Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0040-1713916
Evaluation of Angiogenic Factors (PlGF and sFlt-1) in Pre-eclampsia Diagnosis
Avaliação dos fatores angiogênicos (PlGF e sFlt-1) no diagnóstico de pré-eclâmpsia![](https://www.thieme-connect.de/media/10.1055-s-00030576/202011/lookinside/thumbnails/10-1055-s-0040-1713916_190345-1.jpg)
Abstract
Objective Recent observations support the hypothesis that an imbalance between angiogenic factors has a fundamental role in the pathogenesis of pre-eclampsia and is responsible for the clinical manifestations of the disease. The goal of the present study was to evaluate the sensitivity, specificity, and the best accuracy level of Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in maternal serum and protein/creatinine ratio in urine sample to define the best cutoff point of these tests to discriminate between the patients with gestational hypertension and the patients with pre-eclampsia, to evaluate the possibility of using them as diagnostic methods.
Methods A prospective longitudinal study was performed, and blood samples were collected from 95 pregnant patients with hypertension to measure serum concentrations of biomarkers sFlt-1 and PlGF. Urine samples were collected for protein screening. Significance was set as p < 0.05.
Results The sFlt-1/PlGF ratio demonstrated a sensitivity of 57.5% and a specificity of 60% using 50.4 as a cutoff point. The test that showed the best accuracy in the diagnosis of pre-eclampsia was protein/creatinine ratio, with a sensitivity of 78.9% and a specificity of 70% using 0.4 as a cutoff point and showing an area under the receiver operating characteristic curve of 0.80 (p < 0.001).
Conclusion No studied laboratory test proved to be fairly accurate for the diagnosis of pre-eclampsia, except for the protein/creatinine ratio. The evidence is insufficient to recommend biomarkers sFlt-1 and PlGF to be used for the diagnosis of pre-eclampsia.
Resumo
Objetivo Pesquisas recentes sustentam a hipótese de que um desequilíbrio entre fatores angiogênicos desempenhe um papel fundamental na patogênese da pré-eclâmpsia e seja responsável pelas manifestações clínicas da doença. O objetivo do presente estudo foi avaliar a sensibilidade, a especificidade e o nível de melhor acurácia do Fator semelhante a tirosina quinase 1 (sFlt-1), Fator de crescimento placentário (PlGF), e relação sFlt-1/PlGF no soro materno e relação proteína/creatinina em amostra de urina e definir o melhor ponto de corte desses testes para distinguir pacientes com hipertensão gestacional daquelas com pré-eclâmpsia, a fim de avaliar a possibilidade de utilizá-los como métodos diagnósticos.
Métodos Foi realizado um estudo prospectivo longitudinal e foram coletadas amostras de sangue de 95 gestantes com hipertensão arterial para dosar as concentrações séricas dos biomarcadores sFlt-1 e PlGF. Amostras de urina foram coletadas para pesquisa de proteinúria. Foram consideradas significativas as diferenças com p < 0,05.
Resultados A relação sFlt-1/PlGF demonstrou sensibilidade de 57,5% e especificidade de 60% utilizando 50,4 como ponto de corte. O teste que apresentou a melhor acurácia no diagnóstico de pré-eclâmpsia foi a relação proteína/creatinina, com sensibilidade de 78,9% e especificidade de 70%, utilizando 0,4 como ponto de corte e demostrando uma área sob a curva receiver operating characteristic (ROC, na sigla em inglês) de 0,80 (p < 0,001).
Conclusão Nenhum método de rastreamento isolado se mostrou com boa acurácia para o diagnóstico de pré-eclâmpsia, exceto a relação proteína/creatinina. As evidências são insuficientes para recomendar os biomarcadores sFlt-1 e PlGF como diagnóstico de pré-eclâmpsia.
Contributors
All authors contributed with the project and data interpretation, the writing of the article, the critical review of the intellectual content, and with the final approval of the version to be published.
Publication History
Received: 10 December 2019
Accepted: 28 May 2020
Article published online:
30 November 2020
© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil
-
References
- 1 World Health Organization. The World Health Report 2005: make every mother and child count [Internet]. Geneva: WHO; 2005. [cited 2019 Nov 17]. Available from: https://www.who.int/whr/2005/whr2005_en.pdf?ua=1
- 2 American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122 (05) 1122-1131 DOI: 10.1097/01.AOG.0000437382.03963.88.
