{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:47:51Z","timestamp":1793652471441,"version":"4.5.1"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Recurrent pregnancy loss (RPL) occurs in 1\u20133% of all couples trying to conceive. No consensus exists regarding when to perform testing for risk factors in couples with RPL. Some guidelines recommend testing if a patient has had two pregnancy losses whereas others advise to test after three losses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OBJECTIVE AND RATIONALE<\/jats:title>\n                    <jats:p>The aim of this systematic review was to evaluate the current evidence on the prevalence of abnormal test results for RPL amongst patients with two versus three or more pregnancy losses. We also aimed to contribute to the debate regarding whether the investigations for RPL should take place after two or three or more pregnancy losses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SEARCH METHODS<\/jats:title>\n                    <jats:p>Relevant studies were identified by a systematic search in OVID Medline and EMBASE from inception to March 2019. A search for RPL was combined with a broad search for terms indicative of number of pregnancy losses, screening\/testing for pregnancy loss or the prevalence of known risk factors. Meta-analyses were performed in case of adequate clinical and statistical homogeneity. The quality of the studies was assessed using the Newcastle-Ottawa scale.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OUTCOMES<\/jats:title>\n                    <jats:p>From a total of 1985 identified publications, 21 were included in this systematic review and 19 were suitable for meta-analyses. For uterine abnormalities (seven studies, odds ratio (OR) 1.00, 95% CI 0.79\u20131.27, I2\u00a0=\u20090%) and for antiphospholipid syndrome (three studies, OR 1.04, 95% CI 0.86\u20131.25, I2\u00a0=\u20090%) we found low quality evidence for a lack of a difference in prevalence of abnormal test results between couples with two versus three or more pregnancy losses. We found insufficient evidence of a difference in prevalence of abnormal test results between couples with two versus three or more pregnancy losses for chromosomal abnormalities (10 studies, OR 0.78, 95% CI 0.55\u20131.10), inherited thrombophilia (five studies) and thyroid disorders (two studies, OR 0.52, 95% CI: 0.06\u20134.56).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS<\/jats:title>\n                    <jats:p>A difference in prevalence in uterine abnormalities and antiphospholipid syndrome is unlikely in women with two versus three pregnancy losses. We cannot exclude a difference in prevalence of chromosomal abnormalities, inherited thrombophilia and thyroid disorders following testing after two versus three pregnancy losses. The results of this systematic review may support investigations after two pregnancy losses in couples with RPL, but it should be stressed that additional studies of the prognostic value of test results used in the RPL population are urgently needed. An evidenced-based treatment is not currently available in the majority of cases when abnormal test results are present.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humupd\/dmz048","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T07:11:26Z","timestamp":1574406686000},"page":"356-367","source":"Crossref","is-referenced-by-count":175,"title":["Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9148-587X","authenticated-orcid":false,"given":"Myrthe M","family":"van Dijk","sequence":"first","affiliation":[{"name":"Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M","family":"Kolte","sequence":"first","affiliation":[{"name":"Recurrent Pregnancy Loss Unit, Fertility Clinic 4071, Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Limpens","sequence":"first","affiliation":[{"name":"Medical Library, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Kirk","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Royal Free Hospital NHS Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan","family":"Quenby","sequence":"first","affiliation":[{"name":"University Hospital Coventry, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelon","family":"van Wely","sequence":"first","affiliation":[{"name":"Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9928-9673","authenticated-orcid":false,"given":"Mari\u00ebtte","family":"Goddijn","sequence":"first","affiliation":[{"name":"Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,2,26]]},"reference":[{"key":"2020041610554433400_ref1","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1111\/jog.12385","article-title":"Frequency of hereditary thrombophilia in women with recurrent pregnancy loss in northern Pakistan","volume":"40","author":"Ali","year":"2014","journal-title":"J Obstet Gynaecol Res"},{"key":"2020041610554433400_ref2","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1097\/OGX.0b013e31828aca19","article-title":"Current concepts and new