{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:39:57Z","timestamp":1771339197937,"version":"3.50.1"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Healthcare Insurers Innovation Foundation","award":["3080 B15\u2013191"],"award-info":[{"award-number":["3080 B15\u2013191"]}]},{"name":"Radboud University Medical Centre"},{"name":"Canisius Wilhelmina Hospital"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>In case of early pregnancy loss (EPL) women can either choose for expectant, medical or surgical management. One week of expectant management is known to lead to spontaneous abortion in approximately 50% of women. Medical treatment with misoprostol is known to be safe and less costly than surgical management, however less effective in reaching complete evacuation of the uterus. Recently, a number of trials showed that prompt treatment with the sequential combination of mifepristone with misoprostol is superior to misoprostol alone in reaching complete evacuation. In this analysis we evaluate whether the sequential combination of mifepristone with misoprostol is cost-effective compared to misoprostol alone, in the treatment of EPL.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>A cost-effectiveness analysis (CEA) from a healthcare perspective was performed alongside a randomised controlled trial (RCT) in which standard treatment with misoprostol only was compared with a combination of mifepristone and misoprostol, in women with EPL after a minimum of one week of unsuccessful management. A limited societal perspective scenario was added. This RCT, the Triple M trial, was a multicentre, randomized, double-blinded, placebo-controlled trial executed at 17 hospitals in the Netherlands. The trial started on June 27<jats:sup>th<\/jats:sup> 2018, and ended prematurely in January 2020 due to highly significant outcomes from the predefined interim-analysis. We included 351 women with a diagnosis of EPL between 6 and 14 weeks gestation after at least one week of unsuccessful expectant management. They were randomized between double blinded pre-treatment with oral mifepristone 600mg (N = 175) or placebo (N = 176) taken on day one, both followed by misoprostol orally. In both groups, an intention-to-treat analysis was performed for 172 patients, showing a significant difference in success rates between participants treated with mifepristone and misoprostol versus those treated with misoprostol alone (79.1% vs 58.7% respectively). In this cost-effective analysis we measured the direct, medical costs related to treatment (planned and unplanned hospital visits, medication, additional treatment) and indirect costs based on the IMTA Productivity Cost Questionnaire (iPCQ). Quality Adjusted Life Years (QALY\u2019s) were calculated from participants\u2019 scores on the SF-36 questionnaires sent digitally at treatment start, and one, two and six weeks later. We found medical treatment with placebo followed by misoprostol to be 26% more expensive compared to mifepristone followed by misoprostol (p = 0.001). Mean average medical costs per patient were significantly lower in the mifepristone group compared to the placebo group (\u20ac528.95 \u00b1 328.93 vs \u20ac663.77 \u00b1 456.03, respectively; absolute difference \u20ac134.82, 95% CI 50,46\u2013219,18, p = 0.002). Both indirect costs and QALY\u2019s were similar between both groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The sequential combination of mifepristone with misoprostol is cost-effective compared with misoprostol alone, for treatment of EPL after a minimum of one week of unsuccessful expectant management.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0262894","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T18:36:18Z","timestamp":1644431778000},"page":"e0262894","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Economic evaluation of a randomized controlled trial comparing mifepristone and misoprostol with misoprostol alone in the treatment of early pregnancy loss"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3782-6669","authenticated-orcid":true,"given":"Charlotte C.","family":"Hamel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus P. 