Preeclampsia pp 227-237 | Cite as

Novel Therapies for Preeclampsia

  • Suzanne D. Burke
  • S. Ananth KarumanchiEmail author
Part of the Comprehensive Gynecology and Obstetrics book series (CGO)


Preeclampsia is a complex, hypertensive gestational syndrome that lacks a clear pathogenesis, which has prevented development of effective therapies. Mechanistic evidence points to an augmented anti-angiogenic balance, with sFlt1 and other soluble factors contributing to maternal hypertension and proteinuria. This chapter will review novel research and therapeutic strategies, including recombinant proteins, small molecules, apheresis, and off-label use of medications.


Preeclampsia Pregnancy Vascular endothelial growth factor (VEGF) Anti-angiogenesis 


  1. 1.
    Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011;123(24):2856–69.CrossRefPubMedGoogle Scholar
  2. 2.
    Karumanchi SA. Angiogenic factors in preeclampsia: from diagnosis to therapy. Hypertension. 2016;67(6):1072–9.CrossRefPubMedGoogle Scholar
  3. 3.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Maynard SE, Min JY, Merchan J, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab. 2003;88(11):5555–63.CrossRefPubMedGoogle Scholar
  6. 6.
    Chaiworapongsa T, Romero R, Kim YM, 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Hertig A, Berkane N, Lefevre G, et al. Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem. 2004;50(9):1702–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.CrossRefPubMedGoogle Scholar
  9. 9.
    Chaiworapongsa T, Romero R, Espinoza J, 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 1547–1550.CrossRefPubMedGoogle Scholar
  10. 10.
    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(1):177–82.CrossRefPubMedGoogle Scholar
  11. 11.
    Thadhani R, Mutter WP, Wolf M, 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.CrossRefPubMedGoogle Scholar
  12. 12.
    Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res. 2004;95(9):884–91.CrossRefPubMedGoogle Scholar
  13. 13.
    Lu F, Longo M, Tamayo E, 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(4):396.e1–397; discussion 396.e7.CrossRefGoogle Scholar
  14. 14.
    Szabat M, Johnson JD, Piret JM. Reciprocal modulation of adult beta cell maturity by activin A and follistatin. Diabetologia. 2010;53(8):1680–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Patel TV, Morgan JA, Demetri GD, 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.CrossRefPubMedGoogle Scholar
  17. 17.
    Izzedine H, Escudier B, Lhomme C, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine. 2014;93(24):333–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Eremina V, Sood M, Haigh J, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Burke SD, Zsengeller ZK, Khankin EV, et al. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J Clin Invest. 2016;126(7):2561–74.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Craici IM, Wagner SJ, Bailey KR, et al. Podocyturia predates proteinuria and clinical features of preeclampsia: longitudinal prospective study. Hypertension. 2013;61(6):1289–96.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tuohy JF, James DK. Pre-eclampsia and trisomy 13. Br J Obstet Gynaecol. 1992;99(11):891–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Dotters-Katz SK, Humphrey WM, Senz KL, et al. Trisomy 13 and the risk of gestational hypertensive disorders: a population-based study. J Matern Fetal Neonatal Med. 2017;2:1–5.Google Scholar
  24. 24.
    Bdolah Y, Palomaki GE, Yaron Y, et al. Circulating angiogenic proteins in trisomy 13. Am J Obstet Gynecol. 2006;194(1):239–45.CrossRefPubMedGoogle Scholar
  25. 25.
    Silasi M, Rana S, Powe C, et al. Placental expression of angiogenic factors in Trisomy 13. Am J Obstet Gynecol. 2011;204(6):546.e1–4.CrossRefGoogle Scholar
  26. 26.
    McGinnis R, Steinthorsdottir V, Williams NO, et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nat Genet. 2017;49(8):1255–60.CrossRefPubMedGoogle Scholar
  27. 27.
    Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12(6):642–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Kumar S, Pan CC, Bloodworth JC, et al. Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-beta signaling. Oncogene. 2014;33(30):3970–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Kaitu'u-Lino TJ, Tuohey L, Ye L, Palmer K, Skubisz M, Tong S. MT-MMPs in pre-eclamptic placenta: relationship to soluble endoglin production. Placenta. 2013;34(2):168–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Maharaj AS, Walshe TE, Saint-Geniez M, et al. VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med. 2008;205(2):491–501.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Caniggia I, Taylor CV, Ritchie JW, Lye SJ, Letarte M. Endoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants. Endocrinology. 1997;138(11):4977–88.CrossRefPubMedGoogle Scholar
  32. 32.
    Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355(10):992–1005.CrossRefPubMedGoogle Scholar
  33. 33.
    Romero R, Nien JK, Espinoza J, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Valbuena-Diez AC, Blanco FJ, Oujo B, et al. Oxysterol-induced soluble endoglin release and its involvement in hypertension. Circulation. 2012;126(22):2612–24.CrossRefPubMedGoogle Scholar
  35. 35.
    Rossi E, Smadja DM, Boscolo E, et al. Endoglin regulates mural cell adhesion in the circulatory system. Cell Mol Life Sci. 2016;73(8):1715–39.CrossRefPubMedGoogle Scholar
  36. 36.
    Nakashima A, Yamanaka-Tatematsu M, Fujita N, et al. Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia. Autophagy. 2013;9(3):303–16.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cudmore M, Ahmad S, Al-Ani B, et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation. 2007;115(13):1789–97.CrossRefPubMedGoogle Scholar
  38. 38.
