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Unravelling the potential of angiogenic factors for the early prediction of preeclampsia

Abstract

Preeclampsia is a multisystem, multiorgan hypertensive disorder of pregnancy responsible for maternal and perinatal morbidity and mortality in low- and middle-income countries. The classic diagnostic features hold less specificity for preeclampsia and its associated adverse outcomes, suggesting a need for specific and reliable biomarkers for the early prediction of preeclampsia. The imbalance of pro- and antiangiogenic circulatory factors contributes to the pathophysiology of preeclampsia. Several studies have examined the profile of angiogenic factors in preeclampsia to search for a biomarker that will improve the diagnostic ability of preeclampsia and associated adverse outcomes. This may help in more efficient patient management and the reduction of associated health care costs. This article reviews the findings from previous studies published to date on angiogenic factors and suggests a need to apply a multivariable model from the beginning of pregnancy and continuing throughout gestation for the early and specific prediction of preeclampsia.

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References

  1. Schlembach D, Hund M, Wolf C, Vatish M. Diagnostic utility of angiogenic biomarkers in pregnant women with suspected preeclampsia: a health economics review. Pregnancy Hypertens. 2019;17:28–35. https://doi.org/10.1016/j.preghy.2019.03.002

    Article  PubMed  Google Scholar 

  2. Flint EJ, Cerdeira AS, Redman CW, Vatish M. The role of angiogenic factors in the management of preeclampsia. Acta Obstet Gynecol Scand. 2019;98:700–707. https://doi.org/10.1111/aogs.13540

    Article  PubMed  Google Scholar 

  3. Palmer KR, Tong S, Kaitu’u-Lino TJ. Placental-specific sFLT-1: role in pre-eclamptic pathophysiology and its translational possibilities for clinical prediction and diagnosis. Mol Hum Reprod. 2016;23:69–78. https://doi.org/10.1093/molehr/gaw077

    Article  CAS  Google Scholar 

  4. Govender N, Moodley J, Naicker T. The Use of Soluble FMS-like Tyrosine Kinase 1/Placental Growth Factor Ratio in the Clinical Management of Pre-eclampsia. Afr J Reprod Health. 2018;22:135–143. https://doi.org/10.29063/ajrh2018/v22i1.14

    Article  PubMed  Google Scholar 

  5. Gupte S, Wagh G. Preeclampsia-eclampsia. J Obstet Gynaecol India. 2014;64:4–13. https://doi.org/10.1007/s13224-014-0502-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gorakh Mandrupkar. FOGSI-GESTOSIS-ICOG Hypertensive Disorders in Pregnancy (HDP) Good Clinical Practice Recommendations 2019. The Federation Of Obstetric and Gynaecological Societies of India. https://www.fogsi.org/fogsi-hdp-gcpr-2019/.

  7. 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;4:97–104. https://doi.org/10.1016/j.preghy.2014.02.001

    Article  CAS  PubMed  Google Scholar 

  8. Duhig K, Vandermolen B, Shennan A. Recent advances in the diagnosis and management of pre-eclampsia. F1000Res. 2018;7:242. https://doi.org/10.12688/f1000research.12249.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tomimatsu T, Mimura K, Matsuzaki S, Endo M, Kumasawa K, Kimura T. Preeclampsia: Maternal Systemic Vascular Disorder Caused by Generalized Endothelial Dysfunction Due to Placental Antiangiogenic Factors. Int J Mol Sci. 2019;20:4246. https://doi.org/10.3390/ijms20174246

    Article  CAS  PubMed Central  Google Scholar 

  10. Cerdeira A, Agrawal S, Staff A, Redman C, Vatish M. Angiogenic factors: potential to change clinical practice in pre-eclampsia? BJOG: Int J Obstet Gy. 2018;125:1389–1395. https://doi.org/10.1111/1471-0528.15042

    Article  CAS  Google Scholar 

  11. Ali Z, Ali Z, Khaliq S, Zaki S, Ahmad HU, Lone KP. Differential Expression of Placental Growth Factor, Transforming Growth Factor-β and Soluble Endoglin in Peripheral Mononuclear Cells in Preeclampsia. J Coll Physicians Surg Pak. 2019;29:235–239. https://doi.org/10.29271/jcpsp.2019.03.235

    Article  PubMed  Google Scholar 

  12. Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010. Chapter 1, Overview of Angiogenesis https://www.ncbi.nlm.nih.gov/books/NBK53238/

