{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:42:54Z","timestamp":1791549774730,"version":"4.3.4"},"reference-count":123,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University\u2014Pleven","award":["P15\/2025"],"award-info":[{"award-number":["P15\/2025"]}]},{"award":["P15\/2025"],"award-info":[{"award-number":["P15\/2025"]}],"id":[{"id":"https:\/\/ror.org\/049ztct72","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pre-eclampsia and foetal growth restriction (FGR) are major pregnancy complications primarily driven by placental dysfunction, and remain leading causes of maternal and perinatal morbidity. Ultrasound imaging, Doppler studies, and angiogenic biomarkers like placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) constitute the main diagnostic modalities; however, these predominantly reflect established disease rather than early molecular disturbances underlying placentation. The identification of biomarkers directly associated with trophoblast signalling pathways has the potential to improve early risk stratification and enable mechanistic classifications. Kisspeptin signalling via its receptor (KISS1R) regulates trophoblast invasion, extracellular matrix remodelling, ERK1\/2 activation, and angiogenic balance, thereby modulating spiral artery transformation. Kisspeptin-10 (KP-10), the minimal bioactive fragment of KISS1, is highly expressed in placental syncytiotrophoblasts and exerts its effects through the G-protein-coupled receptor KISS1R. Core features of early-onset FGR and pre-eclampsia (PE)\u2014including defective placentation, maternal vascular malperfusion, and angiogenic imbalance\u2014have been linked to dysregulation of this pathway. During normal gestation, maternal circulating kisspeptin concentrations rise exponentially. In contrast, pregnancies subsequently complicated by FGR or PE, particularly in the early gestation, are associated with reduced levels. However, the comparability of existing studies and their translational applicability are limited by a substantial methodological heterogeneity, including assay variability, gestational age dependence, and inadequate adjustment for maternal confounders. These limitations hinder robust conclusions regarding the role of kisspeptin in placental pathology. This review critically integrates molecular, pathophysiological, and clinical evidence relating to the role of KP-10 in placental dysfunction. The key question is whether KP-10 represents a mechanistic biomarker of trophoblast signalling dysfunction or merely a secondary marker of reduced placental mass; resolving this distinction is essential.<\/jats:p>","DOI":"10.3390\/ijms27093748","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T10:10:17Z","timestamp":1776939017000},"page":"3748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The KISS1\/KISS1R Axis in Human Placentation: Molecular Mechanisms and Implications for Foetal Growth Restriction and Pre-Eclampsia"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-7961","authenticated-orcid":false,"given":"Elitsa","family":"Gyokova","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Medical University\u2014Pleven, 5800 Pleven, Bulgaria"},{"name":"Clinic of Obstetrics and Gynecology, University Hospital \u201cSaint Marina\u201d, 5800 Pleven, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0329-6081","authenticated-orcid":false,"given":"Eleonora","family":"Hristova-Atanasova","sequence":"additional","affiliation":[{"name":"Department of Social Medicine and Public Health, Faculty of Public Health, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3471-0566","authenticated-orcid":false,"given":"Kamelia","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University\u2014Pleven, 5800 Pleven, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"B2","DOI":"10.1016\/j.ajog.2020.05.010","article-title":"Society for Maternal-Fetal Medicine Consult Series #52: Diagnosis and management of fetal growth restriction","volume":"223","author":"Martins","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"(2021). Fetal growth restriction. Obstet. Gynecol., 137, e16\u2013e28.","DOI":"10.1097\/AOG.0000000000004251"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2505774","DOI":"10.1080\/14767058.2025.2505774","article-title":"Maternal factors and perinatal outcomes associated with early-onset versus late-onset fetal growth restriction: A meta-analysis","volume":"38","author":"Tedyanto","year":"2025","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_4","first-page":"486","article-title":"Fetal growth restriction before and after birth","volume":"104","author":"Westby","year":"2021","journal-title":"Am. Fam. Physician"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S790","DOI":"10.1016\/j.ajog.2017.12.003","article-title":"Diagnosis and surveillance of late-onset fetal growth restriction","volume":"218","author":"Figueras","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S855","DOI":"10.1016\/j.ajog.2017.12.004","article-title":"Evidence-based national guidelines for the management of suspected fetal