{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T09:34:23Z","timestamp":1774604063566,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Center of Postgraduate Medical Education","award":["To be determined"],"award-info":[{"award-number":["To be determined"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Multiple gestation is one of the key risk factors for the occurrence of preeclampsia (PE). Soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin are molecules involved in the process of angiogenesis with a proven role in the pathogenesis of PE. The aim of the review was to summarize available data on maternal serum levels of the above-mentioned factors and their usefulness in predicting PE in twin pregnancies. Only original research articles written in English were considered eligible. Reviews, chapters, case studies, conference papers, experts\u2019 opinions, editorials, and letters were excluded from the analysis. No publication date limitations were imposed. The systematic literature search using PubMed\/MEDLINE, Scopus, Embase, and Cochrane Library databases identified 338 articles, 10 of which were included in the final qualitative analyses. The included studies showed significant differences in maternal serum levels of the discussed factors between women with twin pregnancies with PE and those who did not develop PE, and their promising performance in predicting PE, alone or in combination with other factors. The identification of the most effective algorithms, their prompt introduction to the clinical practice, and further assessment of the real-life performance should become a priority.<\/jats:p>","DOI":"10.3390\/jcm9010183","type":"journal-article","created":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T04:06:51Z","timestamp":1578629211000},"page":"183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Maternal Serum Placental Growth Factor, Soluble Fms-Like Tyrosine Kinase-1, and Soluble Endoglin in Twin Gestations and the Risk of Preeclampsia\u2014A Systematic Review"],"prefix":"10.3390","volume":"9","author":[{"given":"Katarzyna","family":"Kosinska-Kaczynska","sequence":"first","affiliation":[{"name":"Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, 01-809 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Zgliczynska","sequence":"additional","affiliation":[{"name":"Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, 01-809 Warsaw, Poland"},{"name":"Chair and Department of Experimental and Clinical Physiology, Laboratory of the Centre for Preclinical Research, Medical University of Warsaw, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szymon","family":"Kozlowski","sequence":"additional","affiliation":[{"name":"University Center for Woman and Newborn Health of the Medical University of Warsaw, 02-015 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukasz","family":"Wicherek","sequence":"additional","affiliation":[{"name":"Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, 01-809 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1161\/HYPERTENSIONAHA.117.10803","article-title":"Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice","volume":"72","author":"Brown","year":"2018","journal-title":"Hypertension"},{"key":"ref_2","unstructured":"(2019). ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet. Gynecol., 133, e1\u2013e25."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejogrb.2013.05.005","article-title":"Global and Regional Estimates of Preeclampsia and Eclampsia: A Systematic Review","volume":"170","author":"Abalos","year":"2013","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1053\/j.semperi.2009.02.010","article-title":"The Global Impact of Pre-Eclampsia and Eclampsia","volume":"33","author":"Duley","year":"2009","journal-title":"Semin. Perinatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1053\/j.semperi.2011.09.011","article-title":"Maternal Mortality from Preeclampsia\/Eclampsia","volume":"36","author":"Ghulmiyyah","year":"2012","journal-title":"Semin. Perinatol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Laine, K., Murzakanova, G., Sole, K.B., Pay, A.D., Heradstveit, S., and Raisanen, S. (2019). Prevalence and Risk of Pre-Eclampsia and Gestational Hypertension in Twin Pregnancies: A Population-Based Register Study. BMJ Open, 9.","DOI":"10.1136\/bmjopen-2019-029908"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1017\/thg.2016.17","article-title":"Twin