    Google Scholar 

  13. Maynard SE, Karumanchi SA. Angiogenic Factors and Preeclampsia. Semin Nephrol. 2011;31:33–46. https://doi.org/10.1016/j.semnephrol.2010.10.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular Endothelial Growth Factor and Angiogenesis. Pharm Rev. 2004;56:549–580. https://doi.org/10.1124/pr.56.4.3

    Article  CAS  PubMed  Google Scholar 

  15. Ngene NC, Moodley J. Role of angiogenic factors in the pathogenesis and management of pre-eclampsia. Int J Gynecol Obstet. 2018;141:5–13. https://doi.org/10.1002/ijgo.12424

    Article  CAS  Google Scholar 

  16. Holmes DIR, Zachary I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol. 2005;6:209. https://doi.org/10.1186/gb-2005-6-2-209

    Article  PubMed  PubMed Central  Google Scholar 

  17. Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci. 2001;114:853–865.

    Article  CAS  Google Scholar 

  18. McCarthy FP, Ryan RM, Chappell LC. Prospective biomarkers in preterm preeclampsia: a review. Pregnancy Hypertens. 2018;14:72–78. https://doi.org/10.1016/j.preghy.2018.03.010

    Article  PubMed  Google Scholar 

  19. Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol. 1998;140:947–959. https://doi.org/10.1083/jcb.140.4.947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhu H, Gao M, Gao X, Tong Y. Vascular endothelial growth factor-B: impact on physiology and pathology. Cell Adh Migr. 2018;12:215–227. https://doi.org/10.1080/19336918.2017.1379634

    Article  CAS  PubMed  Google Scholar 

  21. Eddy AC, Bidwell GL, George EM. Pro-angiogenic therapeutics for preeclampsia. Biol Sex Differ. 2018;9:36 https://doi.org/10.1186/s13293-018-0195-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nissaisorakarn P, Sharif S, Jim B. Hypertension in Pregnancy: defining Blood Pressure Goals and the Value of Biomarkers for Preeclampsia. Curr Cardiol Rep. 2016;18:131. https://doi.org/10.1007/s11886-016-0782-1

    Article  PubMed  Google Scholar 

  23. Park SA, Jeong MS, Ha K-T, Jang SB. Structure and function of vascular endothelial growth factor and its receptor system. BMB Rep. 2018;51:73–78. https://doi.org/10.5483/bmbrep.2018.51.2.233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lecarpentier E, Tsatsaris V. Angiogenic balance (sFlt-1/PlGF) and preeclampsia. Ann Endocrinol (Paris). 2016;77:97–100. https://doi.org/10.1016/j.ando.2016.04.007

    Article  Google Scholar 

  25. Thomas CP, Andrews JI, Liu KZ. Intronic polyadenylation signal sequences and alternate splicing generate human soluble Flt1 variants and regulate the abundance of soluble Flt1 in the placenta. FASEB J. 2007;21:3885–3895. https://doi.org/10.1096/fj.07-8809com

    Article  CAS  PubMed  Google Scholar 

  26. Heydarian M, McCaffrey T, Florea L, Yang Z, Ross MM, Zhou W, et al. Novel splice variants of sFlt1 are upregulated in preeclampsia. Placenta. 2009;30:250–255. https://doi.org/10.1016/j.placenta.2008.12.010

    Article  CAS  PubMed  Google Scholar 

  27. Souders CA, Maynard SE, Yan J, Wang Y, Boatright NK, Sedan J, et al. Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia. Int J Mol Sci. 2015;16:12436–12453. https://doi.org/10.3390/ijms160612436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Palmer KR, Kaitu’u-Lino TJ, Hastie R, Hannan NJ, Ye L, Binder N, et al. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity. Hypertension. 2015;66:1251–1259. doi:10.1161/HYPERTENSIONAHA.115.05883

    Article  CAS  Google Scholar 

  29. Helmo FR, Lopes AMM. Carneiro ACDM, Campos CG, Silva PB, Dos Reis Monteiro MLG, et al. Angiogenic and antiangiogenic factors in preeclampsia. Pathol Res Pr. 2018;214:7–14. https://doi.org/10.1016/j.prp.2017.10.021

    Article  CAS  Google Scholar 

  30. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–649. https://doi.org/10.1038/nm1429