trends in the diagnosis and management of recurrent miscarriage","volume":"68","author":"Alijotas-Reig","year":"2013","journal-title":"Obstet Gynecol Surv"},{"key":"2020041610554433400_ref3","first-page":"201","article-title":"The study of chromosomal abnormalities and heteromorphism in couples with 2 or 3 recurrent abortions in Shahid Beheshti Hospital of Hamedan","volume":"11","author":"Asgari","year":"2013","journal-title":"Iran J Reprod Med"},{"key":"2020041610554433400_ref4","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/j.1471-0528.2010.02566.x","article-title":"Is karyotyping couples experiencing recurrent miscarriage worth the cost?","volume":"117","author":"Barber","year":"2010","journal-title":"BJOG"},{"key":"2020041610554433400_ref5","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1515\/jpm-2011-0295","article-title":"Two versus three or more primary recurrent pregnancy losses are there any differences in epidemiologic characteristics and index pregnancy outcome?","volume":"40","author":"Bashiri","year":"2012","journal-title":"J Perinat Med"},{"key":"2020041610554433400_ref6","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/aji.12144","article-title":"Maternal factor V Leiden and prothrombin mutations do not seem to contribute to the occurrence of two or more than two consecutive miscarriages in Caucasian patients","volume":"70","author":"Baumann","year":"2013","journal-title":"Am J Reprod Immunol"},{"key":"2020041610554433400_ref6a","first-page":"156","article-title":"Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation","volume":"98","author":"Bernardi","year":"2012","journal-title":"Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation"},{"key":"2020041610554433400_ref7","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejogrb.2010.02.015","article-title":"Recurrent miscarriage: are three miscarriages one too many? Analysis of a Scottish population-based database of 151,021 pregnancies","volume":"150","author":"Bhattacharya","year":"2010","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2020041610554433400_ref8","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.rbmo.2010.04.016","article-title":"Hysteroscopic findings in women with two and with more than two first-trimester miscarriages are not significantly different","volume":"21","author":"Bohlmann","year":"2010","journal-title":"Reprod Biomed Online"},{"key":"2020041610554433400_ref9","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1093\/humrep\/14.11.2868","article-title":"A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage","volume":"14","author":"Brigham","year":"1999","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref10","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/humupd\/dmr028","article-title":"The prevalence of congenital uterine anomalies in unselected and high-risk populations: a systematic review","volume":"17","author":"Chan","year":"2011","journal-title":"Hum Reprod Update"},{"key":"2020041610554433400_ref11","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.fertnstert.2004.12.018","article-title":"Evidence-based investigations and treatments of recurrent pregnancy loss","volume":"83","author":"Christiansen","year":"2005","journal-title":"Fertil Steril"},{"key":"2020041610554433400_ref12","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1186\/s12884-017-1620-1","article-title":"Spontaneous first trimester miscarriage rates per woman among parous women with 1 or more pregnancies of 24 weeks or more","volume":"17","author":"Cohain","year":"2017","journal-title":"BMC Pregnancy Childbirth"},{"key":"2020041610554433400_ref13","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0104-4230(11)70084-7","article-title":"Office hysteroscopy study in consecutive miscarriage patients","volume":"57","author":"De Souza","year":"2011","journal-title":"Rev Assoc Med Bras"},{"key":"2020041610554433400_ref14","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/BF00285027","article-title":"Chromosome anomalies in 136 couples with a history of recurrent abortions","volume":"65","author":"Diedrich","year":"1983","journal-title":"Hum Genet"},{"key":"2020041610554433400_ref15","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1093\/humrep\/dex311","article-title":"Constructing the crystal ball: how to get reliable prognostic information for the management of subfertile couples","volume":"32","author":"van Eekelen","year":"2017","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref16","volume-title":"ESHRE Early Pregnancy Guideline Development Group","author":"ESHRE guideline 'Recurrent Pregnancy Loss'","year":"2017"},{"key":"2020041610554433400_ref17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/ajmg.1320160103","article-title":"Repeated pregnancy loss","volume":"16","author":"FitzSimmons","year":"1983","journal-title":"Am J Med Genet"},{"key":"2020041610554433400_ref18","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1136\/bmj.38498.669595.8F","article-title":"Selective