Preeclampsia pp 175-198 | Cite as


  • Holger StepanEmail author
  • Janine Hoffmann
Part of the Comprehensive Gynecology and Obstetrics book series (CGO)


Due to novel scientific knowledge about molecular pathomechanisms, there is a new understanding of preeclampsia as a placental disease. Angiogenic factors were shown to influence placentation, and in the last decade, intensive research emerged particularly the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) and the pro-angiogenic placental growth factor (PlGF) to be most relevant in this process. Technical efforts and the development of commercially available automated methods firstly enabled maternal serum measurements of these factors and the introduction into daily clinical use. In various clinical studies, the additional value of sFlt-1 and PlGF for diagnosis and even prediction of preeclampsia have been confirmed. This major advance firstly allows a better diagnosis and distinction of preeclampsia, a disease with an extremely heterogeneous clinical appearance, from various different gestation-associated symptoms or diseases. A more precise diagnosis and the feasibility of prediction opened new horizons in clinical management of preeclampsia. This article gives an overview about the latest scientific knowledge about the angiogenic factors sFlt-1 and PlGF and provides actual recommendations for its clinical use for suspected preeclampsia.


Preeclampsia Placental disease Pregnancy sFlt-1 PlGF 


  1. 1.
    Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200–4.CrossRefPubMedGoogle Scholar
  2. 2.
    Maynard SE, Min J-Y, Merchan J, Lim K-H, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–58. Scholar
  3. 3.
    Ossada V, Jank A, Stepan H. The impact of uterine curettage postpartum on maternal sFlt-1 concentration. J Perinat Med. 2016;44:351–4. Scholar
  4. 4.
    Yang JC, et al. A randomized double-blind placebo controlled trial of bevacizumab (anti-VEGF antibody) demonstrating a prolongation in time to progression in patients with metastatic renal cancer. Proc Am Soc Clin Oncol. 2002;21:5a.Google Scholar
  5. 5.
    Patel TV, Morgan JA, Demetri GD, George S, Maki RG, Quigley M, Humphreys BD. A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst. 2008;100(4):282. Scholar
  6. 6.
    Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod. 2003;69:1–7. CrossRefPubMedGoogle Scholar
  7. 7.
    Zygmunt M, Herr F, Münstedt K, Lang U, Liang OD. Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2003;110(Suppl 1):S10–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Stillman IE, Karumanchi SA. The glomerular injury of preeclampsia. J Am Soc Nephrol. 2007;18:2281–4. Scholar
  9. 9.
    Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111:707–16. Scholar
  10. 10.
    Lu F, Longo M, Tamayo E, Maner W, Al-Hendy A, Anderson GD, et al. The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice. Am J Obstet Gynecol. 2007;196:396.e1–396.e7; discussion 396.e7. Scholar
  11. 11.
    Levine RJ, Maynard SE, Qian C, Lim K-H, England LJ, KF Y, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–83. Scholar
  12. 12.
    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;202:161. Scholar
  13. 13.
    Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, et al. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab. 2005;90:4895–903. Scholar
  14. 14.
    de VA, Baviera G, Giordano D, Todarello G, Corrado F, D'anna R. Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia. Acta Obstet Gynecol Scand. 2008;87:837–42. Scholar
  15. 15.
    Ohkuchi A, Hirashima C, Suzuki H, Takahashi K, Yoshida M, Matsubara S, Suzuki M. Evaluation of a new and automated electrochemiluminescence immunoassay for plasma sFlt-1 and PlGF levels in women with preeclampsia. Hypertens Res. 2010;33:422–7. Scholar
  16. 16.
    Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA, Hodges-Savola C. Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study. Am J Obstet Gynecol. 2010;202:40.e1–7. Scholar
  17. 17.
    Tsatsaris V, Goffin F, Munaut C, Brichant J-F, Pignon M-R, Noel A, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab. 2003;88:5555–63. Scholar
  18. 18.
    Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med. 2005;17:3–18. Scholar
  19. 19.
    Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol. 2003;188:177–82.CrossRefPubMedGoogle Scholar
  20. 20.
    Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol. 1998;179:1539–44.CrossRefPubMedGoogle Scholar
  21. 21.
    Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol. 2013;209:544.e1–544.e12. Scholar
  22. 22.
    Levine RJ, Karumanchi SA. Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol. 2005;48:372–86.CrossRefPubMedGoogle Scholar
  23. 23.
    Cohen AL, Wenger JB, James-Todd T, Lamparello BM, Halprin E, Serdy S, et al. The association of circulating angiogenic factors and HbA1c with the risk of preeclampsia in women with preexisting diabetes. Hypertens Pregnancy. 2014;33:81–92. Scholar
  24. 24.
    Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 2008;21:9–23. Scholar
  25. 25.
    Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, 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. Scholar
  26. 26.
    Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, et al. L13. The routine measurement of the sFlt1/PlGF ratio allows differential diagnosis of hypertensive pregnancy disorders and has prognostic potential in preeclamptic patients. Pregnancy Hypertens. 2011;1:245–6. Scholar
  27. 27.
    Kim MY, Buyon JP, Guerra MM, Rana S, Zhang D, Laskin CA, 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. Scholar
  28. 28.
    Spradley FT. Metabolic abnormalities and obesity's impact on the risk for developing preeclampsia. Am J Physiol Regul Integr Comp Physiol. 2017;312:R5–R12. Scholar
  29. 29.
    Vellanki K. Pregnancy in chronic kidney disease. Adv Chronic Kidney Dis. 2013;20:223–8. Scholar
  30. 30.
    Tripathi R, Rath G, Jain A, Salhan S. Soluble and membranous vascular endothelial growth factor receptor-1 in pregnancies complicated by pre-eclampsia. Ann Anat. 2008;190:477–89. Scholar
  31. 31.
    Munaut C, Lorquet S, Pequeux C, Blacher S, Berndt S, Frankenne F, Foidart J-M. Hypoxia is responsible for soluble vascular endothelial growth factor receptor-1 (VEGFR-1) but not for soluble endoglin induction in villous trophoblast. Hum Reprod. 2008;23:1407–15. Scholar
  32. 32.
    Stepanian A, Bourguignat L, Hennou S, Coupaye M, Hajage D, Salomon L, et al. Microparticle increase in severe obesity: not related to metabolic syndrome and unchanged after massive weight loss. Obesity (Silver Spring). 2013;21:2236–43. CrossRefGoogle Scholar
  33. 33.
    Zhang X, McGeoch SC, Johnstone AM, Holtrop G, Sneddon AA, MacRury SM, et al. Platelet-derived microparticle count and surface molecule expression differ between subjects with and without type 2 diabetes, independently of obesity status. J Thromb Thrombolysis. 2014;37:455–63. Scholar
  34. 34.
    Sabatier F, Darmon P, Hugel B, Combes V, Sanmarco M, Velut J-G, et al. Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes. 2002;51:2840–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Preston RA, Jy W, Jimenez JJ, Mauro LM, Horstman LL, Valle M, et al. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension. 2003;41:211–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Lacroix R, Plawinski L, Robert S, Doeuvre L, Sabatier F, Martinez de Lizarrondo S, et al. Leukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis. Haematologica. 2012;97:1864–72. Scholar
  37. 37.
    Dignat-George F, Camoin-Jau L, Sabatier F, Arnoux D, Anfosso F, Bardin N, et al. Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. Thromb Haemost. 2004;91:667–73. Scholar
  38. 38.
    Tannetta DS, Dragovic RA, Gardiner C, Redman CW, Sargent IL. Characterisation of syncytiotrophoblast vesicles in normal pregnancy and pre-eclampsia: expression of Flt-1 and endoglin. PLoS One. 2013;8:e56754. Scholar
  39. 39.
    Ali A, Ganai J, Muthukrishnan S, Kohli S. Evaluation of autonomic dysfunction in obese and non-obese hypertensive subjects. J Clin Diagn Res. 2016;10:YC01–3. Scholar
  40. 40.
    Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 2006;12:1065–74. Scholar
  41. 41.
    Wilson ML, Goodwin TM, Pan VL, Ingles SA. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv. 2003;58:39–66. CrossRefPubMedGoogle Scholar
  42. 42.
    Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jüpner A, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest. 1999;103:945–52. Scholar
  43. 43.
    Zhou CC, Zhang Y, Irani RA, Zhang H, Mi T, Popek EJ, et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med. 2008;14:855–62. Scholar
  44. 44.
    ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002;77:67–75.CrossRefGoogle Scholar
  45. 45.
    Tranquilli AL, Brown MA, Zeeman GG, Dekker G, Sibai BM. The definition of severe and early-onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Pregnancy Hypertens. 2013;3:44–7. Scholar
  46. 46.
    Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee Kim Y, Gonçalves LF, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol. 2004;190:1541–1547; discussion 1547–50. Scholar
  47. 47.
    Veas CJ, Aguilera VC, Muñoz IJ, Gallardo VI, Miguel PL, González MA, et al. Fetal endothelium dysfunction is associated with circulating maternal levels of sE-selectin, sVCAM1, and sFlt-1 during pre-eclampsia. J Matern Fetal Neonatal Med. 2011;24:1371–7. Scholar
  48. 48.
    Herse F, Verlohren S, Wenzel K, Pape J, Muller DN, Modrow S, et al. Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study. Hypertension. 2009;53:393–8. Scholar
  49. 49.
