Significance of the sFlt-1/PlGF Ratio in Certain Cohorts – What Needs to be Considered?

Abstract

The sFlt-1/PlGF ratio is an established tool in clinical practice, where it is part of a diagnostic algorithm and informs the prognosis of preeclampsia (PE). Maternal and gestational comorbidities can affect the performance of the sFlt-1/PlGF ratio and its constituent elements, and a good understanding of the potential pitfalls is required. The objective of this paper was to provide a current narrative review of the literature on the diagnostic and predictive performance of the sFlt-1/PlGF ratio in specific patient cohorts. Potential factors which can negatively affect the clinical interpretability and applicability of the sFlt-1/PlGF ratio include chronic kidney disease, twin pregnancy, and maternal obesity. Pathophysiological mechanisms related to these factors and disorders can result in different concentrations of sFlt-1 and/or PlGF in maternal blood, meaning that the use of standard cut-off values in specific cohorts can lead to errors. To what extent the cut-off values should be adapted in certain patient cohorts can only be clarified in large prospective cohort studies. This applies to the use of the ratio both for diagnosis and prognosis.

Keywords

sFlt-1/PlGF ratio - angiogenic factors - preeclampsia

Publikationsverlauf

Eingereicht: 07. März 2024

Angenommen nach Revision: 05. Mai 2024

Artikel online veröffentlicht:
09. Juli 2024

• References/Literatur

• 1 Verlohren S, Brennecke SP, Galindo A. et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertens 2022; 27: 42-50
• 2 Rana S, Burke SD, Karumanchi SA. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol 2022; 226 (Suppl. 2) S1019-S1034
• 3 Greco M, Palumbo C, Sicuro F. et al. Soluble Fms-Like Tyrosine Kinase-1 Is A Marker of Endothelial Dysfunction During Sepsis. J Clin Med Res 2018; 10: 700-706
• 4 Dupont V, Kanagaratnam L, Goury A. et al. Excess Soluble fms-like Tyrosine Kinase 1 Correlates With Endothelial Dysfunction and Organ Failure in Critically Ill Coronavirus Disease 2019 Patients. Clin Infect Dis 2021; 72: 1834-1837
• 5 Greco M, Suppressa S, Lazzari RA. et al. sFlt-1 and CA 15.3 are indicators of endothelial damage and pulmonary fibrosis in SARS-CoV-2 infection. Sci Rep 2021; 11: 19979
• 6 Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med 2012; 2: a011056
• 7 Theilade S, Lajer M, Jorsal A. et al. Evaluation of placental growth factor and soluble Fms-like tyrosine kinase 1 as predictors of all-cause and cardiovascular mortality in patients with Type 1 diabetes with and without diabetic nephropathy. Diabet Med 2012; 29: 337-344
• 8 Zeisler H, Llurba E, Chantraine F. et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med 2016; 374: 13-22
• 9 Cerdeira AS, O’Sullivan J, Ohuma EO. et al. Performance of soluble fms-like tyrosine kinase-1-to-placental growth factor ratio of ≥ 85 for ruling in preeclampsia within 4 weeks. Am J Obstet Gynecol 2021; 224: 322-323
• 10 Verlohren S, Herraiz I, Lapaire O. et al. 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 2014; 63: 346-352
• 11 Villalaín C, Herraiz I, Valle L. et al. Maternal and Perinatal Outcomes Associated With Extremely High Values for the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio. J Am Heart Assoc 2020; 9: e015548
• 12 Rana S, Powe CE, Salahuddin S. et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012; 125: 911-919
• 13 Rolfo A, Attini R, Nuzzo AM. et al. Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers. Kidney Int 2013; 83: 177-181
• 14 Wiles K, Bramham K, Seed PT. et al. Placental and endothelial biomarkers for the prediction of superimposed pre-eclampsia in chronic kidney disease. Pregnancy Hypertens 2021; 24: 58-64
• 15 Zera CA, Seely EW, Wilkins-Haug LE. et al. The association of body mass index with serum angiogenic markers in normal and abnormal pregnancies. Am J Obstet Gynecol 2014; 211: 247.e1-247.e7
• 16 Jääskeläinen T, Heinonen S, Hämäläinen E. FINNPEC. et al. Impact of obesity on angiogenic and inflammatory markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort. Int J Obes (Lond) 2019; 43: 1070-1081