    Article  CAS  PubMed  Google Scholar 

  31. Kapur NK, Morine KJ, Letarte M. Endoglin: a critical mediator of cardiovascular health. Vasc Health Risk Manag. 2013;9:195–206. https://doi.org/10.2147/VHRM.S29144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xu Y-T, Shen M-H, Jin A-Y, Li H, Zhu R. Maternal circulating levels of transforming growth factor-β superfamily and its soluble receptors in hypertensive disorders of pregnancy. Int J Gynaecol Obstet. 2017;137:246–252. https://doi.org/10.1002/ijgo.12142

    Article  CAS  PubMed  Google Scholar 

  33. Saito S, Nakashima A. A review of the mechanism for poor placentation in early-onset preeclampsia: the role of autophagy in trophoblast invasion and vascular remodeling. J Reprod Immunol. 2014;101–102:80–88. https://doi.org/10.1016/j.jri.2013.06.002

    Article  CAS  PubMed  Google Scholar 

  34. Su R-W, Fazleabas AT. Implantation and Establishment of Pregnancy in Human and Nonhuman Primates. Adv Anat Embryol Cell Biol. 2015;216:189–213. https://doi.org/10.1007/978-3-319-15856-3_10

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: pathophysiology, Challenges, and Perspectives. Circ Res. 2019;124:1094–1112. https://doi.org/10.1161/CIRCRESAHA.118.313276

    Article  CAS  PubMed  Google Scholar 

  36. Rajakumar A, Brandon HM, Daftary A, Ness R, Conrad KP. Evidence for the functional activity of hypoxia-inducible transcription factors overexpressed in preeclamptic placentae. Placenta. 2004;25:763–769. https://doi.org/10.1016/j.placenta.2004.02.011

    Article  CAS  PubMed  Google Scholar 

  37. Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol. 2000;157:2111–2122. https://doi.org/10.1016/S0002-9440(10)64849-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Smith RA, Kenny LC. Current thoughts on the pathogenesis of pre-eclampsia. Obstetrician Gynaecologist. 2006;8:7–13. https://doi.org/10.1576/toag.8.1.007.27202

    Article  Google Scholar 

  39. Schrey-Petersen S, Stepan H. Anti-angiogenesis and Preeclampsia in 2016. Curr Hypertens Rep. 2017;19:6. https://doi.org/10.1007/s11906-017-0706-5

    Article  CAS  PubMed  Google Scholar 

  40. Livingston JC, Chin R, Haddad B, McKinney ET, Ahokas R, Sibai BM. Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol. 2000;183:1554–1557. https://doi.org/10.1067/mob.2000.108022

    Article  CAS  PubMed  Google Scholar 

  41. 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 Investig. 2003;111:649–658. https://doi.org/10.1172/JCI17189

    Article  CAS  PubMed  Google Scholar 

  42. Laskowska M, Laskowska K, Leszczyńska-Gorzelak B, Oleszczuk J. Are the maternal and umbilical VEGF-A and SVEGF-R1 altered in pregnancies complicated by preeclampsia with or without intrauterine foetal growth retardation? Preliminary communication. Med Wieku Rozwoj. 2008;12:499–506.

    PubMed  Google Scholar 

  43. Baker PN, Krasnow J, Roberts JM, Yeo KT. Elevated serum levels of vascular endothelial growth factor in patients with preeclampsia. Obstet Gynecol. 1995;86:815–821. https://doi.org/10.1016/0029-7844(95)00259-T

    Article  CAS  PubMed  Google Scholar 

  44. Sharkey AM, Cooper JC, Balmforth JR, McLaren J, Clark DE, Charnock-Jones DS, et al. Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia. Eur J Clin Investig. 1996;26:1182–1185. https://doi.org/10.1046/j.1365-2362.1996.830605.x

    Article  CAS  Google Scholar 

  45. Hunter A, Aitkenhead M, Caldwell C, McCracken G, Wilson D, McClure N. Serum levels of vascular endothelial growth factor in preeclamptic and normotensive pregnancy. Hypertension. 2000;36:965–969. https://doi.org/10.1161/01.hyp.36.6.965

    Article  CAS  PubMed  Google Scholar 

  46. Bosio PM, Wheeler T, Anthony F, Conroy R, O’herlihy C, McKenna P. Maternal plasma vascular endothelial growth factor concentrations in normal and hypertensive pregnancies and their relationship to peripheral vascular resistance. Am J Obstet Gynecol. 2001;184:146–152. https://doi.org/10.1067/mob.2001.108342