    Kim YN, Lee DS, Jeong DH, Sung MS, Kim KT. The relationship of the level of circulating antiangiogenic factors to the clinical manifestations of preeclampsia. Prenat Diagn. 2009;29:464–70. Scholar
  50. 50.
    Masuyama H, Segawa T, Sumida Y, Masumoto A, Inoue S, Akahori Y, Hiramatsu Y. Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia. BJOG. 2010;117:314–20. Scholar
  51. 51.
    Ohkuchi A, Hirashima C, Matsubara S, Suzuki H, Takahashi K, Arai F, et al. Alterations in placental growth factor levels before and after the onset of preeclampsia are more pronounced in women with early onset severe preeclampsia. Hypertens Res. 2007;30:151–9. Scholar
  52. 52.
    Wikström A-K, Larsson A, Eriksson UJ, Nash P, Nordén-Lindeberg S, Olovsson M. Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia. Obstet Gynecol. 2007;109:1368–74. Scholar
  53. 53.
    Levine RJ, Lam C, Qian C, KF Y, Maynard SE, Sachs BP, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005. Scholar
  54. 54.
    Salahuddin S, Lee Y, Vadnais M, Sachs BP, Karumanchi SA, Lim K-H. Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Am J Obstet Gynecol. 2007;197:28.e1–6. Scholar
  55. 55.
    Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ. Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension. Circulation. 2010;122:478–87. Scholar
  56. 56.
    Vuorela P, Helske S, Hornig C, Alitalo K, Weich H, Halmesmäki E. Amniotic fluid—soluble vascular endothelial growth factor receptor-1 in preeclampsia. Obstet Gynecol. 2000;95:353–7.PubMedGoogle Scholar
  57. 57.
    Benton SJ, Hu Y, Xie F, Kupfer K, Lee S-W, Magee LA, von Dadelszen P. Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays. Am J Obstet Gynecol. 2011;205:469.e1–8. Scholar
  58. 58.
    Schiettecatte J, Russcher H, Anckaert E, Mees M, Leeser B, Tirelli AS, et al. Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia. Clin Biochem. 2010;43:768–70. Scholar
  59. 59.
    Wothe D, Gaziano E, Sunderji S, Romero R, Kusanovic JP, Rogers L, et al. Measurement of sVEGF R1 and PlGF in serum: comparing prototype assays from Beckman Coulter, Inc. to R&D Systems microplate assays. Hypertens Pregnancy. 2011;30:18–27. Scholar
  60. 60.
    Verlohren S, Herraiz I, Lapaire O, Schlembach D, Zeisler H, Calda P, 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;63:346–52. Scholar
  61. 61.
    Rana S, Schnettler WT, Powe C, Wenger J, Salahuddin S, Cerdeira AS, et al. Clinical characterization and outcomes of preeclampsia with normal angiogenic profile. Hypertens Pregnancy. 2013;32:189–201. Scholar
  62. 62.
    Hoffmann J, Ossada V, Weber M, Stepan H. An intermediate sFlt-1/PlGF ratio indicates an increased risk for adverse pregnancy outcome. Pregnancy Hypertens. 2017;10:165–70. Scholar
  63. 63.
    Dröge L, Herraìz I, Zeisler H, Schlembach D, Stepan H, Küssel L, 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;45:286–93. Scholar
  64. 64.
    Bdolah Y, Lam C, Rajakumar A, Shivalingappa V, Mutter W, Sachs BP, et al. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol. 2008;198:428. Scholar
  65. 65.
    Rana S, Hacker MR, Modest AM, Salahuddin S, Lim K-H, Verlohren S, et al. Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia. Hypertension. 2012;60:451–8. Scholar
  66. 66.
    Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders in twin versus singleton gestations. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol. 2000;182:938–42.CrossRefPubMedGoogle Scholar
  67. 67.
    Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de PMC, et al. Aspirin versus Placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377:613–22. Scholar
  68. 68.
    Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116:402–14. Scholar
  69. 69.
    Roberge S, Villa P, Nicolaides K, Giguère Y, Vainio M, Bakthi A, et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther. 2012;31:141–6. Scholar
  70. 70.
    National Collaborating Centre for Women’s and Children's Health (UK). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. NICE Clinical Guidelines. 2010.Google Scholar
  71. 71.
    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;122:1122–31. Scholar
  72. 72.
    Committee Opinion No. 638: First-Trimester Risk Assessment for Early-Onset Preeclampsia. Obstet Gynecol. 2015;126:e25–7.
  73. 73.
    Committee Opinion Summary No. 638: First-Trimester Risk Assessment for Early-Onset Preeclampsia. Obstet Gynecol. 2015;126:689.
  74. 74.
    Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. S1-Leitlinie: Diagnostik und Therapie hypertensiver Schwangerschaftserkrankungen. 12/2013.Google Scholar
  75. 75.
    Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. 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. Scholar
  76. 76.
    Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther. 2013;33:8–15. CrossRefPubMedGoogle Scholar
  77. 77.
    Rolnik DL, Wright D, Poon LC, Syngelaki A, O’Gorman N, de Paco Matallana C, et al. ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol. 2017.
  78. 78.
    Poon LCY, Kametas NA, Chelemen T, Leal A, Nicolaides KH. Maternal risk factors for hypertensive disorders in pregnancy: a multivariate approach. J Hum Hypertens. 2010;24:104–10. Scholar
  79. 79.
    Poon LCY, Akolekar R, Lachmann R, Beta J, Nicolaides KH. Hypertensive disorders in pregnancy: screening by biophysical and biochemical markers at 11-13 weeks. Ultrasound Obstet Gynecol. 2010;35:662–70. PubMedGoogle Scholar
  80. 80.
    O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright A, et al. Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks’ gestation. Ultrasound Obstet Gynecol. 2017;49:751–5. Scholar
  81. 81.
    O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, de Alvarado M, et al. Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks’ gestation: comparison with NICE guidelines and ACOG recommendations. Ultrasound Obstet Gynecol. 2017;49:756–60. Scholar
  82. 82.
    Poon LC, Wright D, Rolnik DL, Syngelaki A, Delgado JL, Tsokaki T, et al. ASPRE trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history. Am J Obstet Gynecol. 2017.
  83. 83.
    Poon LCY, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53:812–8. Scholar
  84. 84.
    Baumann MU, Bersinger NA, Mohaupt MG, Raio L, Gerber S, Surbek DV. 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.e1–6. Scholar
  85. 85.
    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;109:1316–24. Scholar
  86. 86.
    Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA, Tamez H, Thadhani R. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Hypertension. 2007;50:137–42. Scholar
  87. 87.
    Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab. 2004;89:770–5. Scholar
  88. 88.
    Bolnick JM, Kohan-Ghadr H-R, Fritz R, Bolnick AD, Kilburn BA, Diamond MP, et al. Altered biomarkers in trophoblast cells obtained noninvasively prior to clinical manifestation of perinatal disease. Sci Rep. 2016;6:32382. Scholar
  89. 89.
    Chappell LC, Duckworth S, Seed PT, Griffin M, Myers J, Mackillop L, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation. 2013;128:2121–31. Scholar
  90. 90.
    Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125:911–9. Scholar
  91. 91.
    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;374:13–22. Scholar
  92. 92.
    Zhang J, Klebanoff MA, Roberts JM. Prediction of adverse outcomes by common definitions of hypertension in pregnancy. Obstet Gynecol. 2001;97:261–7.PubMedGoogle Scholar
  93. 93.
    Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, et al. Soluble fms-ike tyrosine kinase-1-to-Placental growth factor ratio and time to delivery in women with suspected preeclampsia. Obstet Gynecol. 2016;128:261–9.
  94. 94.
    Milne F, Redman C, Walker J, Baker P, Black R, Blincowe J, et al. Assessing the onset of pre-eclampsia in the hospital day unit: summary of the pre-eclampsia guideline (PRECOG II). BMJ. 2009;339:b3129. Scholar
  95. 95.
    Klein E, Schlembach D, Ramoni A, Langer E, Bahlmann F, Grill S, et al. Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia. PLoS One. 2016;11:e0156013. Scholar
  96. 96.
    Chaiworapongsa T, Chaemsaithong P, Korzeniewski SJ, Yeo L, Romero R. Pre-eclampsia part 2: prediction, prevention and management. Nat Rev Nephrol. 2014;10:531–40. Scholar
  97. 97.
    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;45:241–6. Scholar
  98. 98.
    Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vaisbuch E, 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;22:1021–38. Scholar
  99. 99.
    Lim JH, Kim SY, Park SY, Yang JH, Kim MY, Ryu HM. Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors. Obstet Gynecol. 2008;111:1403–9. Scholar
  100. 100.
    Kim S-Y, Ryu H-M, Yang J-H, Kim M-Y, Han J-Y, Kim J-O, et al. Increased sFlt-1 to PlGF ratio in women who subsequently develop preeclampsia. J Korean Med Sci. 2007;22:873–7. Scholar
  101. 101.
    Stepan H, Unversucht A, Wessel N, Faber R. Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion. Hypertension. 2007;49:818–24. Scholar
  102. 102.
    Lapaire O, Shennan A, Stepan H. The preeclampsia biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor: current knowledge, clinical implications and future application. Eur J Obstet Gynecol Reprod Biol. 2010;151:122–9. Scholar
  103. 103.
    Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda). 2009;24:147–58. Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of ObstetricsUniversity of LeipzigLeipzigGermany

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