growth restriction: Comparison, consensus, and controversy","volume":"218","author":"McCowan","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/uog.23664","article-title":"Diagnosis and management of fetal growth restriction: The ISUOG guideline and comparison with the SMFM guideline","volume":"57","author":"Lees","year":"2021","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.bpobgyn.2016.10.006","article-title":"An integrated approach to fetal growth restriction","volume":"38","author":"Figueras","year":"2016","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ajog.2021.11.1357","article-title":"The diagnosis and management of suspected fetal growth restriction: An evidence-based approach","volume":"226","author":"Lees","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0140-6736(20)32335-7","article-title":"Pre-eclampsia","volume":"398","author":"Chappell","year":"2021","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S745","DOI":"10.1016\/j.ajog.2017.11.577","article-title":"Pathophysiology of placental-derived fetal growth restriction","volume":"218","author":"Burton","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41574-020-0372-6","article-title":"Tracking placental development in health and disease","volume":"16","author":"Aplin","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.jacc.2020.08.014","article-title":"Preeclampsia\u2014Pathophysiology and clinical presentations","volume":"76","author":"Ives","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"43","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":"2008","journal-title":"Placenta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S1019","DOI":"10.1016\/j.ajog.2020.10.022","article-title":"Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders","volume":"226","author":"Rana","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1007\/s43032-020-00393-2","article-title":"Fetal Growth restriction: Does an Integrated Maternal Hemodynamic-Placental model fit better?","volume":"28","author":"Mecacci","year":"2020","journal-title":"Reprod. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1161\/HYPERTENSIONAHA.119.13763","article-title":"Combining biomarkers to predict pregnancy complications and redefine preeclampsia","volume":"75","author":"Stepan","year":"2020","journal-title":"Hypertension"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/uog.26032","article-title":"Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of pre-eclampsia and fetal growth restriction","volume":"61","author":"Stepan","year":"2022","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1093\/clinchem\/hvaf024","article-title":"Placental biomarker testing for evaluation of suspected preeclampsia","volume":"71","author":"Silasi","year":"2025","journal-title":"Clin. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/uog.29181","article-title":"Angiogenic factors alone or in combination with ultrasound Doppler criteria for risk classification among late-onset small fetuses with or without pre-eclampsia","volume":"65","author":"Youssef","year":"2025","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.placenta.2024.08.016","article-title":"Utility of placental biomarkers and fetoplacental Dopplers in predicting likely placental pathology in early and late fetal growth restriction\u2014A prospective study","volume":"156","author":"Hong","year":"2024","journal-title":"Placenta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2589630","DOI":"10.1080\/14767058.2025.2589630","article-title":"Clinical use of angiogenesis biomarkers in fetal growth restriction: A narrative review","volume":"38","author":"Galindo","year":"2025","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ajog.2023.03.032","article-title":"Accuracy of placental growth factor alone or in combination with soluble fms-like tyrosine kinase-1 or maternal factors in detecting preeclampsia in asymptomatic women in the second and third trimesters: A systematic review and meta-analysis","volume":"229","author":"Chaemsaithong","year":"2023","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tsoutsouki, J., Patel, B., Comninos, A.N., Dhillo, W.S., and Abbara, A. (2022). Kisspeptin in the prediction of pregnancy complications. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.942664"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ejogrb.2019.07.016","article-title":"Kisspeptin as a potential biomarker throughout pregnancy","volume":"240","author":"Hu","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1210\/clinem\/dgab617","article-title":"Changes in circulating kisspeptin levels during each trimester in women with antenatal complications","volume":"107","author":"Abbara","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E2652","DOI":"10.1210\/jc.2014-1953","article-title":"Reduced levels of plasma kisspeptin during the antenatal booking visit are associated with increased risk of miscarriage","volume":"99","author":"Jayasena","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.placenta.2023.07.012","article-title":"Relationship between kisspeptin levels in the third trimester and late-onset fetal growth restriction: A case-control study","volume":"140","author":"Ibanoglu","year":"2023","journal-title":"Placenta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1093\/humupd\/dmy046","article-title":"Potential roles for the kisspeptin\/kisspeptin receptor system in implantation and placentation","volume":"25","author":"Hu","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1055\/s-0039-3400966","article-title":"Regulation of Pregnancy: Evidence for major roles by the uterine and placental Kisspeptin\/KISS1R signaling systems","volume":"37","author":"Radovick","year":"2019","journal-title":"Semin. Reprod. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A Scale for the Quality Assessment of Narrative Review Articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"RD23230","DOI":"10.1071\/RD23230","article-title":"The role of placental kisspeptin in trophoblast invasion and migration: An assessment in Kiss1r knockout mice, BeWo cell lines and human term placenta","volume":"36","author":"Panting","year":"2024","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e250001","DOI":"10.1530\/JME-25-0001","article-title":"Kisspeptin isoforms: Versatile players in reproduction and beyond","volume":"75","author":"Chakraborty","year":"2025","journal-title":"J. Mol. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1038\/sj.bjp.0707295","article-title":"Kisspeptins: A multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system","volume":"151","author":"Mead","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1530\/JOE-12-0091","article-title":"Altered placental expression of kisspeptin and its receptor in pre-eclampsia","volume":"214","author":"Cartwright","year":"2012","journal-title":"J. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5927","DOI":"10.1210\/en.2010-0565","article-title":"Kisspeptin-10 Inhibits Angiogenesis in Human Placental Vessels ex Vivo and Endothelial Cells in Vitro","volume":"151","author":"Ramaesh","year":"2010","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.placenta.2024.05.138","article-title":"Kisspeptin signalling and its correlation with placental ultrastructure and clinical outcomes in pregnant South African women with obesity and gestational diabetes","volume":"154","author":"Musa","year":"2024","journal-title":"Placenta"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Francis, V.A., Abera, A.B., Matjila, M., Millar, R.P., and Katz, A.A. (2014). Kisspeptin regulation of genes involved in cell invasion and angiogenesis in first trimester human trophoblast cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099680"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1242\/jcs.00971","article-title":"Kisspeptin-10, a KiSS-1\/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts","volume":"117","author":"Bilban","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Qiao, C., Wang, C., Zhao, J., Liu, C., and Shang, T. (2012). Elevated Expression of KiSS-1 in Placenta of Chinese Women with Early-Onset Preeclampsia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048937"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e70120","DOI":"10.1111\/jne.70120","article-title":"Kisspeptin and early pregnancy: Insights from animal models into hormonal regulation and miscarriage","volume":"38","author":"Decourt","year":"2025","journal-title":"J. Neuroendocr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/mrd.22279","article-title":"Kisspeptin\/KISS1R signaling potentiates extravillous trophoblast adhesion to type-I collagen in a PKC- and ERK1\/2-dependent manner","volume":"81","author":"Taylor","year":"2013","journal-title":"Mol. Reprod. Dev."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Szyde\u0142ko-Gorzkowicz, M., Poniedzia\u0142ek-Czajkowska, E., Mierzy\u0144ski, R., Sotowski, M., and Leszczy\u0144ska-Gorzelak, B. (2022). The Role of Kisspeptin in the Pathogenesis of Pregnancy Complications: A Narrative Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126611"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5875","DOI":"10.1210\/en.2012-1747","article-title":"Single-Cell Analyses Reveal That KISS1R-Expressing Cells Undergo Sustained Kisspeptin-Induced Signaling That Is Dependent upon An Influx of Extracellular Ca2+","volume":"153","author":"Babwah","year":"2012","journal-title":"Endocrinology"},{"key":"ref_45","first-page":"10","article-title":"Intracellular signaling pathways activated by kisspeptins through GPR54: Do multiple signals underlie function diversity?","volume":"30","author":"Vaudry","year":"2008","journal-title":"Peptides"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.placenta.2012.02.001","article-title":"Kisspeptin-10 inhibits cell migration in vitro via a receptor-GSK3 beta-FAK feedback loop in HTR8SVneo cells","volume":"33","author":"Roseweir","year":"2012","journal-title":"Placenta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12958-022-00902-9","article-title":"TGF-\u03b21 inhibits human trophoblast cell invasion by upregulating kisspeptin expression through ERK1\/2 but not SMAD signaling pathway","volume":"20","author":"Fang","year":"2022","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Matjila, M., Millar, R., Van Der Spuy, Z., and Katz, A. (2013). The Differential Expression of Kiss1, MMP9 and Angiogenic Regulators across the Feto-Maternal Interface of Healthy Human Pregnancies: Implications for Trophoblast Invasion and Vessel Development. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063574"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1093\/advances\/nmab070","article-title":"Placental Angiogenesis in Mammals: A Review of the Regulatory Effects of Signaling Pathways and Functional Nutrients","volume":"12","author":"Huang","year":"2021","journal-title":"Adv. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1210\/jc.2002-020195","article-title":"Human Placental Vascular Development: Vasculogenic and Angiogenic (Branching and Nonbranching) Transformation Is Regulated by Vascular Endothelial Growth Factor-A, Angiopoietin-1, and Angiopoietin-2","volume":"87","author":"Geva","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1530\/REP-09-0092","article-title":"Regulation of vascular growth and function in the human placenta","volume":"138","author":"Burton","year":"2009","journal-title":"Reproduction"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/S0301-2115(03)00168-4","article-title":"Angiogenesis and vasculogenesis in pregnancy","volume":"110","author":"Zygmunt","year":"2003","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.placenta.2003.10.009","article-title":"Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy","volume":"25","author":"Kaufmann","year":"2003","journal-title":"Placenta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s10456-019-09694-w","article-title":"Reconciling the distinct roles of angiogenic\/anti-angiogenic factors in the placenta and maternal circulation of normal and pathological pregnancies","volume":"23","author":"Umapathy","year":"2019","journal-title":"Angiogenesis"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1042\/CS20171252","article-title":"Regulation of human feto-placental endothelial barrier integrity by vascular endothelial growth factors: Competitive interplay between VEGF-A165a, VEGF-A165b, PIGF and VE-cadherin","volume":"131","author":"Pang","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1530\/rep.0.1260569","article-title":"Angiogenesis during primate placentation in health and disease","volume":"126","author":"Wulff","year":"2003","journal-title":"Reproduction"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Alfaidy, N., Brouillet, S., Rajaraman, G., Kalionis, B., Hoffmann, P., Barjat, T., Benharouga, M., and Murthi, P. (2020). The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.591850"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1095\/biolreprod64.4.1033","article-title":"Angiogenesis in the Placenta1","volume":"64","author":"Reynolds","year":"2001","journal-title":"Biol. Reprod."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1530\/JOE-11-0296","article-title":"Signaling regulation of fetoplacental angiogenesis","volume":"212","author":"Wang","year":"2011","journal-title":"J. Endocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Esposito, M., Paulesu, L., and Mandal\u00e0, M. (2025). The role of placental hormones and metabolites in modulating uterine circulation in physiological and pathological pregnancies. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1637570"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1210\/endrev\/bnaf039","article-title":"Placental Steroid Hormones in Preeclampsia: Multilayered Regulation of Endocrine Pathogenesis","volume":"47","author":"Yang","year":"2025","journal-title":"Endocr. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Chiang, Y.-T., Seow, K.-M., and Chen, K.-H. (2024). The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084532"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S928","DOI":"10.1016\/j.ajog.2020.11.005","article-title":"Placental energy metabolism in health and disease\u2014Significance of development and implications for preeclampsia","volume":"226","author":"Aye","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1111\/febs.15745","article-title":"Revisiting preeclampsia: A metabolic disorder of the placenta","volume":"289","author":"Hu","year":"2021","journal-title":"FEBS J."