{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:07:42Z","timestamp":1784700462302,"version":"3.55.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Reprod. Health"],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In this exploratory case-control study, we investigated the potential associations of pregnancy-associated plasma protein-A (PAPP-A), \u03b2-human chorionic gonadotrophin (\u03b2-HCG), vascular endothelial growth factor (VEGF), and leukemia inhibitory factor (LIF) with ectopic pregnancy (EP), using logistic regression to describe unadjusted associations and receiver operating characteristic (ROC) curve analysis to characterise exploratory biomarker performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a case-control study including 48 patients with EP and 46 patients with normal intrauterine pregnancy as controls, recruited between October 2022 and May 2024 at a single center. Logistic regression was applied to describe associations between each biomarker and EP. ROC curves were derived from these models to explore discrimination, and an exploratory threshold was identified using the Youden index.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The area under the curve (AUC) for \u03b2-HCG and PAPP-A were the highest (0.85 and 0.84, respectively), compared with VEGF (0.73) and LIF (0.54). PAPP-A showed the strongest association among the candidate markers (OR\u2009=\u20090.774), with an exploratory sensitivity of 0.77. VEGF had the highest specificity (0.96). The combined exploratory AUC of PAPP-A and \u03b2-HCG (0.89) was similar to that of PAPP-A and VEGF (0.88).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This exploratory study suggests that PAPP-A may be a promising candidate biomarker for early EP detection in the context of an exploratory case-control comparison with normal intrauterine pregnancy, with performance comparable to \u03b2-HCG. Further prospective studies with external validation in clinically relevant populations are needed to confirm these preliminary findings and assess clinical potential.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/frph.2026.1891223","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:56:38Z","timestamp":1784699798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum PAPP-A as a potential biomarker for early detection of ectopic pregnancy: an exploratory case-control study"],"prefix":"10.3389","volume":"8","author":[{"given":"Xiaoyan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Gynecology, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongtao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Affiliated Qingdao Third People\u2019s Hospital, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/S0140-6736(05)67103-6","article-title":"Ectopic pregnancy","volume":"366","author":"Farquhar","year":"2005","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e65","DOI":"10.1097\/AOG.0000000000002464","article-title":"ACOG Practice bulletin No. 191: tubal ectopic pregnancy","volume":"131","year":"2018","journal-title":"Obstet Gynecol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1097\/AOG.0b013e3182113c10","article-title":"Trends in ectopic pregnancy mortality in the United States: 1980-2007","volume":"117","author":"Creanga","year":"2011","journal-title":"Obstet Gynecol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"508","DOI":"10.3109\/01443615.2014.910181","article-title":"A United Kingdom national survey of trends in ectopic pregnancy management","volume":"34","author":"Taheri","year":"2014","journal-title":"J Obstet Gynaecol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1111\/1471-0528.16756","article-title":"Impact of severe acute respiratory syndrome coronavirus 2 on ectopic pregnancy management in the United Kingdom: a multicentre observational study","volume":"128","author":"Platts","year":"2021","journal-title":"BJOG"},{"key":"B6","first-page":"599","article-title":"Ectopic pregnancy: diagnosis and management","volume":"101","author":"Hendriks","year":"2020","journal-title":"Am Fam Physician"},{"key":"B7","doi-asserted-by":"publisher","first-page":"17455057231160349","DOI":"10.1177\/17455057231160349","article-title":"Overview of ectopic pregnancy diagnosis, management, and innovation","volume":"19","author":"Mullany","year":"2023","journal-title":"Womens Health (Lond)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1097\/OGX.0000000000000492","article-title":"New evidence to guide ectopic pregnancy diagnosis and management","volume":"72","author":"Brady","year":"2017","journal-title":"Obstet Gynecol