Angiogenesis-Related Biomarkers (sFlt-1/PLGF) in the Prediction and Diagnosis of Placental Dysfunction: An Approach for Clinical Integration

Ignacio Herraiz, Elisa Simón, Paula Isabel Gómez-Arriaga, José Manuel Martínez-Moratalla, Antonio García-Burguillo, Elena Ana López Jiménez, Alberto Galindo, Ignacio Herraiz, Elisa Simón, Paula Isabel Gómez-Arriaga, José Manuel Martínez-Moratalla, Antonio García-Burguillo, Elena Ana López Jiménez, Alberto Galindo

Abstract

Placental dysfunction is involved in a group of obstetrical conditions including preeclampsia, intrauterine growth restriction, and placental abruption. Their timely and accurate recognition is often a challenge since diagnostic criteria are still based on nonspecific signs and symptoms. The discovering of the role of angiogenic-related factors (sFlt-1/PlGF) in the underlying pathophysiology of placental dysfunction, taking into account that angiogenesis-related biomarkers are not specific to any particular placental insufficiency-related disease, has marked an important step for improving their early diagnosis and prognosis assessment. However, sFlt-1/PlGF has not been yet established as a part of most guidelines. We will review the current evidence on the clinical utility of sFlt-1/PlGF and propose a new protocol for its clinical integration.

Keywords: PlGF; angiogenesis; intrauterine growth restriction; placental abruption; placental insufficiency; preeclampsia; sFlt-1.

Figures

Figure 1
Figure 1
Maternal serum concentrations of the sFlt-1/PlGF ratio throughout pregnancy: reference normal values (5th/50th/95th centiles) are represented in blue and mean values at time of diagnosis of preeclampsia are represented in dark red. Maximum differences between cases and normal pregnancies occur during the early phase, especially at 24–28 weeks. In the late phase, and especially in term pregnancies, considerably overlapping is observed. For visualization, the sFlt-1/PlGF ratio cutoff of 85 is shown as a black horizontal line. Data have been extracted from references 24 and 39.
Figure 2
Figure 2
Algorithm for the selection of patients at risk of developing placental dysfunction-related diseases. BMI, body mass index (kg/m2); HT, hypertension; p, percentile; PE, preeclampsia; PD, placental dysfunction; UtA, uterine arteries; w, weeks of gestation.
Figure 3
Figure 3
Algorithm for the intensive following-up of patients at risk of developing placental dysfunction-related disorders, including the implementation of angiogenesis-related biomarkers. PD, placental dysfunction; S/P, sFlt-1/PlGF ratio; UtA, uterine arteries; w, weeks of gestation.