Chorionicity and the Risk of Hypertensive Disorders: Gestational Hypertension and Pre-eclampsia","volume":"19","author":"Bartnik","year":"2016","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.3109\/14767058.2013.847414","article-title":"Risk of Preeclampsia: Comparison between Dichorionic and Monochorionic Twin Pregnancies","volume":"27","author":"Sarno","year":"2014","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.3109\/14767058.2013.777701","article-title":"Does Risk of Preeclampsia Differ by Twin Chorionicity?","volume":"26","author":"Sparks","year":"2013","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0020-7292(03)00314-X","article-title":"Maternal Complications of Twin Pregnancy","volume":"84","author":"Campbell","year":"2004","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3109\/10641959909016193","article-title":"Preeclampsia in Twin Pregnancies: Incidence and Outcome","volume":"18","author":"Campbell","year":"1999","journal-title":"Hypertens Pregnancy"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1046\/j.0960-7692.2001.00470.x","article-title":"Twin Chorionicity and Pre-Eclampsia","volume":"18","author":"Savvidou","year":"2001","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1016\/j.ajog.2005.04.007","article-title":"Persistance of Adverse Obstetric and Neonatal Outcomes in Monochorionic Twins after Exclusion of Disorders Unique to Monochorionic Placentation","volume":"193","author":"Leduc","year":"2005","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"390.e391","DOI":"10.1016\/j.ajog.2015.05.027","article-title":"The Impact of Chorionicity on Maternal Pregnancy Outcomes","volume":"213","author":"Carter","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S115","DOI":"10.1016\/j.ajog.2015.08.042","article-title":"Why is Placentation Abnormal in Preeclampsia?","volume":"213","author":"Fisher","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1042\/CS20150702","article-title":"The Role of Inflammation in the Pathology of Preeclampsia","volume":"130","author":"Harmon","year":"2016","journal-title":"Clin. Sci. (Lond)"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ajog.2010.08.009","article-title":"The Great Obstetrical Syndromes are Associated with Disorders of Deep Placentation","volume":"204","author":"Brosens","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/j.placenta.2008.11.003","article-title":"Placental Endoplasmic Reticulum Stress and Oxidative Stress in the Pathophysiology of Unexplained Intrauterine Growth Restriction and Early Onset Preeclampsia","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nrneph.2014.102","article-title":"Pre-Eclampsia Part 1: Current Understanding of its Pathophysiology","volume":"10","author":"Chaiworapongsa","year":"2014","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_20","unstructured":"Bennett, P., and Williamson, C. (2010). Chapter Ten-Physiology. Basic Science in Obstetrics and Gynaecology, Churchill Livingstone. [4th ed]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1172\/JCI70431","article-title":"Preeclampsia: A Link between Trophoblast Dysregulation and an Antiangiogenic State","volume":"123","author":"Romero","year":"2013","journal-title":"J. Clin. Invest."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41581-019-0119-6","article-title":"Pre-Eclampsia: Pathogenesis, Novel Diagnostics and Therapies","volume":"15","author":"Phipps","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.preghy.2018.04.010","article-title":"Predictive Value of sFlt-1, PlGF, sFlt-1\/PlGF ratio and PAPP-A for Late-Onset Preeclampsia and IUGR between 32 and 37 Weeks of Pregnancy","volume":"12","author":"Birdir","year":"2018","journal-title":"Pregnancy Hypertens."