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"De Knegt, V.E., Hedley, P.L., Kanters, J.K., Thagaard, I.N., Krebs, L., Christiansen, M., and Lausten-Thomsen, U. (2021). The Role of Leptin in Fetal Growth during Pre-Eclampsia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094569"},{"key":"ref_66","first-page":"263","article-title":"Regulation of Placental Growth by Aldosterone and Cortisol","volume":"152","author":"Khankin","year":"2010","journal-title":"Endocrinology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ajog.2005.07.049","article-title":"Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia","volume":"195","author":"Ness","year":"2006","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"S963","DOI":"10.1016\/j.ajog.2020.10.023","article-title":"An integrated model of preeclampsia: A multifaceted syndrome of the maternal cardiovascular-placental-fetal array","volume":"226","author":"Yagel","year":"2021","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.placenta.2013.04.012","article-title":"Kiss1 and Kiss1r mRNA expression in the rat placenta: Changes with gestational age and regulation by glucocorticoids","volume":"34","author":"Mark","year":"2013","journal-title":"Placenta"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.devcel.2021.04.001","article-title":"Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease","volume":"56","author":"Zhang","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1007\/s12015-024-10699-2","article-title":"Deciphering the epigenetic landscape: Placental development and its role in pregnancy outcomes","volume":"20","author":"Chen","year":"2024","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"S182","DOI":"10.1016\/j.ajog.2015.07.011","article-title":"Epigenetic regulation of human placental function and pregnancy outcome: Considerations for causal inference","volume":"213","author":"Januar","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.ijdevneu.2013.03.006","article-title":"Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene","volume":"31","author":"Semaan","year":"2013","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00404-019-05408-1","article-title":"Placental protein expression of kisspeptin-1 (KISS1) and the kisspeptin-1 receptor (KISS1R) in pregnancy complicated by diabetes mellitus or preeclampsia","volume":"301","author":"Kapustin","year":"2019","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kariori, M., Katsi, V., and Tsioufis, C. (2025). Late vs. Early Preeclampsia. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262211091"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1111\/aogs.13699","article-title":"Pathologic placental lesions in early and late fetal growth restriction","volume":"98","author":"Spinillo","year":"2019","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1159\/000359969","article-title":"Placental Pathology in Early-Onset and Late-Onset Fetal Growth Restriction","volume":"36","author":"Mifsud","year":"2014","journal-title":"Fetal Diagn. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"S176","DOI":"10.1016\/j.ajog.2025.01.041","article-title":"Placenta at single-cell resolution in early and late preeclampsia: Insights and clinical implications","volume":"232","author":"Solt","year":"2025","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"l2381","DOI":"10.1136\/bmj.l2381","article-title":"Pre-eclampsia: Pathophysiology and clinical implications","volume":"366","author":"Burton","year":"2019","journal-title":"BMJ"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMra2109523","article-title":"Preeclampsia","volume":"386","author":"Magee","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s43032-023-01330-9","article-title":"Early Fetal Growth Restriction with or Without Hypertensive Disorders: A Clinical Overview","volume":"31","author":"Mecacci","year":"2023","journal-title":"Reprod. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"S803","DOI":"10.1016\/j.ajog.2017.11.575","article-title":"A placenta clinic approach to the diagnosis and management of fetal growth restriction","volume":"218","author":"Kingdom","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7276","DOI":"10.1080\/14767058.2021.1946786","article-title":"Doppler abnormalities and perinatal outcomes in pregnant women with early-onset fetal growth restriction","volume":"35","author":"Muniz","year":"2021","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_84","unstructured":"ACOG (2026, January 07). Fetal Growth Restriction. Available online: https:\/\/www.acog.org\/clinical\/clinical-guidance\/practice-bulletin\/articles\/2021\/02\/fetal-growth-restriction."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.ajog.2012.01.022","article-title":"Doppler assessment of the fetus with intrauterine growth restriction","volume":"206","author":"Berkley","year":"2012","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Tay, J., Masini, G., McEniery, C.M., Giussani, D.A., Shaw, C.J., Wilkinson, I.B., Bennett, P.R., and Lees, C.C. (2018). Uterine and fetal placental Doppler indices are associated with maternal cardiovascular function. Am. J. Obstet. Gynecol., 220.","DOI":"10.1016\/j.ajog.2018.09.017"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Marijnen, M.C., Van Der Meeren, L.E., Schoots, M.H., Freedman, A.A., Ernst, L.M., Bazyleva, E., Ganzevoort, W., Gordijn, S.J., Schaaf, J.M., and De Boer, M.A. (2025). Placental lesions in small for gestational age fetuses with and without clinical features of fetal growth restriction: A secondary analysis of the Doppler Ratio In fetal Growth restriction Intervention Trial At (near) Term (DRIGITAT) study. Am. J. Obstet. Gynecol., 233.","DOI":"10.1016\/j.ajog.2025.05.022"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"R41","DOI":"10.1152\/ajpregu.00258.2020","article-title":"From inhibition of trophoblast cell invasion to proapoptosis: What are the potential roles of kisspeptins in preeclampsia?","volume":"321","author":"Gomes","year":"2021","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/pd.2328","article-title":"Decreased serum levels of kisspeptin in early pregnancy are associated with intra-uterine growth restriction and pre-eclampsia","volume":"29","author":"Armstrong","year":"2009","journal-title":"Prenat. Diagn."