    Article  CAS  PubMed  Google Scholar 

  47. Shaarawy M, Al-Sokkary F, Sheba M, Wahba O, Kandil HO, Abdel-Mohsen I. Angiogenin and vascular endothelial growth factor in pregnancies complicated by preeclampsia. Int J Gynaecol Obstet. 2005;88:112–117. https://doi.org/10.1016/j.ijgo.2004.10.005

    Article  CAS  PubMed  Google Scholar 

  48. Lee ES, Oh M-J, Jung JW, Lim J-E, Seol H-J, Lee K-J, et al. The levels of circulating vascular endothelial growth factor and soluble Flt-1 in pregnancies complicated by preeclampsia. J Korean Med Sci. 2007;22:94–98. https://doi.org/10.3346/jkms.2007.22.1.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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;33:561–567. https://doi.org/10.1038/hr.2010.31

    Article  CAS  PubMed  Google Scholar 

  50. Vaisbuch E, Whitty JE, Hassan SS, Romero R, Kusanovic JP, Cotton DB, et al. Circulating angiogenic and antiangiogenic factors in women with eclampsia. Am J Obstet Gynecol. 2011;204:152.e1–9. https://doi.org/10.1016/j.ajog.2010.08.049

    Article  CAS  Google Scholar 

  51. Powers RW, Roberts JM, Plymire DA, Pucci D, Datwyler SA, Laird DM, et al. Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia? Hypertension. 2012;60:239–246. doi:10.1161/HYPERTENSIONAHA.112.191213

    Article  CAS  Google Scholar 

  52. Wei S-Q, Audibert F, Luo Z-C, Nuyt AM, Masse B, Julien P, et al. MIROS Study Group. Maternal plasma 25-hydroxyvitamin D levels, angiogenic factors, and preeclampsia. Am J Obstet Gynecol. 2013;208:390.e1–6. https://doi.org/10.1016/j.ajog.2013.03.025

    Article  CAS  Google Scholar 

  53. 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;109:1316–1324. https://doi.org/10.1097/01.AOG.0000265804.09161.0d

    Article  CAS  PubMed  Google Scholar 

  54. Sibiude J, Guibourdenche J, Dionne M-D, Le Ray C, Anselem O, Serreau R, et al. Placental growth factor for the prediction of adverse outcomes in patients with suspected preeclampsia or intrauterine growth restriction. PLoS ONE. 2012;7:e50208. https://doi.org/10.1371/journal.pone.0050208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cetin I, Mazzocco MI, Giardini V, Cardellicchio M, Calabrese S, Algeri P, et al. PlGF in a clinical setting of pregnancies at risk of preeclampsia and/or intrauterine growth restriction. J Matern Fetal Neonatal Med. 2017;30:144–149. https://doi.org/10.3109/14767058.2016.1168800

    Article  CAS  PubMed  Google Scholar 

  56. 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;49:756–760. https://doi.org/10.1002/uog.17455

    Article  PubMed  Google Scholar 

  57. Poon LCY, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53:812–818. doi:10.1161/HYPERTENSIONAHA.108.127977

    Article  CAS  Google Scholar 

  58. Litwińska E, Litwińska M, Oszukowski P, Szaflik K, Kaczmarek P. Combined screening for early and late pre-eclampsia and intrauterine growth restriction by maternal history, uterine artery Doppler, mean arterial pressure and biochemical markers. Adv Clin Exp Med. 2017;26:439–448. https://doi.org/10.17219/acem/62214

    Article  PubMed  Google Scholar 

  59. Duhig KE, Seed PT, Myers JE, Bahl R, Bambridge G, Barnfield S, et al. Placental growth factor testing for suspected pre-eclampsia: a cost-effectiveness analysis. BJOG. 2019;126:1390–1398. https://doi.org/10.1111/1471-0528.15855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wikström A-K, Larsson A, Eriksson UJ, Nash P, Olovsson M. Early postpartum changes in circulating pro- and anti-angiogenic factors in early-onset and late-onset pre-eclampsia. Acta Obstet Gynecol Scand. 2008;87:146–153. https://doi.org/10.1080/00016340701819262

    Article  CAS  PubMed  Google Scholar 

  61. 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. https://doi.org/10.1016/j.ajog.2004.03.043. discussion 1547-1550

    Article  CAS  PubMed  Google Scholar 

  62. Kaufmann I, Rusterholz C, Hösli I, Hahn S, Lapaire O. Can detection of late-onset PE at triage by sflt-1 or PlGF be improved by the use of additional biomarkers? Prenat Diagn. 2012;32:1288–1294. https://doi.org/10.1002/pd.3995