Surv"},{"key":"B9","first-page":"1707","article-title":"Diagnosis and management of ectopic pregnancy","volume":"72","author":"Lozeau","year":"2005","journal-title":"Am Fam Physician"},{"key":"B10","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.fertnstert.2011.10.037","article-title":"Performance of human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to? The rules","volume":"97","author":"Morse","year":"2012","journal-title":"Fertil Steril"},{"key":"B11","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.fertnstert.2024.04.028","article-title":"Multiplexed serum biomarkers to discriminate nonviable and ectopic pregnancy","volume":"122","author":"Barnhart","year":"2024","journal-title":"Fertil Steril"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.1111\/jog.13127","article-title":"Abdominal ectopic pregnancy with undetectable serum beta-human chorionic gonadotropin 9 days following blastocyst transfer","volume":"42","author":"Irani","year":"2016","journal-title":"J Obstet Gynaecol Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"214","DOI":"10.3906\/sag-1307-103","article-title":"Aberrant expression of leukemia inhibitory factor receptor (LIFR) and leukemia inhibitory factor (LIF) is associated with tubal pregnancy occurrence","volume":"45","author":"Li","year":"2015","journal-title":"Turk J Med Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"801","DOI":"10.3892\/etm.2021.10233","article-title":"Predictive value of PAPP-A for ectopic pregnancy and analysis of related factors","volume":"22","author":"Zhang","year":"2021","journal-title":"Exp Ther Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1590\/1806-9282.20220224","article-title":"Serum vascular endothelial growth factor as a marker for tubal pregnancy","volume":"68","author":"Cabar","year":"2022","journal-title":"Rev Assoc Med Bras (1992)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies","volume":"370","author":"von Elm","year":"2007","journal-title":"Lancet (London, England)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1002\/uog.4015","article-title":"Prediction of ectopic pregnancy in women with a pregnancy of unknown location","volume":"29","author":"Condous","year":"2007","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1093\/humrep\/deq217","article-title":"Does a prediction model for pregnancy of unknown location developed in the UK validate on a US population?","volume":"25","author":"Barnhart","year":"2010","journal-title":"Hum Reprod (Oxford, England)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1111\/j.1553-2712.1996.tb03538.x","article-title":"Statistical methodology: I. Incorporating the prevalence of disease into the sample size calculation for sensitivity and specificity","volume":"3","author":"Buderer","year":"1996","journal-title":"Acad Emerg Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"3163","DOI":"10.1093\/humrep\/dei218","article-title":"The value of a single combined measurement of VEGF, glycodelin, progesterone, PAPP-A, HPL and LIF for differentiating between ectopic and abnormal intrauterine pregnancy","volume":"20","author":"Daponte","year":"2005","journal-title":"Hum Reprod"},{"key":"B21","doi-asserted-by":"publisher","first-page":"91","DOI":"10.4103\/abr.abr_344_21","article-title":"Evaluation of the relationship between pregnancy-associated plasma protein A (PAPP-A) and pregnancy outcomes","volume":"12","author":"Movahedi","year":"2023","journal-title":"Adv Biomed Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"176","DOI":"10.5114\/fn.2024.140447","article-title":"The early predictive value of maternal serum PAPP-A concentration at 11\u201314 weeks of pregnancy for preeclampsia","volume":"63","author":"Wang","year":"2024","journal-title":"Folia Neuropathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1590\/1806-9282.20221238","article-title":"Comment on \u201cSerum vascular endothelial growth factor as a marker for tubal pregnancy\u201d","volume":"69","author":"Li","year":"2023","journal-title":"Rev Assoc Med Bras (1992)"}],"container-title":["Frontiers in Reproductive Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/frph.2026.1891223\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:56:39Z","timestamp":1784699799000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/frph.2026.1891223\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":23,"alternative-id":["10.3389\/frph.2026.1891223"],"URL":"https:\/\/doi.org\/10.3389\/frph.2026.1891223","relation":{},"ISSN":["2673-3153"],"issn-type":[{"value":"2673-3153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]},"article-number":"1891223"}}