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1080\/09513590.2021.2004396","article-title":"Preeclampsia and gestational hypertension are associated to low maternal circulating kisspeptin levels: A systematic review and meta-analysis","volume":"37","author":"Varikasuvu","year":"2021","journal-title":"Gynecol. Endocrinol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s00404-021-06359-2","article-title":"Comparison of the Kisspeptin levels in early onset preeclampsia and late-onset preeclampsia","volume":"306","author":"Ibanoglu","year":"2022","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1111\/j.1365-2265.2011.04317.x","article-title":"Evaluation of kisspeptin levels in obese pregnancy as a biomarker for pre-eclampsia","volume":"76","author":"Logie","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/uog.29204","article-title":"Screening for pre-eclampsia using pregnancy-associated plasma protein-A or placental growth factor measurements in blood samples collected at 8\u201314 weeks\u2019 gestation","volume":"65","author":"Rode","year":"2025","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/uog.23669","article-title":"Routine first-trimester combined screening for pre-eclampsia: Pregnancy-associated plasma protein-A or placental growth factor?","volume":"58","author":"Guy","year":"2021","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/pd.5001","article-title":"Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: Systematic review and meta-analysis","volume":"37","author":"Morris","year":"2016","journal-title":"Prenat. Diagn."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Bian, Z., Shixia, C., and Duan, T. (2015). First-Trimester maternal serum levels of SFLT1, PGF and ADMA predict preeclampsia. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124684"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.fertnstert.2021.04.031","article-title":"Performance of plasma kisspeptin as a biomarker for miscarriage improves with gestational age during the first trimester","volume":"116","author":"Abbara","year":"2021","journal-title":"Fertil. Steril."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/uog.70188","article-title":"Angiogenic factors and fetal Doppler for predicting adverse pregnancy outcome in early-onset small fetuses with and without pre-eclampsia","volume":"67","author":"Bonacina","year":"2026","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.ajog.2025.11.006","article-title":"Serum soluble-fms-like tyrosine kinase 1-to-placental growth factor ratio on Elecsys immunoassay platform predicts preeclampsia with severe features in hospitalized women with hypertensive disorders of pregnancy","volume":"234","author":"Berg","year":"2025","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/uog.70075","article-title":"sFlt-1\/ PlGF ratio thresholds for diagnosing pre-eclampsia in pregnant women with high blood pressure","volume":"66","author":"Pan","year":"2025","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_101","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","volume":"71","author":"Agrawal","year":"2017","journal-title":"Hypertension"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1016\/S0140-6736(18)33212-4","article-title":"Placental growth factor testing to assess women with suspected pre-eclampsia: A multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial","volume":"393","author":"Duhig","year":"2019","journal-title":"Lancet"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/1471-0528.70128","article-title":"Maternal SFLT-1\/ PLGF Ratio to Distinguish Pathological fetal growth restriction from constitutional smallness: Systematic review","volume":"133","author":"Byrne","year":"2026","journal-title":"Int. J. Obstet. Gynaecol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"123904","DOI":"10.1016\/j.jchromb.2023.123904","article-title":"Tutorial review for peptide assays: An ounce of pre-analytics is worth a pound of cure","volume":"1229","author":"Maurer","year":"2023","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1586\/14789450.3.4.409","article-title":"Effects of preanalytical variables on peptide and protein measurements in human serum and plasma: Implications for clinical proteomics","volume":"3","author":"Rai","year":"2006","journal-title":"Expert Rev. Proteom."