References

    1. Friedman A.M., Cleary K.L. Prediction and prevention of ischemic placental disease. Semin. Perinatol. 2014;38:177–182. doi: 10.1053/j.semperi.2014.03.002.
    1. Hagmann H., Thadhani R., Benzing T., Karumanchi S.A., Stepan H. The promise of angiogenic markers for the early diagnosis and prediction of preeclampsia. Clin. Chem. 2012;58:837–845. doi: 10.1373/clinchem.2011.169094.
    1. Menzies J., Magee L.A., Macnab Y.C., Ansermino J.M., Li J., Douglas M.J., Gruslin A., Kyle P., Lee S.K., Moore M.P., et al. Current CHS and NHBPEP criteria for severe preeclampsia do not uniformly predict adverse maternal or perinatal outcomes. Hypertens. Pregnancy. 2007;26:447–462. doi: 10.1080/10641950701521742.
    1. Figueras F., Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn. Ther. 2014;36:86–98. doi: 10.1159/000357592.
    1. Hall D.R. Abruptio placentae and disseminated intravascular coagulopathy. Semin. Perinatol. 2009;33:189–195. doi: 10.1053/j.semperi.2009.02.005.
    1. Burton G.J., Woods A.W., Jauniaux E., Kingdom J.C. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta. 2009;30:473–482. doi: 10.1016/j.placenta.2009.02.009.
    1. Roberts J.M. Pathophysiology of ischemic placental disease. Semin. Perinatol. 2014;38:139–145. doi: 10.1053/j.semperi.2014.03.005.
    1. Maynard S.E., Min J.Y., Merchan J., Lim K.H., Li J., Mondal S., Libermann T.A., Morgan J.P., Sellke F.W., Stillman I.E., et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Investig. 2003;111:649–658. doi: 10.1172/JCI17189.
    1. Shibuya M. Vascular endotelial growth factor and its receptor system: Physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem. 2013;153:13–19. doi: 10.1093/jb/mvs136.
    1. Sircar M., Thadhani R., Karumanchi S.A. Pathogenesis of preeclampsia. Curr. Opin. Nephrol. Hypertens. 2015;24:131–138. doi: 10.1097/MNH.0000000000000105.
    1. Weiler J., Tong S., Palmer K.R. Is fetal growth restriction associated with a more severe maternal phenotype in the setting of early onset pre-eclampsia? A retrospective study. PLoS ONE. 2011;6:e26937. doi: 10.1371/journal.pone.0026937.
    1. Signore C., Mills J.L., Qian C., Yu K., Lam C., Epstein F.H., Karumanchi S.A., Levine R.J. Circulating angiogenic factors and placental abruption. Obstet. Gynecol. 2006;108:338–344. doi: 10.1097/01.AOG.0000216014.72503.09.
    1. Gómez-Arriaga P.I., Herraiz I., López-Jiménez E.A., Escribano D., Denk B., Galindo A. Uterine artery Doppler and sFlt-1/PlGF ratio: Prognostic value in early-onset pre-eclampsia. Ultrasound Obstet. Gynecol. 2014;43:525–532. doi: 10.1002/uog.13224.
    1. Chaiworapongsa T., Romero R., Korzeniewski S.J., Cortez J.M., Pappas A., Tarca A.L., Chaemsaithong P., Dong Z., Yeo L., Hassan S.S. Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: A prospective study. J. Matern. Fetal Neonatal Med. 2014;27:132–144. doi: 10.3109/14767058.2013.806905.
    1. Roberts J.M., Catov J.M. Preeclampsia more than 1 disease or is it? Hypertension. 2008;51:989–990. doi: 10.1161/HYPERTENSIONAHA.107.100248.
    1. Herraiz I., Dröge L.A., Gómez-Montes E., Henrich W., Galindo A., Verlohren S. Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by Fetal Growth Restriction. Obstet. Gynecol. 2014;124:265–273. doi: 10.1097/AOG.0000000000000367.
    1. Rana S., Schnettler W.T., Powe C., Wenger J., Salahuddin S., Cerdeira A.S., Verlohren S., Perschel F.H., Arany Z., Lim K.H., et al. Clinical characterization and outcomes of preeclampsia with normal angiogenic profile. Hypertens. Pregnancy. 2013;32:189–201. doi: 10.3109/10641955.2013.784788.
    1. Espinoza J. Abnormal fetal-maternal interactions: An evolutionary value? Obstet. Gynecol. 2012;120:370–374. doi: 10.1097/AOG.0b013e31825cb96d.