    Cui Y, Wang W, Dong N, et al. Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature. 2012;484(7393):246–50.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ho L, Van Dijk M, Chye STJ, et al. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science. 2017;357(6352):707–13.CrossRefPubMedGoogle Scholar
  40. 40.
    Kanasaki K, Palmsten K, Sugimoto H, et al. Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature. 2008;453(7198):1117–21.CrossRefPubMedGoogle Scholar
  41. 41.
    Chappell LC, Duckworth S, Seed PT, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation. 2013;128(19):2121–31.CrossRefPubMedGoogle Scholar
  42. 42.
    Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125(7):911–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Sunderji S, Gaziano E, Wothe D, 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
  44. 44.
    Verdonk K, Visser W, Russcher H, Danser AH, Steegers EA, van den Meiracker AH. Differential diagnosis of preeclampsia: remember the soluble fms-like tyrosine kinase 1/placental growth factor ratio. Hypertension. 2012;60(4):884–90.CrossRefPubMedGoogle Scholar
  45. 45.
    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(1):58.e1–8.CrossRefGoogle Scholar
  46. 46.
    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(1):13–22.CrossRefPubMedGoogle Scholar
  47. 47.
    Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377:613–22.CrossRefPubMedGoogle Scholar
  48. 48.
    Thadhani R, Hagmann H, Schaarschmidt W, 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.CrossRefPubMedGoogle Scholar
  49. 49.
    Bergmann A, Ahmad S, Cudmore M, et al. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J Cell Mol Med. 2010;14(6B):1857–67.CrossRefPubMedGoogle Scholar
  50. 50.
    Li Z, Zhang Y, Ying Ma J, et al. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension. 2007;50(4):686–92.CrossRefPubMedGoogle Scholar
  51. 51.
    Kumasawa K, Ikawa M, Kidoya H, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A. 2011;108(4):1451–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Makris A, Yeung KR, Lim SM, et al. Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates. Hypertension. 2016;67(6):1263–72.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Spradley FT, Tan AY, Joo WS, et al. Placental growth factor administration abolishes placental ischemia-induced hypertension. Hypertension. 2016;67(4):740–7.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Motta C, Grosso C, Zanuzzi C, et al. Effect of sildenafil on pre-eclampsia-like mouse model induced by L-name. Reprod Domest Anim. 2015;50(4):611–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Ramesar SV, Mackraj I, Gathiram P, Moodley J. Sildenafil citrate improves fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):22–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Trapani A Jr, Goncalves LF, Trapani TF, Vieira S, Pires M, Pires MM. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial. Obstet Gynecol. 2016;128(2):253–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Ganzevoort W, Alfirevic Z, von Dadelszen P, et al. STRIDER: Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction—a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Syst Rev. 2014;3:23.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Rana S, Rajakumar A, Geahchan C, et al. Ouabain inhibits placental sFlt1 production by repressing HSP27-dependent HIF-1alpha pathway. FASEB J. 2014;28(10):4324–34.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Onda K, Tong S, Beard S, et al. Proton pump inhibitors decrease soluble fms-like tyrosine kinase-1 and soluble endoglin secretion, decrease hypertension, and rescue endothelial dysfunction. Hypertension. 2017;69(3):457–68.CrossRefPubMedGoogle Scholar
  60. 60.
    Cluver CA, Walker SP, Mol BW, et al. Double blind, randomised, placebo-controlled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): a study protocol. BMJ Open. 2015;5(10):e008211.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Thadhani R, Kisner T, Hagmann H, et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation. 2011;124(8):940–50.CrossRefPubMedGoogle Scholar
  62. 62.
    Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122–31.Google Scholar
  63. 63.
    Haddad B, Winer N, Chitrit Y, et al. Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications: a randomized controlled trial. Obstet Gynecol. 2016;128(5):1053–63.CrossRefPubMedGoogle Scholar
  64. 64.
    Roberts JM, Myatt L, Spong CY, et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010;362(14):1282–91.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, Group PC. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017;216(2):110–20.e116.CrossRefPubMedGoogle Scholar
  67. 67.
    Unemori E, Sibai B, Teichman SL. Scientific rationale and design of a phase i safety study of relaxin in women with severe preeclampsia. Ann N Y Acad Sci. 2009;1160:381–4.CrossRefPubMedGoogle Scholar
  68. 68.
    Jiang X, Bar HY, Yan J, et al. A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1). FASEB J. 2013;27(3):1245–53.CrossRefPubMedGoogle Scholar
  69. 69.
    Fushima T, Sekimoto A, Oe Y, et al. Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure. Am J Physiol Renal Physiol. 2017;312(2):F366–72.CrossRefPubMedGoogle Scholar
  70. 70.
    Li F, Fushima T, Oyanagi G, et al. Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia. Proc Natl Acad Sci U S A. 2016;113(47):13450–5.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Fisk NM, Atun R. Market failure and the poverty of new drugs in maternal health. PLoS Med. 2008;5(1):e22.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Grigsby PL. Animal models to study placental development and function throughout normal and dysfunctional human pregnancy. Semin Reprod Med. 2016;34(1):11–6.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA

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