Anti-angiogenesis and Preeclampsia in 2016

  • Susanne Schrey-Petersen
  • Holger Stepan
Preeclampsia (V Garovic, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Preeclampsia


Purpose of Review

Preeclampsia remains one of the most important complications in pregnancy worldwide. With this review, we aim to give an overview on important research findings over the last years and their effects on current clinical management.

Recent Findings

The association between preeclampsia and altered angiogenesis is nowadays widely accepted. Only during the last years, assessment of angiogenic factors such as the soluble fms-like tyrosine kinase-1-to-placental growth factor (sFlt-1/PlGF) ratio has become available to everyday clinical practice with commercially available automated measurements. With these, preeclampsia can be confirmed or ruled out in uncertainty of diagnosis, and a short-term prognosis can be given in patients with symptoms of preeclampsia. Pilot studies show that maternal serum levels of sFlt-1 can be reduced by therapeutic apheresis and that this might prolong pregnancy in case of very early severe preeclampsia.


The automated measurement of the sFlt-1/PlGF ratio is starting to influence clinical management of preeclampsia. Apheresis might offer new treatment options, but still needs to be evaluated in randomized trials.


Preeclampsia Anti-angiogenesis Placental growth factor (PlGF) Soluble fms-like tyrosinkinase-1 (sFlt-1) 


