{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:14:10Z","timestamp":1792502050620,"version":"4.5.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["14\/150\/03"],"award-info":[{"award-number":["14\/150\/03"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>What is the capacity of the change between Day 1 and Day 4 post-treatment serum human chorionic gonadotropin (hCG) levels for predicting single-dose methotrexate treatment success in tubal ectopic pregnancy?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>Any fall in Days 1\u20134 serum hCG signified an 85% (95% CI 76.8\u201390.6) likelihood of treatment success for women with tubal ectopic pregnancy (initial hCG of \u22651000 and \u22645000\u2009IU\/l) managed with single-dose methotrexate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>For those with tubal ectopic pregnancy managed by single-dose methotrexate, current guidelines advocate intervention if Days 4\u20137 hCG fails to fall by &amp;gt;15%. The trajectory of hCG over Days 1\u20134 has been proposed as an early indicator that predicts treatment success, allowing early reassurance for women. However, almost all prior studies of Days 1\u20134 hCG changes have been retrospective.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>This was a prospective cohort study of women with tubal ectopic pregnancy (pre-treatment hCG of \u22651000 and \u22645000\u2009IU\/l) managed with single-dose methotrexate. The data were derived from a UK multicentre randomized controlled trial of methotrexate and gefitinib versus methotrexate and placebo for treatment of tubal ectopic pregnancy (GEM3). For this analysis, we include data from both treatment arms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>Participants were categorized according to single-dose methotrexate treatment success or failure. Treatment success for this analysis was defined as complete and uneventful resolution of tubal ectopic pregnancy to serum hCG &amp;lt;30\u2009IU\/l following single-dose methotrexate treatment without additional treatment. Patient characteristics of the treatment success and failure groups were compared. Changes in Days 1\u20134, 1\u20137, and 4\u20137 serum hCG were evaluated as predictors of treatment success through receiver operating characteristic curve analysis. Test performance characteristics were calculated for percentage change ranges and thresholds including optimal classification thresholds.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>A total of 322 women with tubal ectopic pregnancy were treated with single-dose methotrexate. The overall single-dose methotrexate treatment success rate was 59% (n\u2009=\u2009189\/322). For any fall in serum hCG on Days 1\u20134, likelihood ratios were &amp;gt;3, while for any fall of serum hCG &amp;gt;20% on Days 1\u20137, likelihood ratios reached 5. Any rise of serum hCG on Days 1\u20137 and 4\u20137 strongly reduced the chance of success. Any fall in Days 1\u20134 hCG predicted single-dose methotrexate treatment success with a sensitivity of 58% and specificity 84%, resulting in positive and negative predictive values of 85% and 57%, respectively. Any rise in Days 1\u20134 serum hCG &amp;lt;18% was identified as an optimal test threshold that predicted treatment success with 79% sensitivity and 74% specificity, resulting in 82% positive predictive value and 69% negative predictive value.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Our findings may be limited by intervention bias resulting from existing guidelines which influences evaluation of hCG changes reliant on Day 7 serum hCG levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>Examining a large prospective cohort, we show the value of Days 1\u20134 serum hCG changes in predicting single-dose methotrexate treatment success in tubal ectopic pregnancy. We recommend that clinicians provide early reassurance to women who have a fall or only a modest (&amp;lt;18%) rise in Days 1\u20134 serum hCG levels, that their treatment will likely be effective.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This project was supported by funding from the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant reference number 14\/150\/03). A.W.H. has received honoraria for consultancy for Ferring, Roche, Nordic Pharma and AbbVie. W.C.D. has received honoraria from Merck and Guerbet and research funding from Galvani Biosciences. L.H.R.W. has received research funding from Roche Diagnostics. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. also reports consultancy for ObsEva and Merck and travel support from Merck. The other authors declare no competing interests.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                    <jats:p>This study is a secondary analysis of the GEM3 trial (ISRCTN Registry ISRCTN67795930).