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Medical abortion reporting of efficacy: the MARE guidelines

      1. Introduction

      This commentary introduces the Medical Abortion Reporting of Efficacy (MARE) guidelines as a supplement to CONSORT [
      • Schulz K.F.
      • Altman D.G.
      • Moher D.
      • for the CONSORT Group
      CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.
      ] and STROBE [
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gotzsche P.C.
      • Vandenbroucke J.P.
      • et al.
      The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines or reporting observational studies.
      ]. The goal of the recommendations is to standardize early medical abortion efficacy reporting to facilitate comparison of outcomes between studies and to enrich the ability for data synthesis from different studies to create evidence-based guidelines. Although the term medical abortion had most commonly referred to the use of abortion-inducing medication for early pregnancy termination without primary surgical intervention, more recently, the phrase has been used to refer to labor induction abortions as well [
      • Creinin M.D.
      Medical abortion regimens: historical context and overview.
      ,
      • Borgatta L.
      • Kapp N.
      • Society of Family Planning
      Clinical guidelines. Labor induction abortion in the second trimester.
      ]. Accordingly, we consider early medical abortion to refer to procedures in the first trimester.
      Reports of using medical agents to cause early abortion first appeared in the 1950s [
      • Thiersch J.B.
      Therapeutic abortions with a folic acid antagonist, 4-Aminopteroyglutamic acid (4-amino P.G.A.) administered by the oral route.
      ], but the modern era of medical abortion research started in the early 1980s with the discovery of test agents that were ultimately developed into mifepristone. Over the past 30 years, research has evolved, with the use of various drugs including mifepristone, methotrexate, tamoxifen, letrozole and various prostaglandin analogs to induce early abortion [
      • American College of Obstetricians and Gynecologists
      Practice bulletin no. 143: medical management of first-trimester abortion.
      ]. The first drug with a labeled indication for medical abortion, mifepristone, was initially approved in China and France more than two decades ago. The United States Food and Drug Administration approved mifepristone in 2000 for use in combination with the prostaglandin analog misoprostol for abortion through 49 days gestation.
      Over the more than 25 years since mifepristone first became available for women to obtain a medical abortion, researchers have continued to evaluate alternative regimens to improve efficacy and the patient experience. Professional and national organizations now lead the way in promoting the best science by providing evidence-based recommendations for the preferred medical abortion treatment options [
      • American College of Obstetricians and Gynecologists
      Practice bulletin no. 143: medical management of first-trimester abortion.
      ,
      • Society of Family Planning
      Medical management of first-trimester abortion.
      ,
      • Royal College of Obstetricians and Gynaecologists
      Tthe care of women requesting induced abortion.
      ]. Although many individual studies are methodologically strong, the heterogeneity of design, conduct and reporting hinders synthesis of data from multiple studies. Importantly, many studies do not stratify outcomes by week of gestation. These issues became evident during data collation for creation of the 2014 Medical Management of First Trimester Abortion Practice Bulletin written collaboratively by the American College of Obstetricians and Gynecologists and the Society of Family Planning [
      • American College of Obstetricians and Gynecologists
      Practice bulletin no. 143: medical management of first-trimester abortion.
      ,
      • Society of Family Planning
      Medical management of first-trimester abortion.
      ]. More recently, a systematic review including approximately 30,000 patients who received mifepristone and buccal misoprostol found that only 57% had data identifying week of gestation for a stratified evaluation of overall efficacy; only 51% had such information for evaluation of continuing pregnancy [
      • Chen M.J.
      • Creinin M.D.
      Mifepristone with buccal misoprostol for medical abortion: a systematic review.
      ].
      Well-performed and reported research trials provide the basis for evidence-based guidelines and do more than simply inform providers and patients about more cost-effective or therapeutically effective options — they also affect access to care. Methodologically strong research can counter ideologically motivated arguments for legal restrictions on medical abortion regimens and gestational age limits. The medical community can use this evidence to oppose such legislation.
      Future synthesis of the large body of available data to inform patient care and regulatory policy can be facilitated with the use of guidelines to ensure that publications of original data are presented in a standardized way. We herein present reporting recommendations for early medical abortion as a supplement to the CONSORT guidelines (for randomized trials) and STROBE guidelines (for prospective and retrospective cohort studies), referred to as MARE, MARE-C and MARE-S, respectively. The goals of these guidelines align with the CROWN and COMET initiatives to promote core outcome data sets [
      • Khan K.
      The CROWN initiative: journal editors invite researchers to develop core outcomes in women's health.
      ,
      • Williamson P.R.
      • Altman D.G.
      • Blazeby J.M.
      • Clarke M.
      • Devane D.
      • Gargon E.
      • et al.
      Developing core outcome sets for clinical trials: issues to consider.
      ].