• 17 De La Calle M, Delgado JL, Verlohren S. et al. Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies. Fetal Diagn Ther 2021; 48: 288-296
• 18 Zhang JJ, Ma XX, Hao L. et al. A Systematic Review and Meta-Analysis of Outcomes of Pregnancy in CKD and CKD Outcomes in Pregnancy. Clin J Am Soc Nephrol 2015; 10: 1964-1978
• 19 Leaños-Miranda A, Campos-Galicia I, Ramírez-Valenzuela KL. et al. Urinary IgM excretion: a reliable marker for adverse pregnancy outcomes in women with chronic kidney disease. J Nephrol 2019; 32: 241-251
• 20 Piccoli GB, Attini R, Vasario E. et al. Pregnancy and chronic kidney disease: a challenge in all CKD stages. Clin J Am Soc Nephrol 2010; 5: 844-855
• 21 Williams D, Davison J. Chronic kidney disease in pregnancy. BMJ 2008; 336: 211-215
• 22 Wiles K, Chappell LC, Lightstone L. et al. Updates in Diagnosis and Management of Preeclampsia in Women with CKD. Clin J Am Soc Nephrol 2020; 15: 1371-1380
• 23 Hirashima C, Ogoyama M, Abe M. et al. Clinical usefulness of serum levels of soluble fms-like tyrosine kinase 1/placental growth factor ratio to rule out preeclampsia in women with new-onset lupus nephritis during pregnancy. CEN Case Rep 2019; 8: 95-100
• 24 Verlohren S, Dröge LA. The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia. Am J Obstet Gynecol 2022; 226 (Suppl. 2) S1048-S1058
• 25 Molina-Pérez CJ, Nolasco-Leaños AG, Carrillo-Juárez RI. et al. Clinical usefulness of angiogenic factors in women with chronic kidney disease and suspected superimposed preeclampsia. J Nephrol 2022; 35: 1699-1708
• 26 Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e.V. (DGGG), Deutsche Gesellschaft für Nephrologie e.V. (DGfN). Pregnancy and renal disease. Guideline of the DGGG and OEGGG (S2k-Level, AWMF Registry No. 015/090, September 2021). 2021 Zugriff am 09. Juni 2024 unter: https://www.awmf.org/leitlinien/detail/ll/015–090.html
• 27 Levine RJ, Thadhani R, Qian C. et al. Urinary placental growth factor and risk of preeclampsia. JAMA 2005; 293: 77-85
• 28 Matsui M, Takeda Y, Uemura S. et al. Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease. Kidney Int 2014; 85: 393-403
• 29 Onoue K, Uemura S, Takeda Y. et al. Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis. Circulation 2009; 120: 2470-2477
• 30 Wei YM, Yang HX, Zhu WW. et al. Risk of adverse pregnancy outcomes stratified for pre-pregnancy body mass index. J Matern Fetal Neonatal Med 2016; 29: 2205-2209
• 31 Kwaifa IK, Bahari H, Yong YK. et al. Endothelial Dysfunction in Obesity-Induced Inflammation: Molecular Mechanisms and Clinical Implications. Biomolecules 2020; 10: 291
• 32 WHO. Obesity: Preventing and Managing the Global Epidemic; Report of a WHO Consultation. (WHO Technical Report Series; ). Geneva, Switzerland: WHO; 2000. 894.
• 33 Spradley FT, Palei AC, Granger JP. Obese melanocortin-4 receptor-deficient rats exhibit augmented angiogenic balance and vasorelaxation during pregnancy. Physiol Rep 2013; 1: e00081
• 34 Mariman EC, Wang P. Adipocyte extracellular matrix composition, dynamics and role in obesity. Cell Mol Life Sci 2010; 67: 1277-1292
• 35 Herse F, Fain JN, Janke J. et al. Adipose tissue-derived soluble fms-like tyrosine kinase 1 is an obesity-relevant endogenous paracrine adipokine. Hypertension 2011; 58: 37-42
• 36 Karge A, Desing L, Haller B. et al. Performance of sFlt-1/PIGF Ratio for the Prediction of Perinatal Outcome in Obese Pre-Eclamptic Women. J Clin Med 2022; 11: 3023
• 37 von Versen-Höynck F, Schaub AM, Chi YY. et al. Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum. Hypertension 2019; 73: 640-649
• 38 Rana S, Hacker MR, Modest AM. et al. Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia. Hypertension 2012; 60: 451-458
• 39 Binder J, Palmrich P, Pateisky P. et al. The Prognostic Value of Angiogenic Markers in Twin Pregnancies to Predict Delivery Due to Maternal Complications of Preeclampsia. Hypertension 2020; 76: 176-183
• 40 Dröge L, Herraìz I, Zeisler H. et al. Maternal serum sFlt-1/PlGF ratio in twin pregnancies with and without pre-eclampsia in comparison with singleton pregnancies. Ultrasound Obstet Gynecol 2015; 45: 286-293