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M.","family":"Adang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"pone.0262894.ref001","author":"JP Neilson","year":"2009"},{"key":"pone.0262894.ref002","article-title":"Ectopic pregnancy and miscarriage: diagnosis and initial management.","author":"NICE guideline","year":"2019","journal-title":"Natl Inst Heal Care ExcellInternet]"},{"issue":"6","key":"pone.0262894.ref003","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/bdra.23014","article-title":"A systematic review to calculate background miscarriage rates using life table analysis.","volume":"94","author":"L Ammon Avalos","year":"2012","journal-title":"Birth Defects Res Part A\u2014Clin Mol Teratol"},{"issue":"1","key":"pone.0262894.ref004","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.fertnstert.2016.03.009","article-title":"Lifestyle and pregnancy loss in a contemporary cohort of women recruited before conception: The LIFE Study","volume":"106","author":"GM Buck Louis","year":"2016","journal-title":"Fertil Steril"},{"issue":"7342","key":"pone.0262894.ref005","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1136\/bmj.324.7342.873","article-title":"Outcome of expectant management of spontaneous first trimester miscarriage: observational study.","volume":"324","author":"C Luise","year":"2002","journal-title":"BMJ"},{"issue":"9","key":"pone.0262894.ref006","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1093\/humrep\/17.9.2445","article-title":"Management of miscarriage: a randomized controlled trial of expectant management versus surgical evacuation","volume":"17","author":"M Wieringa-de Waard","year":"2002","journal-title":"Hum Reprod"},{"issue":"10","key":"pone.0262894.ref007","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1093\/humrep\/dei163","article-title":"Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: A cost analysis","volume":"20","author":"JHS You","year":"2005","journal-title":"Hum Reprod"},{"key":"pone.0262894.ref008","article-title":"A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage.","volume":"862","author":"M Niinim\u00e4ki","year":"2006","journal-title":"Fertil Steril"},{"issue":"1","key":"pone.0262894.ref009","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1093\/humrep\/dev274","article-title":"Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis","volume":"31","author":"M Lemmers","year":"2016","journal-title":"Hum Reprod"},{"issue":"76","key":"pone.0262894.ref010","first-page":"168","article-title":"Clinical Management Guidelines for Obstetrician\u2013Gynecologists.","volume":"133","author":"ACOG","year":"2019","journal-title":"Obstet Gynecol"},{"key":"pone.0262894.ref011","unstructured":"Pfizer Limited. Cytotec UK SPC (Summary of Product Characteristics) [Internet]. Available from: https:\/\/www.medicines.org.uk\/emc\/product\/1642\/smpc."},{"issue":"1","key":"pone.0262894.ref012","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/uog.18940","article-title":"Misoprostol treatment vs expectant management in women with early non-viable pregnancy and vaginal bleeding: a pragmatic randomized controlled trial.","volume":"51","author":"A Fernlund","year":"2018","journal-title":"Ultrasound Obstet Gynecol"},{"issue":"2","key":"pone.0262894.ref013","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1093\/humrep\/deh049","article-title":"A randomized controlled trial comparing medical and expectant management of first trimester miscarriage.","volume":"19","author":"JS Bagratee","year":"2004","journal-title":"Hum Reprod"},{"issue":"8","key":"pone.0262894.ref014","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1093\/humrep\/deh344","article-title":"Misoprostol versus curettage in women with early pregnancy failure after initial expectant management: A randomized trial.","volume":"19","author":"GCM Graziosi","year":"2004","journal-title":"Hum Reprod"},{"key":"pone.0262894.ref015","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ejogrb.2014.10.010","article-title":"Sequential use of mifepristone and misoprostol in treatment of early pregnancy failure appears more effective than misoprostol alone: A retrospective study.","volume":"183","author":"J Van Den Berg","year":"2014","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"pone.0262894.ref016","article-title":"Mifepristone followed by misoprostol compared with placebo followed by misoprostol as medical treatment for early pregnancy loss (the Triple M Trial): a double-blind placebo-controlled randomised trial.","author":"C Hamel","year":"2020","journal-title":"EClinicalMedicine"},{"issue":"23","key":"pone.0262894.ref017","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1056\/NEJMoa1715726","article-title":"Mifepristone Pretreatment for the Medical Management of Early Pregnancy Loss.","volume":"378","author":"CA Schreiber","year":"2018","journal-title":"N Engl J Med"},{"issue":"20","key":"pone.0262894.ref018","first-page":"1","article-title":"Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.","volume":"6736","author":"JJ Chu","year":"2020","journal-title":"Lancet"},{"issue":"1","key":"pone.0262894.ref019","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12884-019-2497-y","article-title":"Mifepristone and misoprostol versus misoprostol alone for uterine evacuation after early pregnancy failure: Study protocol for a randomized double blinded placebo-controlled comparison (Triple M Trial).","volume":"19","author":"J Van Den Berg","year":"2019","journal-title":"BMC Pregnancy