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI17189","article-title":"Excess Placental Soluble Fms-Like Tyrosine Kinase 1 (sFlt1) May Contribute to Endothelial Dysfunction, Hypertension, and Proteinuria in Preeclampsia","volume":"111","author":"Maynard","year":"2003","journal-title":"J. Clin. Invest"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1056\/NEJMoa055352","article-title":"Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia","volume":"355","author":"Levine","year":"2006","journal-title":"N Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa1414838","article-title":"Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia","volume":"374","author":"Zeisler","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1161\/HYPERTENSIONAHA.117.10182","article-title":"Meta-Analysis and Systematic Review to Assess the Role of Soluble FMS-Like Tyrosine Kinase-1 and Placenta Growth Factor Ratio in Prediction of Preeclampsia: The SaPPPhirE Study","volume":"71","author":"Agrawal","year":"2018","journal-title":"Hypertension"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nm1429","article-title":"Soluble Endoglin Contributes to the Pathogenesis of Preeclampsia","volume":"12","author":"Venkatesha","year":"2006","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1080\/14767050701830480","article-title":"A Longitudinal Study of Angiogenic (Placental Growth Factor) and Anti-Angiogenic (Soluble Endoglin and Soluble Vascular Endothelial Growth Factor Receptor-1) Factors in Normal Pregnancy and Patients Destined to Develop Preeclampsia and Deliver a Small for Gestational Age Neonate","volume":"21","author":"Romero","year":"2008","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1161\/HYPERTENSIONAHA.119.13348","article-title":"Soluble Endoglin As a Marker for Preeclampsia, Its Severity, and the Occurrence of Adverse Outcomes","volume":"74","year":"2019","journal-title":"Hypertension"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., Gotzsche, P.C., Ioannidis, J.P., Clarke, M., Devereaux, P.J., Kleijnen, J., and Moher, D. (2009). The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies that Evaluate Health Care Interventions: Explanation and Elaboration. PLoS Med., 6.","DOI":"10.2427\/5768"},{"key":"ref_32","unstructured":"Wells, G.A., Shea, B., O\u2032Connell, D., Peterson, J., Welch, V., Losos, M., and Tugwell, P. (2019, November 15). The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Available online: http:\/\/www.ohri.ca\/programs\/clinical_epidemiology\/oxford.asp."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Powers, R.W., Jeyabalan, A., Clifton, R.G., Van Dorsten, P., Hauth, J.C., Klebanoff, M.A., Lindheimer, M.D., Sibai, B., Landon, M., and Miodovnik, M. (2010). Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PlGF) in Preeclampsia among High Risk Pregnancies. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013263"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1056\/NEJM199803123381101","article-title":"Low-Dose Aspirin to Prevent Preeclampsia in Women at High Risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units","volume":"338","author":"Caritis","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1161\/HYPERTENSIONAHA.112.195065","article-title":"Circulating Angiogenic Factors and Risk of Adverse Maternal and Perinatal Outcomes in Twin Pregnancies with Suspected Preeclampsia","volume":"60","author":"Rana","year":"2012","journal-title":"Hypertension"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1161\/CIRCULATIONAHA.111.054361","article-title":"Angiogenic Factors and the Risk of Adverse Outcomes in Women with Suspected Preeclampsia","volume":"125","author":"Rana","year":"2012","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/humrep\/der394","article-title":"First Trimester Serum Angiogenic\/Anti-Angiogenic Status in Twin Pregnancies: Relationship with Assisted Reproduction Technology","volume":"27","author":"Llurba","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_38","first-page":"607","article-title":"Risks for Preeclampsia and Small for Gestational Age: Predictive Values of Placental Growth Factor, Soluble Fms-Like Tyrosine Kinase-1, and Inhibin a in Singleton and Multiple-Gestation Pregnancies","volume":"30","author":"Boucoiran","year":"2013","journal-title":"Am. J. Perinatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"239.e1","DOI":"10.1016\/j.ajog.2010.01.050","article-title":"An International Trial of Antioxidants in the Prevention of Preeclampsia (INTAPP)","volume":"202","author":"Xu","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"512.e1","DOI":"10.1016\/j.ajog.2014.04.027","article-title":"Preeclampsia in High Risk Women is Characterized by Risk Group-Specific Abnormalities in Serum Biomarkers","volume":"211","author":"Metz","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/uog.14760","article-title":"Maternal Serum sFlt-1\/PlGF Ratio in Twin Pregnancies with and without Pre-Eclampsia in Comparison with Singleton