- 3 Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33 (03) 130-137 DOI: 10.1053/j.semperi.2009.02.010.
- 4 Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. Canadian Hypertensive Disorders of Pregnancy (HDP) Working Group, Canadian Hypertensive Disorders of Pregnancy HDP Working Group. The hypertensive disorders of pregnancy (29.3). Best Pract Res Clin Obstet Gynaecol 2015; 29 (05) 643-657 DOI: 10.1016/j.bpobgyn.2015.04.001.
- 5 Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W. et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. Pregnancy Hypertens 2014; 4 (02) 97-104 DOI: 10.1016/j.preghy.2014.02.001.
- 6 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol 2019; 133 (01) e1-e25 DOI: 10.1097/AOG.0000000000003018.
- 7 de Oliveira LG, Karumanchi A, Sass N. [Preeclampsia: oxidative stress, inflammation and endothelial dysfunction]. Rev Bras Ginecol Obstet 2010; 32 (12) 609-616 DOI: 10.1590/S0100-72032010001200008.
- 8 Kopcow HD, Karumanchi SA. Angiogenic factors and natural killer (NK) cells in the pathogenesis of preeclampsia. J Reprod Immunol 2007; 76 (1-2): 23-29 DOI: 10.1016/j.jri.2007.03.018.
- 9 Silasi M, Cohen B, Karumanchi SA, Rana S. Abnormal placentation, angiogenic factors, and the pathogenesis of preeclampsia. Obstet Gynecol Clin North Am 2010; 37 (02) 239-253 DOI: 10.1016/j.ogc.2010.02.013.
- 10 Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda) 2009; 24: 147-158 DOI: 10.1152/physiol.00043.2008.
- 11 Lam C, Lim KH, Karumanchi SA. Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 2005; 46 (05) 1077-1085 DOI: 10.1161/01.HYP.0000187899.34379.b0.
- 12 Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Semin Nephrol 2011; 31 (01) 33-46 DOI: 10.1016/j.semnephrol.2010.10.004.
- 13 Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic imbalance. Annu Rev Med 2008; 59: 61-78 DOI: 10.1146/annurev.med.59.110106.214058.
- 14 Kulkarni AV, Mehendale SS, Yadav HR, Kilari AS, Taralekar VS, Joshi SR. Circulating angiogenic factors and their association with birth outcomes in preeclampsia. Hypertens Res 2010; 33 (06) 561-567 DOI: 10.1038/hr.2010.31.
- 15 Alpert B, McCrindle B, Daniels S, Dennison B, Hayman L, Jacobson M. et al; Atherosclerosis, Hypertension, and Obesity in the Young Committee of the American Heart Association Council on Cardiovascular Disease in the Young. Recommendations for blood pressure measurement in human and experimental animals; part 1: blood pressure measurement in humans. Hypertension 2006; 48 (01) e3 , author reply e5 DOI: 10.1161/01.HYP.0000229661.06235.08.
- 16 Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183 (01) S1-S22 DOI: 10.1067/mob.2000.107928.
- 17 Baweja S, Kent A, Masterson R, Roberts S, McMahon LP. Prediction of pre-eclampsia in early pregnancy by estimating the spot urinary albumin: creatinine ratio using high-performance liquid chromatography. BJOG 2011; 118 (09) 1126-1132 DOI: 10.1111/j.1471-0528.2011.02960.x.
- 18 Kleinrouweler CE, Wiegerinck MMJ, Ris-Stalpers C, Bossuyt PMM, van der Post JAM, von Dadelszen P. et al; EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG 2012; 119 (07) 778-787 DOI: 10.1111/j.1471-0528.2012.03311.x.
- 19 Di Lorenzo G, Ceccarello M, Cecotti V, Ronfani L, Monasta L, Vecchi Brumatti L. et al. First trimester maternal serum PIGF, free β-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. Placenta 2012; 33 (06) 495-501 DOI: 10.1016/j.placenta.2012.03.003.
- 20 Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol 2012; 119 (06) 1234-1242 DOI: 10.1097/AOG.0b013e3182571669.