Compliance with Ethical Standards

Conflict of Interest

Drs. Schrey-Petersen declares no conflicts of interest relevant to this manuscript. Dr. Stepan has received speaker fees from and has worked as a consultant for Roche Diagnostics.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    WHO, Make every mother and child count. Geneva: World Health Report 2005. 2005.Google Scholar
  2. 2.
    Knight M K.S., Brocklehurst P, Neilson J, Shakespeare J, Kurinczuk JJ, eds, on behalf of MBRRACEUK. Oxford: National Perinatal Epidemiology Unit, University of Oxford, Saving lives, improving mothers’care—lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–12. 2014.Google Scholar
  3. 3.
    Goldenberg RL, et al. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.PubMedCrossRefGoogle Scholar
  4. 4.
    Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet. 2001;357(9273):2002–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Garovic VD, Hayman SR. Hypertension in pregnancy: an emerging risk factor for cardiovascular disease. Nat Clin Pract Nephrol. 2007;3(11):613–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Grand'Maison S, et al. Markers of vascular dysfunction after hypertensive disorders of pregnancy: a systematic review and meta-analysis. Hypertension. 2016;68(6):1447–58.PubMedCrossRefGoogle Scholar
  7. 7.
    Roberts JM, et al. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161(5):1200–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Stillman IE, Karumanchi SA. The glomerular injury of preeclampsia. J Am Soc Nephrol. 2007;18(8):2281–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Eremina V, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111(5):707–16.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Eremina V, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Patel TV, et al. 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):282–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Chaiworapongsa T, 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(1):3–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993;90(22):10705–9.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Taylor RN, et al. Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol. 2003;188(1):177–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Torry DS, et al. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol. 1998;179(6 Pt 1):1539–44.PubMedCrossRefGoogle Scholar
  17. 17.
    Levine RJ, Karumanchi SA. Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol. 2005;48(2):372–86.PubMedCrossRefGoogle Scholar
  18. 18.
    Thadhani R, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab. 2004;89(2):770–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Thadhani R, et al. First-trimester sex hormone binding globulin and subsequent gestational diabetes mellitus. Am J Obstet Gynecol. 2003;189(1):171–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Salahuddin S, et al. Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Am J Obstet Gynecol. 2007;197(1):28 e1–6.CrossRefGoogle Scholar
  21. 21.
    Chaiworapongsa T, 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(6):1541–7. discussion 1547-50PubMedCrossRefGoogle Scholar
  22. 22.
    Veas CJ, 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(11):1371–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Wikstrom AK, et al. Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia. Obstet Gynecol. 2007;109(6):1368–74.PubMedCrossRefGoogle Scholar
  24. 24.
    Maynard SE, 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(5):649–58.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Levine RJ, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355(10):992–1005.PubMedCrossRefGoogle Scholar
  26. 26.
    Herse F, 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(2):393–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Kim YN, et al. The relationship of the level of circulating antiangiogenic factors to the clinical manifestations of preeclampsia. Prenat Diagn. 2009;29(5):464–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Masuyama H, et al. Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia. BJOG. 2010;117(3):314–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Tripathi R, et al. Soluble and membranous vascular endothelial growth factor receptor-1 in pregnancies complicated by pre-eclampsia. Ann Anat. 2008;190(5):477–89.PubMedCrossRefGoogle Scholar
  30. 30.
    Ohkuchi A, 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(2):151–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Verlohren S, 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(2):161 e1–161 e11.CrossRefGoogle Scholar
  32. 32.
    Benton SJ, et al. Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays. Am J Obstet Gynecol. 2011;205(5):469 e1–8.CrossRefGoogle Scholar
  33. 33.
    Ohkuchi A, et al. Evaluation of a new and automated electrochemiluminescence immunoassay for plasma sFlt-1 and PlGF levels in women with preeclampsia. Hypertens Res. 2010;33(5):422–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Schiettecatte J, et al. Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia. Clin Biochem. 2010;43(9):768–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Sunderji S, et al. 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(1):40 e1–7.CrossRefGoogle Scholar
  36. 36.
    Wothe D, 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(1):18–27.PubMedCrossRefGoogle Scholar
  37. 37.
    • Rana S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125(7):911–9. This prospective study in 616 women who presented with suspected preeclampsia showed that the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (area under the curve, 0.93 for hypertension, proteinuria, and sFlt1/PlGF versus 0.84 for hypertension and proteinuria alone; P =0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt1/PlGF ratio ≥85 compared with 15.8% of women with an sFlt1/PlGF ratio <85 (hazard ratio, 15.2; 95% confidence interval, 8.0-28.7) PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Verlohren S, 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(2):346–52.PubMedCrossRefGoogle Scholar
  39. 39.
    Droge 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(3):286–93.PubMedCrossRefGoogle Scholar
  40. 40.
    • Zeisler H, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(1):13–22. This large prospective, observational study demonstrated that an sFlt-1/PlGF ratio of ≤38 could be used to rule out onset of preeclampsia within 1 week with a negative predictive value of 99.3% in women who presented with symptoms of preeclampsia before 37 weeks of gestation PubMedCrossRefGoogle Scholar