      2. The MARE supplement

      The MARE supplement consists of 14 additional items that clarify the existing CONSORT (MARE-C, Table 1) and STROBE (MARE-S, Table 2) guidelines for early medical abortion trials. The aims of the statement are primarily to ensure standardized reporting of the regimen used, number of women treated, number who had follow-up (outcome) data available and efficacy outcomes by gestational age. Reporting outcomes in a standard manner will ensure that data are available for better synthesis into evidence-based guidelines. These guidelines will be helpful in designing prospective early medical abortion studies to ensure that the data can be reported systematically. Although retrospective studies may not have enough information to always meet the recommendations, authors can use the guidelines to identify limitations of their dataset. The MARE supplements are not intended to be an independent assessment of the quality of the clinical trial.
      Table 1The CONSORT supplement checklist for early MARE (MARE-C)
      Section/TopicItem NoChecklist itemSupplement for MAREReported on page #
      TITLE AND ABSTRACT
      1aIdentification as a randomized trial in the title__________
      1bStructured summary of trial design, methods, results, and conclusions__________
      INTRODUCTION
      Background and objectives2aScientific background and explanation of rationale__________
      2bSpecific objectives or hypotheses__________
      METHODS
      Trial design3aDescription of trial design including allocation ratio__________
      3bImportant changes to methods after trial commencement (such as eligibility criteria), with reasons__________
      Participants4aEligibility criteria for participants4a-1 Detail the range of gestational age for participants determined a priori to be included in the research, including a lower limit when applicable.__________
      4a-2 Explain the methods used to determine gestational age (e.g., physical examination, last menstrual period, ultrasonography). If ultrasonography is used, detail the type (vaginal and/or abdominal) and consider describing the criteria used for determination of gestational age.__________
      4bSettings and locations where the data were collected__________
      Interventions5The interventions for each group with sufficient details to allow replication, including how and when they were actually administeredDetail the medications used, including dose(s) and route(s) of administration. If more than one medication is used, state the planned time interval between medications, preferably in hours.__________
      Outcomes6aCompletely defined pre-specified primary and secondary outcome measures, including how and when they were assessed6a-1 Outcome: Define successful medical abortion (should most commonly be considered as successful expulsion of the intrauterine pregnancy without need for surgical intervention).__________
      6a-2 Outcome: Define the types of medical abortion failure (e.g., ongoing pregnancy, incomplete abortion, participant symptoms). Continuing pregnancy should be defined as a viable pregnancy following treatment (to be differentiated from a non-viable [i.e., retained gestational sac]).__________
      6a-3 Assessment: Explain the follow-up assessments used to determine outcome (e.g., urine pregnancy test, serum pregnancy test, ultrasonography, physical exam, symptoms checklists).__________
      6a-4 Assessment: Explain the length of time planned to follow participants for determination of outcomes.__________
      6bAny changes to trial outcomes after the trial commenced, with reasons__________
      Sample size7aHow sample size was determined__________
      7bWhen applicable, explanation of any interim analyses and stopping guidelines__________
      RANDOMIZATION
      Sequence generation8aMethod used to generate the random allocation sequence__________
      8bType of randomization; details of any restriction (such as blocking and block size)__________
      Allocation concealment9Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned__________
      Implementation10Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions__________
      Blinding11aIf done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how__________
      11bIf relevant, description of the similarity of interventions__________
      Statistical methods12aStatistical methods used to compare groups for primary and secondary outcomes__________
      12bMethods for additional analyses, such as subgroup analyses and adjusted analyses__________
      RESULTS
      Participant flow (a diagram is strongly recommended)13aFor each group, the numbers of participants who were randomly assigned, received intended treatment, and were analyzed for the primary outcome13a-1 Report the number of participants who started medical abortion treatment and the number who did not complete any follow-up for each group overall and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      13a-2 Report the number of participants used in the denominator for outcome evaluations for each group overall and by gestational age
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      , which most commonly will be the number of women with any follow-up.
      __________
      13a-3 Include a description of the number of women who used the drug(s) as planned in the protocol (treatment adherence).__________
      13a-4 When more than one drug is used (e.g. mifepristone and a prostaglandin analog), the actual time interval between the agents should be reported, preferably in hours.__________
      13bFor each group, losses and exclusions after randomization, together with reasons__________
      Recruitment14aDates defining the periods of recruitment and follow-up__________
      14bWhy the trial ended or was stopped__________
      Baseline data15A table showing baseline demographic and clinical characteristics for each group__________
      Numbers analyzed16For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups__________
      Outcomes and estimation17aFor each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval)17a-1 Present treatment success for each group overall and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      17a-2 Present continuing pregnancies for each group overall and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      17a-3 Present reasons for surgical intervention other than continuing pregnancy for each group overall and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      17bFor binary outcomes, presentation of both absolute and relative effect sizes is recommended__________
      Ancillary analyses18Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory__________
      Harms19All important harms or unintended effects in each group__________
      DISCUSSION
      Limitations20Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses__________
      Generalizability21Generalizability (external validity, applicability) of the trial findings__________
      Interpretation22Interpretation consistent with results, balancing benefits and harms, and considering other relative evidence__________
      OTHER INFORMATION
      Registration23Registration number and name of trial registry__________
      Protocol24Where the full trial protocol can be accessed, if available__________