    1. Roberts J.M., Hubel C.A. The two stage model of preeclampsia: Variations on the theme. Placenta. 2009;30:S32–S37. doi: 10.1016/j.placenta.2008.11.009.
    1. Wright D., Syngelaki A., Akolekar R., Poon L.C., Nicolaides K.H. Competing risks model in screening for preeclampsia by maternal characteristics and medical history. Am. J. Obstet. Gynecol. 2015;213:62–e1. doi: 10.1016/j.ajog.2015.02.018.
    1. Redman C.W., Sargent I.L., Staff A.C. IFPA Senior Award Lecture: Making sense of pre-eclampsia—Two placental causes of preeclampsia? Placenta. 2014;35(Suppl. 102):20–25. doi: 10.1016/j.placenta.2013.12.008.
    1. Espinoza J. Uteroplacental ischemia in early- and late-onset pre-eclampsia: A role for the fetus? Ultrasound Obstet. Gynecol. 2012;40:373–382. doi: 10.1002/uog.12280.
    1. Levine R.J., Maynard S.E., Qian C., Lim K.H., England L.J., Yu K.F., Schisterman E.F., Thadhani R., Sachs B.P., Epstein F.H., et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 2004;350:672–683. doi: 10.1056/NEJMoa031884.
    1. Verlohren S., Herraiz I., Lapaire O., Schlembach D., Zeisler H., Calda P., Sabria J., Markfeld-Erol F., Galindo A., Schoofs K., 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. doi: 10.1161/HYPERTENSIONAHA.113.01787.
    1. Verlohren S., Galindo A., Schlembach D., Zeisler H., Herraiz I., Moertl M.G., Pape J., Dudenhausen J.W., Denk B., Stepan H. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. Am. J. Obstet. Gynecol. 2010;202:161.e1–161.e11. doi: 10.1016/j.ajog.2009.09.016.
    1. Stepan H., Herraiz I., Schlembach D., Verlohren S., Brennecke S., Chantraine F., Klein E., Lapaire O., Llurba E., Ramoni A., 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;45:241–246. doi: 10.1002/uog.14799.
    1. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet. 1994;343:619–629.
    1. Caritis S., Sibai B., Hauth J., Lindheimer M.D., Klebanoff M., Thom E., van Dorsten P., Landon M., Paul R., Miodovnik M., et al. Low-dose aspirin to prevent preeclampsia in women at high risk. N. Engl. J. Med. 1998;338:701–705. doi: 10.1056/NEJM199803123381101.
    1. Yu C.K., Papageorghiou A.T., Parra M., Palma Dias R., Nicolaides K.H. Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation. Ultrasound Obstet. Gynecol. 2003;22:233–239. doi: 10.1002/uog.218.
    1. National Collaborating Centre for Women’s and Children’s Health . Hypertension in Pregnancy: The Management of Hypertensive Disorders during Pregnancy. Clinical Guideline. RCOG Press; London, UK: August 2010.
    1. Verlohren S., Stepan H., Dechend R. Angiogenic growth factors in the diagnosis and prediction of pre-eclampsia. Clin. Sci. 2012;122:43–52. doi: 10.1042/CS20110097.
    1. Thadhani R., Mutter W.P., Wolf M., Levine R.J., Taylor R.N., Sukhatme V.P., Ecker J., Karumanchi S.A. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J. Clin. Endocrinol. Metab. 2004;89:770–775. doi: 10.1210/jc.2003-031244.
    1. Baumann M.U., Bersinger N.A., Mohaupt M.G., Raio L., Gerber S., Surbek D.V. First-trimester serum levels of soluble endoglin and soluble fms-like tyrosine kinase-1 as first-trimester markers for late-onset preeclampsia. Am. J. Obstet. Gynecol. 2008;199:266.e1–266.e6. doi: 10.1016/j.ajog.2008.06.069.
    1. Akolekar R., Syngelaki A., Sarquis R., Zvanca M., Nicolaides K.H. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11–13 weeks. Prenat. Diagn. 2011;31:66–74. doi: 10.1002/pd.2660.
    1. Crovetto F., Crispi F., Scazzocchio E., Mercade I., Meler E., Figueras F., Gratacos E. First-trimester screening for early and late small-for-gestational-age neonates using maternal serum biochemistry, blood pressure and uterine artery Doppler. Ultrasound Obstet. Gynecol. 2014;43:34–40. doi: 10.1002/uog.12537.