    Article  CAS  PubMed  Google Scholar 

  63. Furuya K, Kumasawa K, Nakamura H, Nishimori K, Kimura T. Novel biomarker profiles in experimental aged maternal mice with hypertensive disorders of pregnancy. Hypertens Res. 2019;42:29–39. https://doi.org/10.1038/s41440-018-0092-7

    Article  CAS  PubMed  Google Scholar 

  64. Levine RJ, Maynard SE, Qian C, Lim K-H, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl J Med. 2004;350:672–683. https://doi.org/10.1056/NEJMoa031884

    Article  CAS  PubMed  Google Scholar 

  65. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al. CPEP Study Group. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005. https://doi.org/10.1056/NEJMoa055352

    Article  CAS  PubMed  Google Scholar 

  66. Sahay AS, Patil VV, Sundrani DP, Joshi AA, Wagh GN, Gupte SA, et al. A longitudinal study of circulating angiogenic and antiangiogenic factors and AT1-AA levels in preeclampsia. Hypertens Res. 2014;37:753–758. https://doi.org/10.1038/hr.2014.71

    Article  CAS  PubMed  Google Scholar 

  67. Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA, Tamez H, et al. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Hypertension. 2007;50:137–142. doi:10.1161/HYPERTENSIONAHA.107.087700

    Article  CAS  Google Scholar 

  68. Hertig A, Berkane N, Lefevre G, Toumi K, Marti H-P, Capeau J, et al. Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem. 2004;50:1702–1703. https://doi.org/10.1373/clinchem.2004.036715

    Article  CAS  PubMed  Google Scholar 

  69. 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. https://doi.org/10.1080/14767050701830480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Krauss T, Pauer H-U, Augustin HG. Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy. 2004;23:101–111. https://doi.org/10.1081/PRG-120028286

    Article  CAS  PubMed  Google Scholar 

  71. Bersinger NA, Ødegård RA. Second- and third-trimester serum levels of placental proteins in preeclampsia and small-for-gestational age pregnancies. Acta Obstet Gynecol Scand. 2004;83:37–45.

    Article  Google Scholar 

  72. 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;21:279–287. https://doi.org/10.1080/14767050802034545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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;22:1021–1038. https://doi.org/10.3109/14767050902994754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Perni U, Sison C, Sharma V, Helseth G, Hawfield A, Suthanthiran M, et al. Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy. Hypertension. 2012;59:740–746. doi:10.1161/HYPERTENSIONAHA.111.181735

    Article  CAS  Google Scholar 

  75. Rizos D, Eleftheriades M, Karampas G, Rizou M, Haliassos A, Hassiakos D, et al. Placental growth factor and soluble fms-like tyrosine kinase-1 are useful markers for the prediction of preeclampsia but not for small for gestational age neonates: a longitudinal study. Eur J Obstet Gynecol Reprod Biol. 2013;171:225–230. https://doi.org/10.1016/j.ejogrb.2013.08.040

    Article  CAS  PubMed  Google Scholar 

  76. Myatt L, Clifton RG, Roberts JM, Spong CY, Wapner RJ, Thorp JM, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population? BJOG. 2013;120:1183–1191. https://doi.org/10.1111/1471-0528.12128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Khalil A, Maiz N, Garcia-Mandujano R, Elkhouli M, Nicolaides KH. Longitudinal changes in maternal soluble endoglin and angiopoietin-2 in women at risk for pre-eclampsia. Ultrasound Obstet Gynecol. 2014;44:402–410. https://doi.org/10.1002/uog.13439

    Article  CAS  PubMed  Google Scholar 

  78. Khalil A, Maiz N, Garcia-Mandujano R, Penco JM, Nicolaides KH. Longitudinal changes in maternal serum placental growth factor and soluble fms-like tyrosine kinase-1 in women at increased risk of pre-eclampsia. Ultrasound Obstet Gynecol. 2016;47:324–331. https://doi.org/10.1002/uog.15750

    Article  CAS  PubMed  Google Scholar 

  79. Erez O, Romero R, Maymon E, Chaemsaithong P, Done B, Pacora P, et al. The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study. PLoS ONE. 2017;12:e0181468 https://doi.org/10.1371/journal.pone.0181468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jääskeläinen T, Heinonen S, Hämäläinen E, Pulkki K, Romppanen J, Laivuori H. FINNPEC. Angiogenic profile in the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort. Pregnancy Hypertens. 2018;14:252–259. https://doi.org/10.1016/j.preghy.2018.03.004