Childbirth"},{"key":"pone.0262894.ref020","first-page":"1","volume":"44","author":"Committee for Medicinal Products for Human Use (CHMP)","year":"2010","journal-title":"Guideline on missing data in confirmatory clinical trialsLondon Eur Med Agency"},{"issue":"2","key":"pone.0262894.ref021","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0167-6296(01)00130-8","article-title":"The estimation of a preference-based measure of health from the SF-36.","volume":"21","author":"J Brazier","year":"2002","journal-title":"J Health Econ"},{"issue":"1","key":"pone.0262894.ref022","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s40273-015-0337-0","article-title":"Myths and Misconceptions of Within-Cycle Correction: A Guide for Modelers and Decision Makers.","volume":"34","author":"EH Elbasha","year":"2016","journal-title":"Pharmacoeconomics"},{"issue":"3","key":"pone.0262894.ref023","doi-asserted-by":"crossref","first-page":"e201594","DOI":"10.1001\/jamanetworkopen.2020.1594","article-title":"Cost-effectiveness of Mifepristone Pretreatment for the Medical Management of Nonviable Early Pregnancy: Secondary Analysis of a Randomized Clinical Trial","volume":"3","author":"D Nagendra","year":"2020","journal-title":"JAMA Netw open"},{"issue":"4","key":"pone.0262894.ref024","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1097\/AOG.0000000000004063","article-title":"Mifepristone Combination Therapy Compared With Misoprostol Monotherapy for the Management of Miscarriage: A Cost-Effectiveness Analysis.","volume":"136","author":"HH Berkley","year":"2020","journal-title":"Obstet Gynecol."},{"issue":"9","key":"pone.0262894.ref025","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1111\/j.1471-0528.2009.02223.x","article-title":"Manual vacuum aspiration: A safe alternative for the surgical management of early pregnancy loss.","volume":"116","author":"DS Milingos","year":"2009","journal-title":"BJOG An Int J Obstet Gynaecol"},{"issue":"2","key":"pone.0262894.ref026","article-title":"Manual vacuum aspiration: a safe and cost-effective substitute of electric vacuum aspiration for the surgical management of early pregnancy loss.","volume":"61","author":"N Tasnim","year":"2011","journal-title":"J Pak Med Assoc"},{"key":"pone.0262894.ref027","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ejogrb.2015.09.025","article-title":"Pain during medical abortion: A multicenter study in France.","volume":"194","author":"MJ Saurel-Cubizolles","year":"2015","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"issue":"9","key":"pone.0262894.ref028","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1056\/NEJMp1405158","article-title":"Updating cost-effectiveness\u2014The curious resilience of the $50,000-per-QALY threshold.","volume":"371","author":"PJ Neumann","year":"2014","journal-title":"N Engl J Med"},{"key":"pone.0262894.ref029","unstructured":"Dutch Institute National Health Care (Zorginstituut Nederland). Richtlijn voor het uitvoeren van economische evaluaties in de gezondheidzorg (Protocol for the execution of economic evaluation in healthcare). 29-02-2016 [Internet]. 2016;(november):120. Available from: https:\/\/www.ispor.org\/PEguidelines\/source\/NL-Economic_Evaluation_Guidelines.pdf."},{"key":"pone.0262894.ref030","article-title":"Towards well-defined diagnostic criteria for retained products of conception (RPOC): a systematic scoping review.","author":"CC Hamel","journal-title":"Manuscr Submitt Publ"},{"key":"pone.0262894.ref031","first-page":"83","article-title":"MisoREST: Surgical versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage: A cohort study","volume":"211","author":"M Lemmers","year":"2017","journal-title":"Hum Reprod"},{"issue":"7","key":"pone.0262894.ref032","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1097\/01.ogx.0000540046.38424.1c","article-title":"Cost-effectiveness of curettage versus expectant management in women with an incomplete evacuation after misoprostol treatment for first-trimester miscarriage: a randomized controlled trial and cohort study.","volume":"73","author":"M Lemmers","year":"2018","journal-title":"Obstet Gynecol Surv"},{"key":"pone.0262894.ref033","first-page":"i185","article-title":"Quality of life for curettage versus expectant management in women with incomplete evacuation of the uterus after treatment with misoprostol for miscarriage: the misorest trial","volume":"30","author":"M Lemmers","year":"2015","journal-title":"Hum Reprod"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262894","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T18:37:01Z","timestamp":1644431821000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262894"}},"subtitle":[],"editor":[{"given":"Stefan","family":"Gebhardt","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,9]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0262894","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,9]]}}}