{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T21:25:39Z","timestamp":1785533139682,"version":"3.56.0"},"reference-count":32,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Consejer\u00eda de Salud, Junta de Andaluc\u00eda","award":["PI-0456-2018"],"award-info":[{"award-number":["PI-0456-2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To assess the association between known (PlGF, sFlt-1, betaHCG, PAPPA) and novel (cell-free DNA, cfDNA, and total endothelial and platelet microvesicles, MVs) maternal blood biomarkers measured at the first trimester with the later development of preeclampsia (PE) and PE-related severe adverse events (SAE), we conducted a retrospective case\u2013control study including women with an established diagnosis of preeclampsia (cases) and healthy pregnant women (controls). Biomarkers were measured from first-trimester blood samples stored in a hospital biobank. A total of 89 women, 54 women with PE and 35 controls were included. PlGF showed good performance for diagnosing overall preeclampsia (AUC: 0.71; 95% CI 0.59\u20130.82), early-onset preeclampsia (AUC 0.80; 95% CI 0.68\u20130.9) and fetal-neonatal SAEs (AUC: 0.73; 95% CI 0.63\u20130.84). Multivariate models including clinical variables, PlGF and other biomarkers showed good to very good discrimination for the development of PE, early-onset PE and fetal-neonatal SAEs (AUCs of 0.87, 0.89 and 0.79, respectively). Platelet-derived MVs were the best isolated biomarker for late-onset PE and, combined with systolic blood pressure, showed good discrimination (AUC: 0.81; 95% CI 0.71\u20130.92). For maternal SAEs, a model incorporating cfDNA and sFlt-1 provided excellent discrimination (AUC 0.92; 95% CI 0.82\u20131.00). Our findings suggest that multivariate models incorporating both clinical variables and first-trimester biomarkers may improve risk stratification for PE, especially for late-onset PE and for identifying women at risk of severe maternal or fetal complications. Notably, the inclusion of novel biomarkers such as cfDNA and MVs added value in clinical scenarios where the predictive performance of existing tools remains suboptimal.<\/jats:p>","DOI":"10.3390\/ijms26146684","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T14:22:36Z","timestamp":1752243756000},"page":"6684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Association of First-Trimester Maternal Biomarkers with Preeclampsia and Related Maternal and Fetal Severe Adverse Events"],"prefix":"10.3390","volume":"26","author":[{"given":"Ana","family":"Camacho-Carrasco","sequence":"first","affiliation":[{"name":"Internal Medicine, Infanta Elena Hospital, 21080 Huelva, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Montenegro-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Virgen del Roc\u00edo University Hospital, 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Miranda-Guisado","sequence":"additional","affiliation":[{"name":"Internal Medicine, Virgen del Roc\u00edo University Hospital, 41013 Seville, Spain"},{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3765-6276","authenticated-orcid":false,"given":"Roc\u00edo","family":"Mu\u00f1oz-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Investigaci\u00f3n Cl\u00ednica y Traslacional en Enfermedades Hep\u00e1ticas y Digestivas\u2013SeLiver, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Sevilla, Spain"},{"name":"Departamento de Fisiolog\u00eda, Facultad de Biolog\u00eda, Universidad de Sevilla, 41012 Sevilla, Spain"},{"name":"CIBEREHD, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8218-1882","authenticated-orcid":false,"given":"Roc\u00edo","family":"Salsoso","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5883-7936","authenticated-orcid":false,"given":"Daniel","family":"Fatela-Cantillo","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Virgen del Roc\u00edo University Hospital, 41013 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutgardo","family":"Garc\u00eda-D\u00edaz","sequence":"additional","affiliation":[{"name":"Unidad de Medicina Maternofetal, Gen\u00e9tica y Reproducci\u00f3n, Hospital Universitario Virgen del Roc\u00edo, 41013 Sevilla, Spain"},{"name":"Departamento de Cirug\u00eda, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Stiefel Garc\u00eda-Junco","sequence":"additional","affiliation":[{"name":"Internal Medicine, Virgen del Roc\u00edo University Hospital, 41013 Seville, Spain"},{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2719-8825","authenticated-orcid":false,"given":"Alfonso","family":"Mate","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2999-3582","authenticated-orcid":false,"given":"Carmen M.","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Departamento de Fisiolog\u00eda, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Alfaro-Lara","sequence":"additional","affiliation":[{"name":"Internal