    1. Oliveira N., Magder L.S., Blitzer M.G., Baschat A.A. First-trimester prediction of pre-eclampsia: External validity of algorithms in a prospectively enrolled cohort. Ultrasound Obstet. Gynecol. 2014;44:279–285. doi: 10.1002/uog.13435.
    1. Shmueli A., Meiri H., Gonen R. Economic assessment of screening for pre-eclampsia. Prenat. Diagn. 2012;32:29–38. doi: 10.1002/pd.2871.
    1. Abou E.l., Hassan M., Diamandis E.P., Karumanchi S.A., Shennan A.H., Taylor R.N. Preeclampsia: An old disease with new tools for better diagnosis and risk management. Clin. Chem. 2015;61:694–698. doi: 10.1373/clinchem.2014.230565.
    1. Gómez-Arriaga P.I., Herraiz I., López-Jiménez E.A., Gómez-Montes E., Denk B., Galindo A. Uterine artery Doppler and sFlt-1/PlGF ratio: Usefulness in diagnosis of pre-eclampsia. Ultrasound Obstet. Gynecol. 2013;41:530–537. doi: 10.1002/uog.12400.
    1. Sagol S., Ozkinay E., Oztekin K., Ozdemir N. The comparison of uterine artery Doppler velocimetry with the histopathology of the placental bed. Aust. N. Zeal. J. Obstet. Gnaecol. 1999;39:324–329. doi: 10.1111/j.1479-828X.1999.tb03407.x.
    1. Sciscione A.C., Hayes E.J. Uterine artery Doppler flow studies in obstetric practice. Am. J. Obstet. Gynecol. 2009;201:121–126. doi: 10.1016/j.ajog.2009.03.027.
    1. Martin A.M., Bindra R., Curcio P., Cicero S., Nicolaides K.H. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks of gestation. Ultrasound Obstet. Gynecol. 2001;18:583–586. doi: 10.1046/j.0960-7692.2001.00594.x.
    1. Cnossen J.S., Morris R.K., ter Riet G., Mol B.W., van der Post J.A., Coomarasamy A., Zwinderman A.H., Robson S.C., Bindels P.J., Kleijnen J., et al. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: A aystematic review and bivariable meta-analysis. CMAJ. 2008;178:701–711. doi: 10.1503/cmaj.070430.
    1. Velauthar L., Plana M.N., Kalidindi M., Zamora J., Thilaganathan B., Illanes S.E., Khan K.S., Aquilina J., Thangaratinam S. First-trimester uterine artery Doppler and adverse pregnancy outcome: A meta-analysis involving 55974 women. Ultrasound Obstet. Gynecol. 2014;43:500–507. doi: 10.1002/uog.13275.
    1. Ghi T., Contro E., Youssef A., Giorgetta F., Farina A., Pilu G., Pelusi G. Persistence of increased uterine artery resistance in the third trimester and pregnancy outcome. Ultrasound Obstet. Gynecol. 2010;36:577–581. doi: 10.1002/uog.7602.
    1. Stepan H., Unversucht A., Wessel N., Faber R. Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion. Hypertension. 2007;49:818–824. doi: 10.1161/01.HYP.0000258404.21552.a3.
    1. Crispi F., Llurba E., Domínguez C., Martín-Gallán P., Cabero L., Gratacós E. Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet. Gynecol. 2008;31:303–309. doi: 10.1002/uog.5184.
    1. Kusanovic J.P., Romero R., Chaiworapongsa T., Erez O., Mittal P., Vaisbuch E., Mazaki-Tovi S., Gotsch F., Edwin S.S., Gomez R., et al. A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. J. Matern. Fetal Neonatal Med. 2009;22:1021–1038. doi: 10.3109/14767050902994754.
    1. Stubert J., Ullmann S., Bolz M., Külz T., Dieterich M., Richter D.-U., Reimer T. Prediction of preeclampsia and induced delivery at <34 weeks gestation by sFLT-1 and PlGF in patients with abnormal midtrimester uterine Doppler velocimetry: A prospective cohort analysis. BMC Pregnancy Childbirth. 2014;14:292. doi: 10.1186/1471-2393-14-292..
    1. Lai J., Garcia-Tizon Larroca S., Peeva G., Poon L.C., Wright D., Nicolaides K.H. Competing risks model in screening for preeclampsia by serum placental growth factor and soluble fms-like tyrosine kinase-1 at 30–33 weeks’ gestation. Fetal Diagn. Ther. 2014;35:240–248. doi: 10.1159/000359968.
