not meet the inclusion criteria will be excluded, and the reasons for each exclusion will be listed in the final review report.

    Data extraction

    We will extract data from the included studies using a data-extraction tool adapted from one developed by the Cochrane Effective Practice and Organisation of Care (EPOC) group.35 The adapted form will be reviewed by the team before data extraction commences. Data extraction will be carried out by two independent reviewers. The data will be extracted as defined in table 1 below and will include details on the study design and characteristics, study participants, intervention details, outcome details and data analysis and intervention effects. Any disagreement that arises in the process of data extraction will be resolved through discussions, and if no agreement is reached, a third reviewer will be consulted for consensus. If there is missing data or incomplete reporting of data, the authors of the papers will be contacted using their corresponding email addresses to request for missing or additional data as required. A second email will be sent as follow-up, and if no response is received, it will be classified as missing data.

    View this table:
    Table 1

    Data-extraction tool

    Methodological quality assessment and risk of bias in individual studies

    The quality of the studies will be assessed by two independent reviewers using the Cochrane EPOC risk of bias tool.36 The tool is designed to guide the assessment of the quality of the methodology for randomised control trials, evaluating risk of bias for randomisation, quality of randomisation, allocation concealment, level of blinding, masking and losses to follow-up. We will assess studies for selection bias, performance bias, detection bias, attrition bias, reporting bias and other sources of bias. The tool defines three ratings for reporting of bias: ‘high,’ ‘low’ and ‘unclear.’ For non-randomised trials, we will use the New Castle Ottawa Scale, which is recommended to be useful for systematic reviews,37 but the variations in non-randomised trials make it difficult to apply; therefore, in addition to applying the above tool, we will critically appraise the studies and look for potential confounding factors and evaluate how the authors adjusted for confounding and how they considered the items in reporting observational studies. Any disagreement that arises during the quality-assessment process will be discussed and resolved. If no agreement is achieved, a third reviewer will be consulted for consensus. We will apply the same tool for non-randomised studies and critically appraise the studies for any potential confounding and how authors adjusted for cofounders.

    Data synthesis

    We will describe the characteristics of the included studies, including the items that are listed in table 1 above. A narrative description and structured synthesis will be used to present the intervention effect on the outcomes. If we have enough papers that meet eligibility criteria for meta-analysis, the papers will be pooled for meta-analysis to synthesise the effect size using random and/or fixed effect models. We will use the JBI SUMARI software for meta-analysis.34 Our primary analysis will focus on estimating the intervention (mifepristone) effectiveness by estimating contraceptive effectiveness for different dosage by cycles or months. Given that most of the studies are likely to be single-arm studies, we will use the approach recommended for meta-analysis of single-arm studies and conduct analysis of proportion38 for different dosage by cycles and present result of pregnancy rates of the pooled estimates with their 95% confidence intervals. We will also generate subgroup estimates by region and age groups. If we find studies that compare mifepristone with other contraceptives, we will meta analyse the effect sizes separately. Data will be re-analysed where applicable.

    We will assess heterogeneity through visual inspection of forest plots, and statistical heterogeneity will be assessed using I2. The I2 indicates the percentage of the total variation across studies where 0%–40% is considered low heterogeneity, 30%–60% moderate heterogeneity and 75%–100% is considerable heterogeneity.39 If we observe substantial heterogeneity, we will examine the sources of the heterogeneity through subgroup and sensitivity analyses. We will also test heterogeneity using χ2 test with p<0.05 indicating statistical significance. We will assess publication bias through visual inspection of funnel plots if there are 10 or more studies in a meta-analysis, and Egger’s test.

    Sensitivity analysis will be conducted to assess frequency of administration and if we find low-quality studies or if some studies are different from the rest. If statistical pooling of data is not possible, we will present the result findings using the Synthesis Without Meta-analysis guidelines40 and the EPOC recommended tables for presenting systematic review findings without meta-analysis.41 42 All data collected on acceptability will be reported in a narrative format.

    We will assess the certainty of the evidence for all outcomes using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE).43 We will rate the certainty of the evidence using the GRADE assessment tool to assess risk of bias of inconsistency, indirectness, imprecision and publication bias for the outcomes. We will use the Cochrane EPOC group summary of findings table to present the rating of the evidence for GRADE using the EPOC criteria (high, moderate, low or very low).42 If we are unable to conduct a meta-analysis, we will use the EPOC table recommended for presenting findings without meta-analysis and assess the level of certainty to present the direction of the effect of the intervention with justifications. GRADE assessment will be conducted by two independent reviewers and any disagreement will be discussed and resolved by a third reviewer.

    Interpretation and reporting of the review findings

    The findings from the included studies will be presented using the PRISMA flow diagram,44 providing justification for exclusions at each level for included and excluded papers. We will present the clinical and methodologic components of the final synthesised evidence in tabulated format with summary narratives and forest plots. We will use the AMSTAR tool checklist, a critical appraisal tool that can be used by reviewers in the conduct of the systematic review to guide the review process.45 Finally, we will report the review according to the PRISMA guidelines.46

    Ethics and dissemination

    This review is focused on secondary data and does not require any ethical approval. We aim to publish the review in a peer-reviewed scientific journal to promote knowledge transfer and present results using other knowledge translation mediums.

    Patient and public involvement

    No patient was involved in the development of the protocol and no public engagement was performed.

    Discussion

    The findings of this systematic review will influence contraception drug development programmes and provide valuable evidence to inform decision-makers in regulatory, policy and advocacy settings.

    Strengths and Limitations

    To our knowledge, this will be the first systematic review to investigate the contraceptive effectiveness of mifepristone as a non-emergency contraceptive. Another strength of the review is the inclusion of all studies regardless of language to ensure we capture all available evidence on the topic. The protocol has been designed according to the Cochrane Collaboration’s standards for conducting a systematic review. Our search strategy was carefully designed in consultation with an experienced research librarian, and a second librarian peer reviewed the search strategy for quality control.

    In terms of study limitations, this review may face potential heterogeneity in study designs and dosages studied that may limit our ability to statistically assess the effectiveness of a specific dose. The certainty of the evidence of the systematic review may be limited by a limited number of studies and potentially low quality of the individual studies.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    We would like to thank librarian Peter Farrell at the University of Ottawa who reviewed the search strategy for quality control. Special thanks to Emily Dorman at Population Council for her initial inputs and guidance on the protocol.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • X @cbpolis

    • Contributors KG-D and LH conceived the idea for the systematic review. MN led the design of the protocol and methodology and wrote the first draft of the manuscript with inputs from LH, KG-D, CP, CF, MP and TC. ES developed the search strategy and it was revised by CF, CP, MN, RG, KG-D and LH. All authors critically revised the manuscript and provided valuable subject-matter inputs. All authors have read and approved the final manuscript. MN is the guarantor.

    • Funding This systematic review was funded by Children’s Investment Fund Foundation (CIFF). The sponsor did not play any role in the design and writing of the protocol.

    • Competing interests KG-D received funding from CIFF to conduct a contraceptive trial with mifepristone. RG received funding to conduct a study on the use of mifepristone 50 mg as a weekly contraceptive.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.