Placental and Maternal Serum Expression of sFlt-1 e15a and PlGF Reveal Distinct Angiogenic Patterns in Early-Onset Preeclampsia

Rina  Gustuti; Yusrawati; Reyhan Julio  Azwan; Sara  Uzlifah

doi:10.6000/1929-6029.2026.15.18

Authors

Rina Gustuti Fetomaternal Division, Obstetrics and Gynecology Department, Medical Faculty of Andalas University, Padang, Indonesia
Yusrawati Fetomaternal Division, Obstetrics and Gynecology Department, Medical Faculty of Andalas University, Padang, Indonesia
Reyhan Julio Azwan Fetomaternal Division, Obstetrics and Gynecology Department, Medical Faculty of Andalas University, Padang, Indonesia
Sara Uzlifah Fetomaternal Division, Obstetrics and Gynecology Department, Medical Faculty of Andalas University, Padang, Indonesia

DOI:

https://doi.org/10.6000/1929-6029.2026.15.18

Keywords:

Early-onset preeclampsia, angiogenesis, biomarker

Abstract

Background: Early-onset preeclampsia (EOPE) represents a severe pregnancy disorder occurring before 34 weeks of gestation and is strongly associated with impaired placental angiogenesis. This condition is characterized by an imbalance between antiangiogenic and proangiogenic factors, particularly soluble fms-like tyrosine kinase-1 (sFlt-1) e15a and placental growth factor (PlGF). Despite their recognized roles, data regarding the concurrent expression of these biomarkers in maternal serum and placental tissue remain limited.

Methods: This analytical observational study used a comparative cross-sectional design involving 91 pregnant women with preeclampsia, categorized into EOPE (n=45) and late-onset preeclampsia (LOPE; n=46). Maternal serum and placental levels of sFlt-1 e15a and PlGF were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using independent t-tests or Mann–Whitney tests depending on the data distribution. Receiver operating characteristic (ROC) analysis and Spearman correlation were conducted to evaluate diagnostic performance and biomarker relationships.

Results: Serum sFlt-1 e15a levels were higher in EOPE than LOPE, although not statistically significant (p=0.082), while serum PlGF levels were significantly lower (p<0.001). Consequently, the serum sFlt-1/PlGF ratio was significantly elevated in EOPE (p<0.001). In placental tissue, sFlt-1 e15a levels were significantly lower, whereas PlGF levels were markedly reduced in EOPE compared to LOPE (both p<0.001), resulting in a higher placental sFlt-1/PlGF ratio (p<0.001). ROC analysis demonstrated good discriminative performance for both serum (AUC=0.772) and placental ratios (AUC=0.782). Significant correlations were observed between serum and placental biomarkers, particularly for the sFlt-1/PlGF ratio (ρ=0.859, p<0.001).

Conclusion: EOPE is characterized by a pronounced angiogenic imbalance in both maternal serum and placental tissue. The sFlt-1/PlGF ratio demonstrates strong diagnostic potential and may serve as a reliable biomarker for early identification and risk stratification of EOPE.

References

Sausan R, Yusrawati Y, Karmia HR. The Role of Endothelial Nitrit Oxide in Preeclampsia Onset. Andalas Obstetrics And Gynecology Journal 2025; 9(1): 41-48. DOI: https://doi.org/10.25077/aoj.9.1.41-48.2025

Sinambela M, Dasman H, Yusrawati Y, Bachtiar A, Muchtar M, Mudjiran M, Malini H, Defrin D. A New Model for Improving Quality of Hypertension’s Determinant Factors in Pregnancy. The Open Public Health Journal 2024; 17(1): 1-7. DOI: https://doi.org/10.2174/0118749445303154240403084428

Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circulation Research 2019; 124(7): 1094-1112. DOI: https://doi.org/10.1161/CIRCRESAHA.118.313276

Rana S, Burke SD, Karumanchi SA. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. American Journal of Obstetrics and Gynecology 2022; 226(2): S1019-S1034. DOI: https://doi.org/10.1016/j.ajog.2020.10.022

Soufal JH, Yusrawati Y, Basyir V. PAPP-A Levels and IGF-1 Levels in Early-Onset Preeclampsia and Late-Onset Preeclampsia. Andalas Obstetrics And Gynecology Journal 2024; 8(1): 519-524. DOI: https://doi.org/10.25077/aoj.8.1.525-530.2024

Hod T, Cerdeira AS, Karumanchi SA. Molecular Mechanisms of Preeclampsia. Cold Spring Harbor Perspectives in Medicine 2015; 5(10). DOI: https://doi.org/10.1101/cshperspect.a023473

Stepan H, Hund M, Andraczek T. Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome. Hypertension 2020; 75(4) 918-926. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.119.13763

Maynard SE, Min J-Y, Merchan J, Lim K-H, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Journal of Clinical Investigation 2003; 111(5): 649-658. DOI: https://doi.org/10.1172/JCI17189

Lokeswara AW, Hiksas R, Irwinda R, Wibowo N. Preeclampsia: From Cellular Wellness to Inappropriate Cell Death, and the Roles of Nutrition. Frontiers in Cell and Developmental Biology 2021; 9. DOI: https://doi.org/10.3389/fcell.2021.726513

Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, Lim K-H, Wenger JB, Thadhani R, Karumanchi SA. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012; 125(7): 911-919. DOI: https://doi.org/10.1161/CIRCULATIONAHA.111.054361

Andersen LLT, Helt A, Sperling L, Overgaard M. Decision Threshold for Kryptor sFlt-1/PlGF Ratio in Women With Suspected Preeclampsia: Retrospective Study in a Routine Clinical Setting. Journal of the American Heart Association 2021; 10(17): e021376. DOI: https://doi.org/10.1161/JAHA.120.021376

Saleh L, Vergouwe Y, Van Den Meiracker AH, Verdonk K, Russcher H, Bremer HA, Versendaal HJ, Steegers EAPP, Jan Danser AH, Visser W, Danser AHJ, Visser W. Angiogenic Markers Predict Pregnancy Complications and Prolongation in Preeclampsia: Continuous Versus Cutoff Values. Hypertension 2017; 70(5): 1025-1033. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.117.09913

Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. American Journal of Obstetrics and Gynecology 2012; 206(1): 58.e1-58.e8. DOI: https://doi.org/10.1016/j.ajog.2011.07.037

Rowson S, Reddy M, De Guingand DL, Langston-Cox A, Marshall SA, da Silva Costa F, Palmer KR. Comparison of circulating total sFLT-1 to placental-specific sFLT-1 e15a in women with suspected preeclampsia. Placenta 2022; 120: 73-78. DOI: https://doi.org/10.1016/j.placenta.2022.02.017

Palmer KR, Kaitu’u-Lino TJ, Hastie R, Hannan NJ, Ye L, Binder N, Cannon P, Tuohey L, Johns TG, Shub A, Tong S. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity. Hypertension (Dallas, Tex. : 1979) 2015; 66(6): 1251-1259. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.115.05883

Palmer KR, Tong S, Kaitu’u-Lino TJ. Placental-specific sFLT-1: role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis. Molecular Human Reproduction 2017; 23(2): 69-78. DOI: https://doi.org/10.1093/molehr/gaw077

Verlohren S, Herraiz I, Lapaire O, Schlembach D, Zeisler H, Calda P, Sabria J, Markfeld-Erol F, Galindo A, Schoofs K, Denk B, Stepan H. 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. Hypertension (Dallas, Tex. : 1979) 2014; 63(2): 346-352. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.113.01787