    1. Lisonkova S., Sabr Y., Mayer C., Young C., Skoll A., Joseph K.S. Maternal morbidity associated with early-onset and late-onset preeclampsia. Obstet. Gynecol. 2014;124:771–781. doi: 10.1097/AOG.0000000000000472.
    1. Bombrys A.E., Barton J.R., Nowacki E.A., Habli M., Pinder L., How H., Sibai B.M. Expectant management of severe preeclampsia at less than 27 weeks’ gestation: Maternal and perinatal outcomes according to gestational age by weeks at onset of expectant management. Am. J. Obstet. Gynecol. 2008;247:247.e1–247.e6. doi: 10.1016/j.ajog.2008.06.086.
    1. Belghiti J., Kayem G., Tsatsaris V., Goffinet F., Sibai B.M., Haddad B. Benefits and risks of expectant management of severe preeclampsia at less than 26 weeks gestation: The impact of gestational age and severe fetal growth restriction. Am. J. Obstet. Gynecol. 2011;205:465.e1–465.e6. doi: 10.1016/j.ajog.2011.06.062.
    1. Manktelow B.N., Seaton S.E., Field D.J., Draper E.S. Population-based estimates of in-unit survival for very preterm infants. Pediatrics. 2013;131:e425–e432. doi: 10.1542/peds.2012-2189.
    1. Menzies J., Magee L.A., Li J., MacNab Y.C., Yin R., Stuart H., Baraty B., Lam E., Hamilton T., Lee S.K., et al. Instituting surveillance guidelines and adverse outcomes in preeclampsia. Obstet. Gynecol. 2007;110:121–127. doi: 10.1097/01.AOG.0000266977.26311.f0.
    1. Zeisler H., Llurba E., Chantraine F., Vatish M., Staff A., Sennström M., Olovsson M., Brennecke S., Stepan H., Allegranza D., et al. Prediction of short-term outcome in pregnant women with suspected preeclampsia: The PROGNOSIS study. [(accessed on 11 August 2015)]. COGI 2014, Paris. Abstract P79. Available online: .
    1. Rana S., Karumanchi S.A., Lindheimer M.D. Angiogenic factors in diagnosis, management, and research in preeclampsia. Hypertension. 2014;63:198–202. doi: 10.1161/HYPERTENSIONAHA.113.02293.
    1. Schnettler W., Dukhovny D., Wenger J., Salahuddin S., Ralston S., Rana S. Cost and resource implications with serum angiogenic factor estimation in the triage of pre-eclampsia. BJOG. 2013;120:1224–1232. doi: 10.1111/1471-0528.12259.
    1. Verlohren S., Herraiz I., Lapaire O., Schlembach D., Moertl M., Zeisler H., Calda P., Holzgreve W., Galindo A., Engels T., 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. doi: 10.1016/j.ajog.2011.07.037.
    1. Rana S., Powe C.E., Salahuddin S., Verlohren S., Perschel F.H., Levine R.J., Lim K.H., Wenger J.B., Thadhani R., Karumanchi S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125:911–919. doi: 10.1161/CIRCULATIONAHA.111.054361.
    1. Schaarschmidt W., Rana S., Stepan H. The course of angiogenic factors in early- vs. late-onset preeclampsia and HELLP síndrome. J. Perinat. Med. 2013;41:511–516.
    1. Dröge L., Herraìz I., Zeisler H., Schlembach D., Stepan H., Küssel L., Henrich W., Galindo A., Verlohren S. 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. doi: 10.1002/uog.14760.
    1. Rana S., Venkatesha S., DePaepe M., Chien E.K., Paglia M., Karumanchi S.A. Cytomegalovirus-induced mirror syndrome associated with elevated levels of circulating antiangiogenic factors. Obstet. Gynecol. 2007;109:549–552. doi: 10.1097/.
    1. Bdolah Y., Palomaki G.E., Yaron Y., Bdolah-Abram T., Goldman M., Levine R.J., Sachs B.P., Haddow J.E., Karumanchi S.A. Circulating angiogenic proteins in trisomy 13. Am. J. Obstet. Gynecol. 2006;194:239–245. doi: 10.1016/j.ajog.2005.06.031.
    1. Llurba E., Sánchez O., Ferrer Q., Nicolaides K.H., Ruíz A., Domínguez C., Sánchez-de-Toledo J., García-García B., Soro G., Arévalo S., Goya M., et al. Maternal and foetal angiogenic imbalance in congenital heart defects. Eur. Heart J. 2014;35:701–707. doi: 10.1093/eurheartj/eht389.

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