chromosome analysis in couples with two or more miscarriages: case-control study","volume":"331","author":"Franssen","year":"2005","journal-title":"BMJ"},{"key":"2020041610554433400_ref19","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1136\/bmj.38735.459144.2F","article-title":"Reproductive outcome after chromosome analysis in couples with two or more miscarriages: index-control study","volume":"332","author":"Franssen","year":"2006","journal-title":"BMJ"},{"key":"2020041610554433400_ref20","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/humrep\/deh172","article-title":"Clinical relevance of diagnosing structural chromosome abnormalities in couples with repeated miscarriage","volume":"19","author":"Goddijn","year":"2004","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3109\/14767058.2014.900752","article-title":"Index pregnancy versus post-index pregnancy in patients with recurrent pregnancy loss","volume":"28","author":"Greenberg","year":"2015","journal-title":"J Matern Fetal Neonatal Med"},{"key":"2020041610554433400_ref22","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3109\/14767058.2014.920811","article-title":"Diagnostic value of screening tests in subgroups of women with recurrent pregnancy loss","volume":"28","author":"Guzel","year":"2015","journal-title":"J Matern-Fetal Neonat Med"},{"key":"2020041610554433400_ref23","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1016\/j.fertnstert.2013.01.152","article-title":"Effect of prior birth and miscarriage frequency on the prevalence of acquired and congenital uterine anomalies in women with recurrent miscarriage: a cross-sectional study","volume":"99","author":"Jaslow","year":"2013","journal-title":"Fertil Steril"},{"key":"2020041610554433400_ref24","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1016\/j.fertnstert.2009.01.166","article-title":"Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses","volume":"93","author":"Jaslow","year":"2010","journal-title":"Fertil Steril"},{"key":"2020041610554433400_ref25","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1093\/humrep\/del150","article-title":"Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage","volume":"21","author":"Jauniaux","year":"2006","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref26","doi-asserted-by":"crossref","first-page":"376","DOI":"10.5336\/medsci.2011-23624","article-title":"There is no relationship between the number of subsequent pregnancy losses and thrombophilic factors","volume":"32","author":"Karadeniz","year":"2012","journal-title":"Turkiye Klinikleri J Med Sci"},{"key":"2020041610554433400_ref27","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s00404-015-4001-x","article-title":"Two-year outcome after recurrent first trimester miscarriages: prognostic value of the past obstetric history","volume":"293","author":"Kling","year":"2016","journal-title":"Arch Gynecol Obstet"},{"key":"2020041610554433400_ref28","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0028-2243(91)90138-B","article-title":"Prognosis of a new pregnancy following previous spontaneous abortions","volume":"39","author":"Knudsen","year":"1991","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2020041610554433400_ref29","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1093\/humrep\/deu042","article-title":"ESHRE special interest group early pregnancy. Non-visualized pregnancy losses are prognostically important for unexplained recurrent miscarriage","volume":"29","author":"Kolte","year":"2014","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/AOG.0b013e31823c0413","article-title":"Prognosis for live birth in women with recurrent miscarriage: what is the best measure of success?","volume":"119","author":"Lund","year":"2012","journal-title":"Obstet Gynecol"},{"key":"2020041610554433400_ref31","doi-asserted-by":"crossref","first-page":"l869","DOI":"10.1136\/bmj.l869","article-title":"Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study","volume":"364","author":"Magnus","year":"2019","journal-title":"BMJ"},{"key":"2020041610554433400_ref32","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.fertnstert.2009.06.041","article-title":"Etiology of recurrent pregnancy loss in women over the age of 35 years","volume":"94","author":"Marquard","year":"2010","journal-title":"Fertil Steril"},{"key":"2020041610554433400_ref33","first-page":"507","article-title":"Chromosome translocations in couples with multiple spontaneous abortions","volume":"34","author":"Michels","year":"1982","journal-title":"Am J Hum Genet"},{"key":"2020041610554433400_ref34","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1538-7836.2006.01753.x","article-title":"International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)","volume":"4","author":"Miyakis","year":"2006","journal-title":"J Thromb Haemost"},{"key":"2020041610554433400_ref35","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/humrep\/des374","article-title":"Supportive care for women with recurrent miscarriage: a