Pregnancies","volume":"45","author":"Herraiz","year":"2015","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1161\/HYPERTENSIONAHA.113.01787","article-title":"New Gestational Phase-Specific Cutoff Values for the Use of the Soluble Fms-Like Tyrosine Kinase-1\/Placental Growth Factor Ratio as a Diagnostic Test for Preeclampsia","volume":"63","author":"Verlohren","year":"2014","journal-title":"Hypertension"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"161.e1","DOI":"10.1016\/j.ajog.2009.09.016","article-title":"An Automated Method for the Determination of the sFlt-1\/PIGF Ratio in the Assessment of Preeclampsia","volume":"202","author":"Verlohren","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1002\/uog.14873","article-title":"First-and Second-Trimester Maternal Serum Markers of Pre-Eclampsia in Twin Pregnancy","volume":"47","author":"Svirsky","year":"2016","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1080\/10641955.2016.1242605","article-title":"Developing a New Algorithm for First and Second Trimester Preeclampsia Screening in Twin Pregnancies","volume":"36","author":"Maymon","year":"2017","journal-title":"Hypertens. Pregnancy"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/uog.17531","article-title":"Competing-Risks Model in Screening for Pre-Eclampsia in Twin Pregnancy according to Maternal Factors and Biomarkers at 11\u201313 Weeks\u2019 Gestation","volume":"50","author":"Francisco","year":"2017","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.preghy.2018.03.014","article-title":"The Predictive Value of the sFlt-1\/PlGF Ratio on Short-Term Absence of Preeclampsia and Maternal and Fetal or Neonatal Complications in Twin Pregnancies","volume":"14","author":"Saleh","year":"2018","journal-title":"Pregnancy Hypertens."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1161\/HYPERTENSIONAHA.117.09913","article-title":"Angiogenic Markers Predict Pregnancy Complications and Prolongation in Preeclampsia: Continuous Versus Cutoff Values","volume":"70","author":"Saleh","year":"2017","journal-title":"Hypertension"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"200.e1","DOI":"10.1016\/j.ajog.2007.08.042","article-title":"Circulating Angiogenic Factors in Singleton vs Multiple-Gestation Pregnancies","volume":"198","author":"Maynard","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"428.e421","DOI":"10.1016\/j.ajog.2007.10.783","article-title":"Twin Pregnancy and the Risk of Preeclampsia: Bigger Placenta or Relative Ischemia?","volume":"198","author":"Bdolah","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"636.e1","DOI":"10.1016\/j.ajog.2014.11.035","article-title":"Maternal Circulating Angiogenic Factors in Twin and Singleton Pregnancies","volume":"212","author":"McElrath","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1002\/pd.4243","article-title":"First Trimester Maternal Serum Placental Growth Factor Levels in Twin Pregnancies","volume":"33","author":"Cowans","year":"2013","journal-title":"Prenat. Diagn."},{"key":"ref_53","unstructured":"The Fetal Medicine Foundation (2019, November 15). Risk for preeclampsia 11+0 to 14+1 weeks. Available online: https:\/\/fetalmedicine.org\/research\/assess\/preeclampsia\/first-trimester."},{"key":"ref_54","unstructured":"The Fetal Medicine Foundation (2019, November 15). Risk for preeclampsia 19+0 to 24+6 weeks. Available online: https:\/\/fetalmedicine.org\/research\/assess\/preeclampsia\/second-trimester."},{"key":"ref_55","unstructured":"The Fetal Medicine Foundation (2019, November 15). Risk for preeclampsia 30+0 to 37+6 weeks. Available online: https:\/\/fetalmedicine.org\/research\/assess\/preeclampsia\/third-trimester."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1159\/000477903","article-title":"Spanish Group for the Study of Angiogenic Markers in, P. Update on the Diagnosis and Prognosis of Preeclampsia with the Aid of the sFlt-1\/ PlGF Ratio in Singleton Pregnancies","volume":"43","author":"Herraiz","year":"2018","journal-title":"Fetal Diagn. Ther."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/1\/183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:04:22Z","timestamp":1760364262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/1\/183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,9]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["jcm9010183"],"URL":"https:\/\/doi.org\/10.3390\/jcm9010183","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,9]]}}}