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jchromb.2013.02.027","article-title":"LC\u2013MS\/MS quantification of a neuropeptide fragment kisspeptin-10 (NSC 741805) and characterization of its decomposition product and pharmacokinetics in rats","volume":"926","author":"Liu","year":"2013","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.fertnstert.2017.09.029","article-title":"Kisspeptin as a new serum biomarker to discriminate miscarriage from viable intrauterine pregnancy","volume":"109","author":"Haisenleder","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Medina, A.C., G\u00f3mez-Acebo, I., De Largy, C.C.G., Alonso-Molero, J., Calvo, S.V., Feu, J.M.O., Medina, M.C., and Dierssen-Sotos, T. (2025). Study of first-trimester serum levels of \u03b2-hCG and PAPP-A as a screening test for fetal development of intrauterine growth restriction. BMC Pregnancy Childbirth, 25.","DOI":"10.1186\/s12884-025-07787-7"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"170433","DOI":"10.1016\/j.peptides.2020.170433","article-title":"Associations of serum kisspeptin levels with metabolic and reproductive parameters in men","volume":"135","author":"Sitticharoon","year":"2020","journal-title":"Peptides"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1177\/0004563214551612","article-title":"The identification of elevated urinary kisspeptin-immunoreactivity during pregnancy","volume":"52","author":"Jayasena","year":"2014","journal-title":"Ann. Clin. Biochem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2215869","DOI":"10.1080\/09513590.2023.2215869","article-title":"Correlation between kisspeptin and biochemical markers in obese and non-obese women with polycystic ovary syndrome","volume":"39","author":"Gao","year":"2023","journal-title":"Gynecol. Endocrinol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2555477","DOI":"10.1080\/14767058.2025.2555477","article-title":"Assessing placental endocrine and vascular function for prenatal prediction of adverse pregnancy outcomes in advanced maternal age pregnancies","volume":"38","author":"Ling","year":"2025","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1042\/CS20220300","article-title":"Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction","volume":"137","author":"Hong","year":"2023","journal-title":"Clin. Sci."},{"key":"ref_114","first-page":"671","article-title":"Temporal Changes in Fetal and maternal parameters in Early-Onset Fetal Growth Restriction: A Multicenter, Retrospective Cohort study","volume":"133","author":"Schuit","year":"2025","journal-title":"Int. J. Obstet. Gynaecol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/aogs.13499","article-title":"Defining early vs. late fetal growth restriction by placental pathology","volume":"98","author":"Aviram","year":"2018","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2322610","DOI":"10.1080\/14767058.2024.2322610","article-title":"Clinical significance of three-dimensional power Doppler combined with two-dimensional Doppler ultrasonography for evaluating fetal growth restriction","volume":"37","author":"Fan","year":"2024","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/uog.27521","article-title":"Ophthalmic artery Doppler and biomarkers of impaired placentation at 36 weeks\u2019 gestation in pregnancies with small fetuses","volume":"63","author":"Arechvo","year":"2023","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/uog.19196","article-title":"Essential variables for reporting research studies on fetal growth restriction: A Delphi consensus","volume":"53","author":"Khalil","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/uog.19067","article-title":"Maternal hemodynamics, fetal biometry and Doppler indices in pregnancies followed up for suspected fetal growth restriction","volume":"52","author":"Roberts","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1002\/uog.29223","article-title":"Prediction of small-for-gestational age and fetal growth restriction at routine ultrasound examination at 35\u201337 weeks\u2019 gestation","volume":"65","author":"Lopian","year":"2025","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.placenta.2021.03.014","article-title":"Doppler studies of placental function","volume":"108","author":"Meler","year":"2021","journal-title":"Placenta"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Agrawal, S., Parks, W.T., Zeng, H.D., Ravichandran, A., Ashwal, E., Windrim, R.C., Hobson, S.R., Melamed, N., and Kingdom, J.C. (2022). Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction. Am. J. Obstet. Gynecol., 227.","DOI":"10.1016\/j.ajog.2022.05.043"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Lai, J., Syngelaki, A., Nicolaides, K.H., Von Dadelszen, P., and Magee, L.A. (2022). Using ultrasound and angiogenic markers from a 19- to 23-week assessment to inform the subsequent diagnosis of preeclampsia. Am. J. Obstet. Gynecol., 227.","DOI":"10.1016\/j.ajog.2022.03.007"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3748\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T10:12:46Z","timestamp":1776939166000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/3748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":123,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27093748"],"URL":"https:\/\/doi.org\/10.3390\/ijms27093748","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]}}}