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humrep\/dead089","type":"journal-article","created":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T14:15:26Z","timestamp":1683987326000},"page":"1261-1267","source":"Crossref","is-referenced-by-count":21,"title":["Early (Days 1\u20134) post-treatment serum hCG level changes predict single-dose methotrexate treatment success in tubal ectopic pregnancy"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5823-4334","authenticated-orcid":false,"given":"Scott C","family":"Mackenzie","sequence":"first","affiliation":[{"name":"MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0473-0532","authenticated-orcid":false,"given":"Catherine A","family":"Moakes","sequence":"additional","affiliation":[{"name":"Birmingham Clinical Trials Unit, University of Birmingham , Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8726-7186","authenticated-orcid":false,"given":"Ann M","family":"Doust","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8337-550X","authenticated-orcid":false,"given":"Ben W","family":"Mol","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Monash University , Melbourne, Australia"},{"name":"Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen , Aberdeen, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7170-5740","authenticated-orcid":false,"given":"W Colin","family":"Duncan","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2319-0586","authenticated-orcid":false,"given":"Stephen","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Melbourne , Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9656-493X","authenticated-orcid":false,"given":"Andrew W","family":"Horne","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-6551","authenticated-orcid":false,"given":"Lucy H R","family":"Whitaker","sequence":"additional","affiliation":[{"name":"MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,13]]},"reference":[{"key":"2023070507334617600_dead089-B1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.fertnstert.2006.11.138","article-title":"Prognostic value of human chorionic gonadotropin changes after methotrexate injection for ectopic pregnancy","volume":"88","author":"Agostini","year":"2007","journal-title":"Fertil Steril"},{"key":"2023070507334617600_dead089-B2","doi-asserted-by":"crossref","first-page":"e91","DOI":"10.1097\/AOG.0000000000002560","article-title":"ACOG Practice Bulletin No. 193: tubal ectopic pregnancy","volume":"131","author":"American College of Obstetricians and Gynecologists","year":"2018","journal-title":"Obstet Gynecol"},{"key":"2023070507334617600_dead089-B3","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"2023070507334617600_dead089-B4","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1111\/1471-0528.14189","article-title":"Diagnosis and management of ectopic pregnancy","volume":"123","author":"Elson","year":"2016","journal-title":"BJOG"},{"key":"2023070507334617600_dead089-B5","doi-asserted-by":"crossref","first-page":"e011864","DOI":"10.1136\/bmjopen-2016-011864","article-title":"Post-traumatic stress, anxiety and depression following miscarriage or ectopic pregnancy: a prospective cohort study","volume":"6","author":"Farren","year":"2016","journal-title":"BMJ Open"},{"key":"2023070507334617600_dead089-B6","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ejogrb.2020.10.036","article-title":"Day 1 to day 4 serum hCG change in predicting single-dose methotrexate treatment failure for tubal ectopic pregnancies","volume":"255","author":"Goh","year":"2020","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2023070507334617600_dead089-B7","doi-asserted-by":"crossref","first-page":"213","DOI":"10.32614\/RJ-2016-042","article-title":"easyROC: an interactive web-tool for ROC curve analysis using R language environment","volume":"8","author":"Goksuluk","year":"2016","journal-title":"R J"},{"key":"2023070507334617600_dead089-B8","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0140-6736(22)02478-3","article-title":"Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial","volume":"401","author":"Horne","year":"2023","journal-title":"Lancet"},{"key":"2023070507334617600_dead089-B9","doi-asserted-by":"crossref","first-page":"d3397","DOI":"10.1136\/bmj.d3397","article-title":"Diagnosis and management of ectopic pregnancy","volume":"342","author":"Jurkovic","year":"2011","journal-title":"BMJ"},{"key":"2023070507334617600_dead089-B10","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1093\/humrep\/del433","article-title":"A validation of the most commonly used protocol to predict the success of single-dose methotrexate in the treatment of ectopic pregnancy","volume":"22","author":"Kirk","year":"2007","journal-title":"Hum Reprod"},{"key":"2023070507334617600_dead089-B11","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/S0015-0282(16)56638-2","article-title":"Serum human chorionic gonadotropin dynamics during spontaneous resolution of ectopic pregnancy","volume":"61","author":"Korhonen","year":"1994","journal-title":"Fertil Steril"},{"key":"2023070507334617600_dead089-B12","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.rbmo.2019.02.005","article-title":"Early prediction of the success of methotrexate treatment success by 24\u2013hour pretreatment increment in HCG and day 1\u20134 change in HCG","volume":"39","author":"Levin","year":"2019","journal-title":"Reprod Biomed Online"},{"key":"2023070507334617600_dead089-B13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/ijgo.12395","article-title":"Predicting success of methotrexate treatment by pretreatment HCG level and 24-hour HCG increment","volume":"141","author":"Levin","year":"2018","journal-title":"Int J Gynaecol Obstet"},{"key":"2023070507334617600_dead089-B14","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1097\/GRF.0b013e3182516d7b","article-title":"Ectopic