• 41 Bdolah Y, Lam C, Rajakumar A. et al. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?. Am J Obstet Gynecol 2008; 198: 428.e1-428.e6
• 42 Karge A, Seiler A, Flechsenhar S. et al. Prediction of adverse perinatal outcome and the mean time until delivery in twin pregnancies with suspected pre-eclampsia using sFlt-1/PIGF ratio. Pregnancy Hypertens 2021; 24: 37-43
• 43 Saleh L, Tahitu SIM, Danser AHJ. et al. 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. Pregnancy Hypertens 2018; 14: 222-227
• 44 Verlohren S, Herraiz I, Lapaire O. et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 2012; 206: 58.e1-58.e8
• 45 Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e.V. (DGGG). Hypertensive Pregnancy Disorders: Diagnosis and Therapy. Guideline of the German Society of Gynecology and Obstetrics (S2k-Level, AWMF-Registry No. 015/018, March 2019). 2019 Zugriff am 09. Juni 2024 unter: https://register.awmf.org/de/leitlinien/detail/015–018#anmeldung
• 46 Perni U, Sison C, Sharma V. et al. Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy. Hypertension 2012; 59: 740-746
• 47 Brown MA, Magee LA, Kenny LC. International Society for the Study of Hypertension in Pregnancy (ISSHP). et al. Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice. Hypertension 2018; 72: 24-43
• 48 Binder J, Kalafat E, Palmrich P. et al. Should angiogenic markers be included in diagnostic criteria of superimposed pre-eclampsia in women with chronic hypertension?. Ultrasound Obstet Gynecol 2022; 59: 192-201
• 49 Minakami H, Morikawa M, Yamada T. et al. Differentiation of acute fatty liver of pregnancy from syndrome of hemolysis, elevated liver enzymes and low platelet counts. J Obstet Gynaecol Res 2014; 40: 641-649
• 50 Suzuki H, Nagayama S, Hirashima C. et al. Markedly higher sFlt-1/PlGF ratio in a woman with acute fatty liver of pregnancy compared with HELLP syndrome. J Obstet Gynaecol Res 2019; 45: 96-103
• 51 Neuman RI, Hesselink ERM, Saleh L. et al. Angiogenic markers are elevated in women with acute fatty liver of pregnancy. Ultrasound Obstet Gynecol 2020; 56: 465-466
• 52 Brügge M, Pecks U, Iannaccone A. et al. Akute Schwangerschaftsfettleber – Fallserie einer seltenen Schwangerschaftskomplikation [Acute Fatty Liver of Pregnancy – Case Series]. Z Geburtshilfe Neonatol 2023; 227: 466-473
• 53 Trottmann F, Raio L, Amylidi-Mohr S. et al. Soluble fms-like tyrosine kinase 1 (sFlt-1): A novel biochemical marker for acute fatty liver of pregnancy. Acta Obstet Gynecol Scand 2021; 100: 1876-1884
• 54 Coulon S, Heindryckx F, Geerts A. et al. Angiogenesis in chronic liver disease and its complications. Liver Int 2011; 31: 146-162
• 55 Oe Y, Ko M, Fushima T. et al. Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase. Sci Rep 2018; 8: 102
• 56 Uda Y, Hirano T, Son G. et al. Angiogenesis is crucial for liver regeneration after partial hepatectomy. Surgery 2013; 153: 70-77
• 57 Trottmann F, Baumann M, Amylidi-Mohr S. et al. Angiogenic profiling in HELLP syndrome cases with or without hypertension and proteinuria. Eur J Obstet Gynecol Reprod Biol 2019; 243: 93-96
• 58 Sammaritano LR, Bermas BL, Chakravarty EE. et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol 2020; 72: 529-556
• 59 Kuschel B, Schäfer-Graf UM, Schmidt M. AGG – Section Maternal Diseases in Pregnancy. et al. Management of Rheumatic Diseases During Pregnancy and Breastfeeding: Position Paper of the Working Group for Obstetrics and Prenatal Medicine in the German Society for Gynecology and Obstetrics e. V. (AGG - Section Maternal Diseases in Pregnancy). Geburtshilfe Frauenheilkd 2024; 84: 130-143
• 60 Kim MY, Buyon JP, Guerra MM. et al. Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study. Am J Obstet Gynecol 2016; 214: 108.e1-108.e14
• 61 Béranger N, Tsatsaris V, Coppo P. et al. High sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Pregnancy-Onset Thrombotic Thrombocytopenic Purpura. Hypertension 2023; 80: e140-e142
• 62 Tanner MS, de Guingand D, Reddy M. et al. The effect of comorbidities on the sFLT-1:PlGF ratio in preeclampsia. Pregnancy Hypertens 2022; 29: 98-100