      Funding25Sources of funding and other support (such as supply of drugs), role of funders__________
      low asterisk Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      Table 2The STROBE supplement checklist for early MARE (MARE-S)
      Section/TopicItem NoChecklist itemSupplement for MAREReported on page #
      TITLE AND ABSTRACT
      Title1aIndicate the study's design with a commonly used term in the title or the abstract__________
      Abstract1bProvide in the abstract an informative and balanced summary of what was done and what was found__________
      INTRODUCTION
      Background/rationale2Explain the scientific background and rationale for the investigation being reported__________
      Objectives3State specific objectives, including any pre-specified hypotheses__________
      METHODS
      Study design4Present key elements of study design early in the paper__________
      Setting5Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection__________
      Participants6Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up.6–1 Detail the range of gestational age for participants determined a priori to be included in the research, including a lower limit when applicable.__________
      6–2 Explain the methods used to determine gestational age (e.g., physical examination, last menstrual period, ultrasonography). If ultrasonography is used, detail the type (vaginal and/or abdominal) and consider describing the criteria used for determination of gestational age.__________
      Variables7Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable.7–1 Exposure: Detail the medications used, including dose(s) and route(s) of administration. If more than one medication is used, state the planned time interval between medications, preferably in hours.__________
      7–2 Outcome: Define successful medical abortion (should most commonly be considered as successful expulsion of the intrauterine pregnancy without need for surgical intervention).__________
      7–3 Outcome: Define the types of medical abortion failure (e.g., ongoing pregnancy, incomplete abortion, participant symptoms). Continuing pregnancy should be defined as a viable pregnancy following treatment (to be differentiated from a non-viable [i.e., retained gestational sac]).__________
      Data sources/measurement8
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group.8–1 Assessment: Explain the follow-up assessments used to determine outcome (e.g., urine pregnancy test, serum pregnancy test, ultrasonography, physical exam, symptoms checklist).__________
      8–2 Assessment: Explain the length of time planned to follow participants for determination of outcomes.__________
      Bias9Describe any efforts to address potential sources of bias__________
      Study size10Explain how the study size was arrived at__________
      Quantitative variables11Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why.__________
      Statistical methods12aDescribe all statistical methods, including those used to control for confounding__________
      12bDescribe any methods used to examine subgroups and interactions__________
      12cExplain how missing data were addressed__________
      12dIf applicable, explain how loss to follow-up was addressed__________
      12eDescribe any sensitivity analyses__________
      RESULTS
      Participants13a
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Report numbers of individuals at each stage of study (e.g., numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed)13a-1 Report the number of participants who started medical abortion treatment and the number who did not complete any follow-up for each cohort and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      13a-2 Report the number of participants used in the denominator for outcome evaluation for each cohort and by gestational age
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      , which most commonly will be the number of women with any follow-up.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      13a-3 Include a description of the number of women who used the drug(s) as planned in the protocol (treatment adherence).__________
      13a-4 When more than one drug is used (e.g. mifepristone and a prostaglandin analog), the actual time interval between the agents should be reported, preferably in hours.__________
      13b
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Give reasons for non-participation at each stage__________
      13c
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Consider use of a flow diagram__________
      Descriptive data14a
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Give characteristics of study participants (e.g., demographic, clinical, social) and information on exposures and potential confounders__________
      14b
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Indicate number of participants with missing data for each variable of interest__________
      14c
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Summarize follow-up time (average and total amount)__________
      Outcome data15
      Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Report numbers of outcome events or summary measures over time__________
      Main results16aGive unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and why they were included.16a-1 Present treatment success for each cohort and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      16a-2 Present continuing pregnancies for each cohort and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      16a-3 Present reasons for surgical intervention other than continuing pregnancy for each cohort and by gestational age.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      __________
      16bReport category boundaries when continuous variables were categorized__________
      16cIf relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period__________
      Other analyses17Report other analyses done (e.g., analyses of subgroups and interactions, and sensitivity analyses)__________
      DISCUSSION
      Key results18Summarize key results with reference to study objectives__________
      Limitations19Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias.__________
      Interpretation20Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence__________
      Generalizability21Discuss the generalizability (external validity) of the study results__________
      OTHER INFORMATION
      Funding22Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based__________
      low asterisk Give information separately, if applicable, for exposed and unexposed groups in cohort studies.
      Present the number as a total and with detail by gestational age in days in reference to completed weeks (e.g., ≤49 days, 50–56 days, 57–63 days, 64–70 days). Note that gestations less than 49 days can be further differentiated at the discretion of the investigators.
      To facilitate searching through publication and clinical trial databases for studies to include in outcome data sets, we recommend standardization of key words to be included with each manuscript or trial registration. These words should include, at a minimum, the term medical abortion (or “medication abortion”), each of the agents used for treatment (e.g., mifepristone, misoprostol) and the route of the prostaglandin analog (e.g., oral, vaginal, buccal, sublingual).