pregnancy: history, incidence, epidemiology, and risk factors","volume":"55","author":"Marion","year":"2012","journal-title":"Clin Obstet Gynecol"},{"key":"2023070507334617600_dead089-B15","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.ejogrb.2018.10.046","article-title":"Significant increase in serum hCG levels following methotrexate therapy is associated with lower treatment success rates in ectopic pregnancy patients","volume":"231","author":"Mashiach","year":"2018","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2023070507334617600_dead089-B16","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/uog.12401","article-title":"Efficacy and safety of a clinical protocol for expectant management of selected women diagnosed with a tubal ectopic pregnancy","volume":"42","author":"Mavrelos","year":"2013","journal-title":"Ultrasound Obstet Gynecol"},{"key":"2023070507334617600_dead089-B17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13063-018-3008-6","article-title":"A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol","volume":"19","author":"May","year":"2018","journal-title":"Trials"},{"key":"2023070507334617600_dead089-B18","doi-asserted-by":"crossref","first-page":"630.e1","DOI":"10.1016\/j.ajog.2010.03.022","article-title":"Are early human chorionic gonadotropin levels after methotrexate therapy a predictor of response in ectopic pregnancy?","volume":"202","author":"Nguyen","year":"2010","journal-title":"Am J Obstet Gynecol"},{"key":"2023070507334617600_dead089-B19","doi-asserted-by":"crossref","first-page":"3940","DOI":"10.1093\/bioinformatics\/bti623","article-title":"ROCR: visualizing classifier performance in R","volume":"21","author":"Sing","year":"2005","journal-title":"Bioinformatics"},{"key":"2023070507334617600_dead089-B20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2393-13-30","article-title":"Using a decline in serum hCG between days 0\u20134 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study","volume":"13","author":"Skubisz","year":"2013","journal-title":"BMC Pregnancy Childbirth"},{"key":"2023070507334617600_dead089-B21","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1111\/j.1471-0528.2011.03133.x","article-title":"Decline in betahCG levels between days 0 and 4 after a single dose of methotrexate for ectopic pregnancy predicts treatment success: a retrospective cohort study","volume":"118","author":"Skubisz","year":"2011","journal-title":"BJOG"},{"key":"2023070507334617600_dead089-B22","author":"Stevenson","year":"2022"},{"key":"2023070507334617600_dead089-B23","first-page":"754","article-title":"Single-dose methotrexate for treatment of ectopic pregnancy","volume":"77","author":"Stovall","year":"1991","journal-title":"Obstet Gynecol"},{"key":"2023070507334617600_dead089-B24","first-page":"693","article-title":"The diagnosis and treatment of ectopic pregnancy","volume":"112","author":"Taran","year":"2015","journal-title":"Dtsch Arztebl Int"},{"key":"2023070507334617600_dead089-B25","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1007\/s00404-013-2879-8","article-title":"Role of initial and day 4 human chorionic gonadotropin levels in predicting the outcome of single-dose methotrexate treatment in women with tubal ectopic pregnancy","volume":"288","author":"Ustunyurt","year":"2013","journal-title":"Arch Gynecol Obstet"},{"key":"2023070507334617600_dead089-B26","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/humrep\/des373","article-title":"Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison","volume":"28","author":"van Mello","year":"2013","journal-title":"Hum Reprod"},{"key":"2023070507334617600_dead089-B27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2393-12-98","article-title":"Has increased clinical experience with methotrexate reduced the direct costs of medical management of ectopic pregnancy compared to surgery?","volume":"12","author":"Westaby","year":"2012","journal-title":"BMC Pregnancy Childbirth"},{"key":"2023070507334617600_dead089-B28","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/ijgo.12419","article-title":"Trends in serum human chorionic gonadotropin levels 0\u20134 days after methotrexate administration for predicting tubal ectopic pregnancy treatment success","volume":"141","author":"Wong","year":"2018","journal-title":"Int J Gynaecol Obstet"},{"key":"2023070507334617600_dead089-B29","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12884-020-03350-8","article-title":"Predictors and clinical features of methotrexate (MTX) therapy for ectopic pregnancy","volume":"20","author":"Zhang","year":"2020","journal-title":"BMC Pregnancy Childbirth"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/38\/7\/1261\/50785464\/dead089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/38\/7\/1261\/50785464\/dead089.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T12:49:42Z","timestamp":1688561382000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/38\/7\/1261\/7161745"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,13]]},"references-count":29,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,5,13]]},"published-print":{"date-parts":[[2023,7,5]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/dead089","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,7,1]]},"published":{"date-parts":[[2023,5,13]]}}}