{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:13:39Z","timestamp":1783660419500,"version":"3.55.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"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. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify preconception clinical and multi-omics factors associated with conception and early pregnancy loss in women with unexplained recurrent pregnancy loss (URPL).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective cohort study, 149 women with URPL selected from 420 outpatients based on guideline-recommended criteria were enrolled between November 2024 and May 2025 and followed-up for 12 months. Preconception fasting plasma was analyzed for clinical biomarkers, untargeted metabolomics, and data-independent acquisition proteomics. Outcomes included conception, ongoing pregnancy beyond 12 weeks and early pregnancy loss before 12 weeks. Multivariable logistic regression was used to evaluate the associations of clinical and multi-omics factors with reproductive outcomes, adjusting for maternal age, body mass index, number of prior losses, and use of assisted reproductive technology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 149 women, 99 conceived (66.4%) during the follow-up. By 12 weeks of gestation, 67 (67.7%) had ongoing pregnancies and 32 (32.3%) experienced early pregnancy loss. Higher testosterone was associated with lower probability of conception (adjusted odds ratio [aOR] 0.50, 95% confidence interval [CI] 0.28\u20130.89,\n                      <jats:italic>p<\/jats:italic>\n                      =\u00a00.019). Women who conceived showed higher levels of progesterone-related metabolites, including 17-hydroxyprogesterone (fold change, FC\u00a0=\u00a03.89), pregnanediol 3-O-glucuronide (FC\u00a0=\u00a02.37), and pregnanetriol 3\u03b1-O-\u03b2-D-glucuronide (FC\u00a0=\u00a02.39). Among women who conceived, higher prolactin was associated with higher odds of early pregnancy loss (aOR 1.09, 95% CI 1.01\u20131.18,\n                      <jats:italic>p<\/jats:italic>\n                      =\u00a00.036), and anti-phosphatidylserine\/prothrombin showed a borderline association (aOR 1.07, 95% CI 1.00\u20131.14,\n                      <jats:italic>p<\/jats:italic>\n                      =\u00a00.052). Early pregnancy loss was characterized by lower bile acid-related metabolites and higher caffeine and methylxanthine metabolites. Proteomic analysis showed enrichment of bile acid biosynthetic process. After adjustment, higher 7\u03b1,12\u03b1-dihydroxy-3-oxocholest-4-en-27-oic acid was associated with lower odds of early pregnancy loss (aOR 0.64, 95% CI 0.44\u20130.95,\n                      <jats:italic>p<\/jats:italic>\n                      =\u00a00.025).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Higher testosterone was associated with lower odds of conception. Among women who conceived, early pregnancy loss was associated with higher prolactin, borderline higher anti-PS\/PT, lower bile acid-related metabolites, and higher caffeine-related metabolites, with 7\u03b1,12\u03b1-dihydroxy-3-oxocholest-4-en-27-oic acid identified as an exploratory metabolomic candidate. These findings suggest that potential androgen-related biology, prolactin, non-criteria antiphospholipid antibodies, and bile acid metabolism may be associated with reproductive outcomes in URPL, warranting validation in independent cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1875194","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:24:06Z","timestamp":1783657446000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical, metabolomic, and proteomic profiles associated with reproductive outcomes in unexplained recurrent pregnancy loss"],"prefix":"10.3389","volume":"17","author":[{"given":"Zicheng","family":"Song","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yishi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai Engineering Research Center for Big Data in Pediatric Precision Medicine; Center for Biomedical Informatics, Shanghai Children\u2019s Hospital; School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Che","sequence":"additional","affiliation":[{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Changzhou Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Changzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/s41572-020-00228-z","article-title":"Recurrent pregnancy loss","volume":"6","author":"Dimitriadis","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00682-6","article-title":"Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss","volume":"397","author":"Quenby","year":"2021","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/hropen\/hoy004","article-title":"ESHRE guideline: recurrent pregnancy loss","volume":"2018","author":"Bender Atik","year":"2018","journal-title":"Hum Reprod Open"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/hropen\/hoad002","article-title":"ESHRE guideline: recurrent pregnancy loss: an update in 2022","volume":"2023","author":"Bender Atik","year":"2023","journal-title":"Hum Reprod Open"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10040869","article-title":"Immunological risk factors in recurrent pregnancy loss: guidelines versus current state of the art","volume":"10","author":"Vomstein","year":"2021","journal-title":"J Clin Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2023-224609","article-title":"The 2023 ACR\/EULAR antiphospholipid syndrome classification criteria","volume":"75","author":"Barbhaiya","year":"2023","journal-title":"Arthritis Rheumatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2012.06.048","article-title":"Evaluation and treatment of recurrent pregnancy loss: a committee opinion","volume":"98","year":"2012","journal-title":"Fertility Sterility"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10102094","article-title":"Anti-phosphatidylserine\/prothrombin antibodies in healthy women with unexplained recurrent pregnancy loss","volume":"10","author":"Pleguezuelo","year":"2021","journal-title":"J Clin Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"Cd008883","DOI":"10.1002\/14651858.cd008883","article-title":"Dopamine agonists for preventing future miscarriage in women with idiopathic hyperprolactinemia and recurrent miscarriage history","volume":"7","author":"Chen","year":"2016","journal-title":"Cochrane Database Syst Rev"},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2020.08.1421","article-title":"Recurrent pregnancy loss: a shared stressor---couple-orientated psychological research findings","volume":"114","author":"Voss","year":"2020","journal-title":"Fertil Steril"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmz048","article-title":"Recurrent pregnancy loss: diagnostic workup after two or three pregnancy losses? 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