      3. Endorsement

      The Society of Family Planning, an academic society dedicated to improving sexual and reproductive health, endorses these guidelines. We hope that abortion researchers as well as funders of abortion research will support the MARE supplements to CONSORT (MARE-C) and STROBE (MARE-S). We invite the editors of women's health scientific journals to include the MARE supplements in author guidelines. The supplements will be maintained and updated by the Society of Family Planning.

      Acknowledgement

      • 1.
        Meeting participants for discussion of possible medical abortion efficacy reporting guidelines (October 7, 2015, Vancouver, BC, Canada).
      Meeting attendees.
      Paul Blumenthal, MD, MPH; Stanford University.
      Mitchell Creinin, MD; University of California, Davis; Sacramento, CA.
      Bela Ganatra, MD; World Health Organization.
      Daniel Grossman, MD, MPH; University of California, San Francisco; IBIS Reproductive Health.
      Susan Higginbotham; Executive Director, Society of Family Planning.
      Elizabeth Raymond, MD, MPH; Gynuity Health Projects.
      Matthew Reeves, MD, MPH; Medical Director, National Abortion Federation, Washington, DC.
      Courtney Schreiber, MD, MPH; University of Pennsylvania.
      Carolyn Westhoff, MD, MSc; Columbia University.
      Beverly Winikoff, MD, MPH; Gynuity Health Projects.
      • 2.
        The authors also thank David Grimes, MD and Eve Espey, MD, MPH, for their initial reviews and comments on the MARE supplement checklists.

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