- 21 Masoura S, Kalogiannidis IA, Gitas G, Goutsiolis A, Koiou E, Athanasiadis A, Vavatsi N. Biomarkers in pre-eclampsia: a novel approach to early detection of the disease. J Obstet Gynaecol 2012; 32 (07) 609-616 DOI: 10.3109/01443615.2012.709290.
- 22 Espinoza J. Recent biomarkers for the identification of patients at risk for preeclampsia: the role of uteroplacental ischemia. Expert Opin Med Diagn 2012; 6 (02) 121-130 DOI: 10.1517/17530059.2012.659726.
- 23 Moore Simas TA, Crawford SL, Solitro MJ, Frost SC, Meyer BA, Maynard SE. Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet Gynecol 2007; 197 (03) 244.e1-244.e8 DOI: 10.1016/j.ajog.2007.06.030.
- 24 Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP. et al. The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age. J Matern Fetal Neonatal Med 2008; 21 (05) 279-287 DOI: 10.1080/14767050802034545.
- 25 Leaños-Miranda A, Campos-Galicia I, Isordia-Salas I, , Rivera-Leaños, Romero-Arauz, Ayala-Méndez JA, Ulloa-Aguirre A. Changes in circulating concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor measured by automated electrochemiluminescence immunoassays methods are predictors of preeclampsia. J Hypertens 2012; 30 (11) 2173-2181 DOI: 10.1097/HJH.0b013e328357c0c9.
- 26 Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG. et al. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. Am J Obstet Gynecol 2010; 202 (02) 161.e1-161.e11 DOI: 10.1016/j.ajog.2009.09.016.
- 27 Hagmann H, Thadhani R, Benzing T, Karumanchi SA, Stepan H. The promise of angiogenic markers for the early diagnosis and prediction of preeclampsia. Clin Chem 2012; 58 (05) 837-845 DOI: 10.1373/clinchem.2011.169094.
- 28 Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M. et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 2016; 374 (01) 13-22 DOI: 10.1056/NEJMoa1414838.
- 29 Stepan H, Herraiz I, Schlembach D, Verlohren S, Brennecke S, Chantraine F. et al. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol 2015; 45 (03) 241-246 DOI: 10.1002/uog.14799.
- 30 Smith GCS, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD. et al. Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet Gynecol 2007; 109 (06) 1316-1324 DOI: 10.1097/01.AOG.0000265804.09161.0d.
- 31 Srinivas SK, Larkin J, Sammel MD, Appleby D, Bastek J, Andrella CM. et al. The use of angiogenic factors in discriminating preeclampsia: are they ready for prime time?. J Matern Fetal Neonatal Med 2010; 23 (11) 1294-1300 DOI: 10.3109/14767051003677988.
- 32 Widmer M, Villar J, Benigni A, Conde-Agudelo A, Karumanchi SA, Lindheimer M. Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol 2007; 109 (01) 168-180 DOI: 10.1097/01.AOG.0000249609.04831.7c.
- 33 Scazzocchio E, Figueras F. Contemporary prediction of preeclampsia. Curr Opin Obstet Gynecol 2011; 23 (02) 65-71 DOI: 10.1097/GCO.0b013e328344579c.
- 34 Martins-Costa SH, Vettorazzi J, Valério E, Maurmann C, Benevides G, Hemessath M. et al. Protein creatinine ratio in random urine sample of hypertensive pregnant women: maternal and perinatal outcomes. Hypertens Pregnancy 2011; 30 (03) 331-337 DOI: 10.3109/10641950903454564.
- 35 Papanna R, Mann LK, Kouides RW, Glantz JC. Protein/creatinine ratio in preeclampsia: a systematic review. Obstet Gynecol 2008; 112 (01) 135-144 DOI: 10.1097/AOG.0b013e3181778cfc.
- 36 Morris RK, Riley RD, Doug M, Deeks JJ, Kilby MD. Diagnostic accuracy of spot urinary protein and albumin to creatinine ratios for detection of significant proteinuria or adverse pregnancy outcome in patients with suspected pre-eclampsia: systematic review and meta-analysis. BMJ 2012; 345: e4342 DOI: 10.1136/bmj.e4342.
- 37 Narkiewicz K. Obesity and hypertension–the issue is more complex than we thought. Nephrol Dial Transplant 2006; 21 (02) 264-267 DOI: 10.1093/ndt/gfi290.