Medicine, Virgen del Roc\u00edo University Hospital, 41013 Seville, Spain"},{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7954-1253","authenticated-orcid":false,"given":"Antonio J.","family":"Vallejo-Vaz","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red (CIBER) de Epidemiolog\u00eda y Salud P\u00fablica, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8048-9106","authenticated-orcid":false,"given":"Luis M.","family":"Beltr\u00e1n-Romero","sequence":"additional","affiliation":[{"name":"Internal Medicine, Virgen del Roc\u00edo University Hospital, 41013 Seville, Spain"},{"name":"Clinical Epidemiology and Vascular Risk, Instituto de Biomedicina de Sevilla, IBiS\/Hospital Universitario Virgen del Roc\u00edo\/CSIC\/Universidad de Sevilla, 41013 Seville, Spain"},{"name":"Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, 41009 Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41572-023-00417-6","article-title":"Pre-Eclampsia","volume":"9","author":"Dimitriadis","year":"2023","journal-title":"Nat. Rev. Dis. Primer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S0140-6736(15)00070-7","article-title":"Pre-Eclampsia","volume":"387","author":"Mol","year":"2016","journal-title":"Lancet Lond. Engl."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e323","DOI":"10.1016\/S2214-109X(14)70227-X","article-title":"Global Causes of Maternal Death: A WHO Systematic Analysis","volume":"2","author":"Say","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1002\/ijgo.12802","article-title":"The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Preeclampsia (PE): A Pragmatic Guide for First Trimester Screening and Prevention","volume":"145","author":"Poon","year":"2019","journal-title":"Int. J. Gynaecol. Obstet. Off. Organ Int. Fed. Gynaecol. Obstet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.preghy.2021.09.008","article-title":"The 2021 International Society for the Study of Hypertension in Pregnancy Classification, Diagnosis & Management Recommendations for International Practice","volume":"27","author":"Magee","year":"2022","journal-title":"Pregnancy Hypertens."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1111\/1471-0528.16683","article-title":"Pre-Eclampsia and Long-Term Health Outcomes for Mother and Infant: An Umbrella Review","volume":"128","author":"Pittara","year":"2021","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S1102","DOI":"10.1016\/j.ajog.2020.10.047","article-title":"The Prediction of Preeclampsia: The Way Forward","volume":"226","author":"Myatt","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"MacDonald, T.M., Walker, S.P., Hannan, N.J., Tong, S., and Kaitu\u2019u-Lino, T.J. (2022). Clinical Tools and Biomarkers to Predict Preeclampsia. EBioMedicine, 75.","DOI":"10.1016\/j.ebiom.2021.103780"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1161\/HYPERTENSIONAHA.120.14781","article-title":"Subtypes of Preeclampsia: Recognition and Determining Clinical Usefulness","volume":"77","author":"Roberts","year":"2021","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2013.08.019","article-title":"Incidence of Preeclampsia: Risk Factors and Outcomes Associated with Early- versus Late-Onset Disease","volume":"209","author":"Lisonkova","year":"2013","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S954","DOI":"10.1016\/j.ajog.2020.10.024","article-title":"The Placenta and Preeclampsia: Villain or Victim?","volume":"226","author":"Melchiorre","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S1071","DOI":"10.1016\/j.ajog.2020.07.020","article-title":"First Trimester Preeclampsia Screening and Prediction","volume":"226","author":"Chaemsaithong","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.preghy.2019.09.004","article-title":"Prediction of Adverse Maternal Outcomes in Preeclampsia at Term","volume":"18","author":"Paul","year":"2019","journal-title":"Pregnancy Hypertens."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Cristodoro, M., Messa, M., Tossetta, G., Marzioni, D., Dell\u2019Avanzo, M., Inversetti, A., and Di Simone, N. (2024). First Trimester Placental Biomarkers for Pregnancy Outcomes. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116136"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1093\/ajh\/hpt187","article-title":"Role of Circulating Cell-Free DNA Levels in Patients with Severe Preeclampsia and HELLP Syndrome","volume":"26","author":"Miranda","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s40291-016-0245-9","article-title":"Cell-Free Fetal DNA for the Prediction of Pre-Eclampsia at the First and Second Trimesters: A Systematic Review and Meta-Analysis","volume":"21","author":"Contro","year":"2017","journal-title":"Mol. Diagn. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1177\/0300060513504362","article-title":"Evaluation of Plasma Endothelial Microparticles in Pre-Eclampsia","volume":"42","author":"Ling","year":"2014","journal-title":"J. Int. Med. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"McElrath, T.F., Cantonwine, D.E., Gray, K.J., Mirzakhani, H., Doss, R.C., Khaja, N., Khalid, M., Page, G., Brohman, B., and Zhang, Z. (2020). Late First Trimester Circulating Microparticle Proteins Predict the Risk of Preeclampsia < 35 Weeks and Suggest Phenotypic Differences among Affected Cases. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-74078-w"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1111\/aogs.13051","article-title":"Prediction of Progression to Severe Disease in Women with Late Preterm Hypertensive Disorders of Pregnancy","volume":"96","author":"Zwertbroek","year":"2017","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1161\/HYPERTENSIONAHA.117.10318","article-title":"Assessment of the fullPIERS Risk Prediction Model in Women with Early-Onset Preeclampsia","volume":"71","author":"Ukah","year":"2018","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1161\/HYPERTENSIONAHA.119.12760","article-title":"Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble Fms-Like Tyrosine Kinase 1)\/PlGF (Placental Growth Factor) Ratio in Asian Women with Suspected Preeclampsia","volume":"74","author":"Bian","year":"2019","journal-title":"Hypertension"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/uog.24851","article-title":"Role of Placental, Fetal and Maternal Cardiovascular Markers in Predicting Adverse Outcome in Women with Suspected or Confirmed Pre-Eclampsia","volume":"59","author":"Reddy","year":"2022","journal-title":"Ultrasound Obstet. Gynecol. Off. J. Int. Soc. Ultrasound Obstet. Gynecol."},{"key":"ref_23","first-page":"364","article-title":"Correlation of Serum IGF-1 and sFlt-1 Levels with Adverse Pregnancy Outcomes in Patients with Severe Preeclampsia","volume":"29","author":"Sun","year":"2023","journal-title":"Altern. Ther. Health Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/uog.20117","article-title":"Prediction of Pre-Eclampsia: Review of Reviews","volume":"54","author":"Townsend","year":"2019","journal-title":"Ultrasound Obstet. Gynecol. Off. J. Int. Soc. Ultrasound Obstet. Gynecol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"(2020). Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin Summary, Number 222. Obstet. Gynecol., 135, 1492\u20131495.","DOI":"10.1097\/AOG.0000000000003892"},{"key":"ref_26","unstructured":"(2023, October 12). Overview|Hypertension in Pregnancy: Diagnosis and Management|Guidance|NICE. Available online: https:\/\/www.nice.org.uk\/guidance\/ng133."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1002\/uog.19039","article-title":"Comparison of Diagnostic Accuracy of Early Screening for Pre-Eclampsia by NICE Guidelines and a Method Combining Maternal Factors and Biomarkers: Results of SPREE","volume":"51","author":"Tan","year":"2018","journal-title":"Ultrasound Obstet. Gynecol. Off. J. Int. Soc. Ultrasound Obstet. Gynecol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ajog.2019.11.1247","article-title":"The Competing Risk Approach for Prediction of Preeclampsia","volume":"223","author":"Wright","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Huang, X., Jia, L., Jia, Y., Xu, X., Wang, R., Wei, M., Li, H., Peng, H., Wei, Y., and He, Q. (2023). sFlt-1-Enriched Exosomes Induced Endothelial Cell Dysfunction and a Preeclampsia-like Phenotype in Mice. Cytokine, 166.","DOI":"10.1016\/j.cyto.2023.156190"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhai, Y., Liu, Y., Qi, Y., Long, X., Gao, J., Yao, X., Chen, Y., Wang, X., Lu, S., and Zhao, Z. (2020). The Soluble VEGF Receptor sFlt-1 Contributes to Endothelial Dysfunction in IgA Nephropathy. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234492"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.atherosclerosis.2022.02.026","article-title":"Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) Is Associated with Subclinical and Clinical Atherosclerotic Cardiovascular Disease: The Dallas Heart Study","volume":"346","author":"Mauricio","year":"2022","journal-title":"Atherosclerosis"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hammadah, M., Georgiopoulou, V.V., Kalogeropoulos, A.P., Weber, M., Wang, X., Samara, M.A., Wu, Y., Butler, J., and Tang, W.H.W. (2016). Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated with Development and Mortality Risk in Heart Failure. Circ. Heart Fail., 9.","DOI":"10.1161\/CIRCHEARTFAILURE.115.002115"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6684\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:08:49Z","timestamp":1760033329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,11]]},"references-count":32,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146684"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146684","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,11]]}}}