survey to quantify women's preferences","volume":"28","author":"Musters","year":"2013","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref36","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1136\/bmj.320.7251.1708","article-title":"Maternal age and fetal loss: population based register linkage study","volume":"320","author":"Nybo Andersen","year":"2000","journal-title":"BMJ"},{"key":"2020041610554433400_ref36a","author":"Oxford Centre for Evidence-based Medicine \u2013 Levels of Evidence","year":"2009"},{"key":"2020041610554433400_ref37","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1111\/j.1471-0528.1988.tb06525.x","article-title":"Short-term reproductive prognosis when no cause can be found for recurrent miscarriage","volume":"95","author":"Parazzini","year":"1988","journal-title":"Br J Obstet Gynaecol"},{"key":"2020041610554433400_ref38","first-page":"132","article-title":"Predicting recurring miscarriage: what is important?","volume":"82","author":"Quenby","year":"1993","journal-title":"Obstet Gynecol"},{"key":"2020041610554433400_ref39","article-title":"The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage","author":"RCOG. Green-top Guideline No. 17","year":"2011"},{"key":"2020041610554433400_ref40","first-page":"375","article-title":"Chromosome studies of 500 couples with two or more abortions","volume":"65","author":"Sachs","year":"1985","journal-title":"Obstet Gynecol"},{"key":"2020041610554433400_ref41","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/BF00285393","article-title":"Chromosomal findings in 164 couples with repeated spontaneous abortions: with special consideration to prior reporductive history","volume":"63","author":"Schwartz","year":"1983","journal-title":"Hum Genet"},{"key":"2020041610554433400_ref42","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3109\/13625187.2012.698767","article-title":"Office hysteroscopic findings in patients with two, three, and four or more, consecutive miscarriages","volume":"17","author":"Seckin","year":"2012","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"2020041610554433400_ref43","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1097\/00007611-198812000-00014","article-title":"Cytogenetic studies in couples with recurrent pregnancy loss","volume":"81","author":"Sider","year":"1988","journal-title":"South Med J"},{"key":"2020041610554433400_ref44","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1600-0897.2006.00454.x","article-title":"Combined thrombophilic mutations in women with unexplained recurrent miscarriage","volume":"57","author":"Sotiriadis","year":"2007","journal-title":"Am J Reprod Immunol"},{"key":"2020041610554433400_ref45","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1093\/humrep\/17.2.446","article-title":"Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study","volume":"17","author":"Stephenson","year":"2002","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref46","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.fertnstert.2012.06.048","article-title":"Evaluation and treatment of recurrent pregnancy loss: a committee opinion","volume":"98","author":"The Practice Committee of the American Society for Reproductive Medicine (ASRM)","year":"2012","journal-title":"Fertil Steril"},{"key":"2020041610554433400_ref47","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.fertnstert.2012.09.002","article-title":"Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage","volume":"99","author":"Van den Boogaard","year":"2013","journal-title":"Fertil Steril"},{"key":"2020041610554433400_ref48","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/humrep\/dei081","article-title":"Hysteroscopy may be justified after two miscarriages","volume":"20","author":"Weiss","year":"2005","journal-title":"Hum Reprod"},{"key":"2020041610554433400_ref49","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.jclinepi.2015.04.002","article-title":"Strengthening the reporting of observational studies in epidemiology for respondent-driven sampling studies: \"STROBE-RDS\" statement","volume":"68","author":"White","year":"2015","journal-title":"J Clin Epidemiol"}],"container-title":["Human Reproduction Update"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/humupd\/article-pdf\/26\/3\/356\/33050966\/dmz048.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/humupd\/article-pdf\/26\/3\/356\/33050966\/dmz048.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T12:36:20Z","timestamp":1587040580000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humupd\/article\/26\/3\/356\/5760375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,26]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,2,26]]},"published-print":{"date-parts":[[2020,4,15]]}},"URL":"https:\/\/doi.org\/10.1093\/humupd\/dmz048","relation":{},"ISSN":["1355-4786","1460-2369"],"issn-type":[{"value":"1355-4786","type":"print"},{"value":"1460-2369","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,5]]},"published":{"date-parts":[[2020,2,26]]}}}