  41. 41.
    • Chappell LC, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation. 2013;128(19):2121–31. This prospective multicenter study showed that in women with suspected preeclampsia before 35 weeks onset of preeclampsia within 2 weeks could be ruled out by a PlGF <5th perecentile with a high sensitivity (0.96; 95% CI, 0.89-0.99) and negative predictive value (0.98; 0.93-0.995) PubMedCrossRefGoogle Scholar
  42. 42.
    Guidelines, N.. PlGF-based testing to help diagnose suspected preeclampsia (Triage PlGF test, Elecsys immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1–2-3 test, and Brahms sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio). Published May 2016, N. Guidelines, Editor. 2016.Google Scholar
  43. 43.
    Noori M, et al. Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension. Circulation. 2010;122(5):478–87.PubMedCrossRefGoogle Scholar
  44. 44.
    Romero R, 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(1):9–23.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    De Vivo A, et al. Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia. Acta Obstet Gynecol Scand. 2008;87(8):837–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Lim JH, et al. Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors. Obstet Gynecol. 2008;111(6):1403–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Hertig A, et al. Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem. 2004;50(9):1702–3.PubMedCrossRefGoogle Scholar
  48. 48.
    Madazli R, et al. Prediction of preeclampsia with maternal mid-trimester placental growth factor, activin a, fibronectin and uterine artery Doppler velocimetry. Int J Gynaecol Obstet. 2005;89(3):251–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Baumann MU, et al. 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(3):266 e1–6.CrossRefGoogle Scholar
  50. 50.
    Smith GC, 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(6):1316–24.PubMedCrossRefGoogle Scholar
  51. 51.
    Rana S, et al. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Hypertension. 2007;50(1):137–42.PubMedCrossRefGoogle Scholar
  52. 52.
    Costa SL, et al. Screening for placental insufficiency in high-risk pregnancies: is earlier better? Placenta. 2008;29(12):1034–40.PubMedCrossRefGoogle Scholar
  53. 53.
    Poon LC, et al. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53(5):812–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Moore Simas TA, et al. Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet Gynecol. 2007;197(3):244 e1–8.CrossRefGoogle Scholar
  55. 55.
    Powers RW, et al. Soluble fms-like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies. PLoS One. 2010;5(10):e13263.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Sibai BM, et al. Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia? Am J Obstet Gynecol. 2008;199(3):268 e1–9.CrossRefGoogle Scholar
  57. 57.
    Stepan H, 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(3):241–6.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Schlembach D, et al. Angiogenic growth factor levels in maternal and fetal blood: correlation with Doppler ultrasound parameters in pregnancies complicated by pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol. 2007;29(4):407–13.PubMedCrossRefGoogle Scholar
  59. 59.
    Petzold K, et al. Relation between maternal angiogenic factors and utero-placental resistance in normal first- and second-trimester pregnancies. Hypertens Pregnancy. 2011;30(4):401–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Soto E, et al. Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion. J Matern Fetal Neonatal Med. 2012;25(5):498–507.PubMedCrossRefGoogle Scholar
  61. 61.
    Gomez-Arriaga PI, et al. Uterine artery Doppler and sFlt-1/PlGF ratio: usefulness in diagnosis of pre-eclampsia. Ultrasound Obstet Gynecol. 2013;41(5):530–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Chaiworapongsa T, et al. The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation. J Matern Fetal Neonatal Med. 2008;21(1):25–40.PubMedCrossRefGoogle Scholar
  63. 63.
    Crispi F, et al. 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(3):303–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Diab AE, et al. Angiogenic factors for the prediction of pre-eclampsia in women with abnormal midtrimester uterine artery Doppler velocimetry. Int J Gynaecol Obstet. 2008;102(2):146–51.PubMedCrossRefGoogle Scholar
  65. 65.
    Espinoza J, et al. Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor. Am J Obstet Gynecol. 2007;196(4):326 e1–13.CrossRefGoogle Scholar
  66. 66.
    Stepan H, et al. Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion. Am J Obstet Gynecol. 2008;198(2):175 e1–6.CrossRefGoogle Scholar
  67. 67.
    Bolnick JM, et al. Altered biomarkers in trophoblast cells obtained noninvasively prior to clinical manifestation of perinatal disease. Sci Rep. 2016;6:32382.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Klein E, et al. Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia. PLoS One. 2016;11(5):e0156013.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Davison JM. Dialysis, transplantation, and pregnancy. Am J Kidney Dis. 1991;17(2):127–32.PubMedCrossRefGoogle Scholar
  70. 70.
    Martin Jr JN, et al. Plasma exchange for preeclampsia: II. Unsuccessful antepartum utilization for severe preeclampsia with or without HELLP syndrome. J Clin Apher. 1994;9(3):155–61.PubMedCrossRefGoogle Scholar
  71. 71.
    • Thadhani R, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011;124(8):940–50. This small pilot study showed that circulating sFlt-1 levels in the maternal serum could be lowered by extra-corporal removal with a negatively charged adsoprtion column, which might offer the possibility to prolong pregnancy in very preterm preeclampsia. Further studies are needed to study the efficacy and safety of apheresis in this setting PubMedCrossRefGoogle Scholar
  72. 72.
    Thadhani R, et al. Removal of soluble fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J Am Soc Nephrol. 2016;27(3):903–13.PubMedCrossRefGoogle Scholar
  73. 73.
    Makris A, Yeung KR, Lim SM, Sunderland N, Heffernan S, Thompson JF, Iliopoulos J, Killingsworth MC, Yong J, Xu B, Ogle RF, Thadhani R, Karumanchi SA, Hennessy A. Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in non-human primates. Hypertension. 2016 Jun;67(6):1263–72.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyUniversity of Leipzig Faculty of MedicineLeipzigGermany

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