    Article  PubMed  Google Scholar 

  81. Teixeira PG, Reis ZSN, Andrade SP, Rezende CA, Lage EM, Velloso EP, et al. Presymptomatic prediction of preeclampsia with angiogenic factors, in high risk pregnant women. Hypertens Pregnancy. 2013;32:312–320. https://doi.org/10.3109/10641955.2013.807818

    Article  CAS  PubMed  Google Scholar 

  82. Sarween N, Drayson MT, Hodson J, Knox EM, Plant T, Day CJ, et al. Humoral immunity in late-onset Pre-eclampsia and linkage with angiogenic and inflammatory markers. Am J Reprod Immunol. 2018;80:e13041 https://doi.org/10.1111/aji.13041

    Article  CAS  PubMed  Google Scholar 

  83. Pinheiro CC, Rayol P, Gozzani L, Reis LM, dos, Zampieri G, Dias CB, et al. The relationship of angiogenic factors to maternal and neonatal manifestations of early-onset and late-onset preeclampsia. Prenat Diagn. 2014;34:1084–1092. https://doi.org/10.1002/pd.4432

    Article  CAS  PubMed  Google Scholar 

  84. Zhang K, Zen M, Popovic NL, Lee VW, Alahakoon TI. Urinary placental growth factor in preeclampsia and fetal growth restriction: An alternative to circulating biomarkers? J Obstet Gynaecol Res. 2019;45:1828–1836. https://doi.org/10.1111/jog.14038

    Article  CAS  PubMed  Google Scholar 

  85. Pant V, Yadav BK, Sharma J. A cross sectional study to assess the sFlt-1:PlGF ratio in pregnant women with and without preeclampsia. BMC Pregnancy Childbirth. 2019;19:266 https://doi.org/10.1186/s12884-019-2399-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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.e1–161.e11. https://doi.org/10.1016/j.ajog.2009.09.016

    Article  CAS  Google Scholar 

  87. 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.e1–8. https://doi.org/10.1016/j.ajog.2011.07.037

    Article  CAS  Google Scholar 

  88. 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;63:346–352. doi:10.1161/HYPERTENSIONAHA.113.01787

    Article  CAS  Google Scholar 

  89. 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. https://doi.org/10.3109/10641955.2013.784788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Leaños-Miranda A, Méndez-Aguilar F, Ramírez-Valenzuela KL, Serrano-Rodríguez M, Berumen-Lechuga G, Molina-Pérez CJ, et al. Circulating angiogenic factors are related to the severity of gestational hypertension and preeclampsia, and their adverse outcomes. Med (Baltim). 2017;96:e6005. doi:10.1097/MD.0000000000006005

    Article  Google Scholar 

  91. Hund M, Allegranza D, Schoedl M, Dilba P, Verhagen-Kamerbeek W, Stepan H. Multicenter prospective clinical study to evaluate the prediction of short-term outcome in pregnant women with suspected preeclampsia (PROGNOSIS): study protocol. BMC Pregnancy Childbirth. 2014;14:324 https://doi.org/10.1186/1471-2393-14-324

    Article  PubMed  PubMed Central  Google Scholar 

  92. 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. https://doi.org/10.1056/NEJMoa1414838

    Article  CAS  PubMed  Google Scholar 

  93. Bian X, Biswas A, Huang X, Lee KJ, Li TK-T, Masuyama H, et al. Short-Term Prediction of Adverse Outcomes Using the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Asian Women With Suspected Preeclampsia. Hypertension. 2019;74:164–172. doi: 10.1161/HYPERTENSIONAHA.119.12760

    Article  CAS  Google Scholar 

  94. Sovio U, Gaccioli F, Cook E, Hund M, Charnock-Jones DS, Smith GCS. Prediction of Preeclampsia Using the Soluble fms-Like Tyrosine Kinase 1 to Placental Growth Factor Ratio: a Prospective Cohort Study of Unselected Nulliparous Women. Hypertension. 2017;69:731–738. doi:10.1161/HYPERTENSIONAHA.116.08620

    Article  CAS  Google Scholar 

  95. Agrawal S, Cerdeira AS, Redman C, Vatish M. Meta-Analysis and Systematic Review to Assess the Role of Soluble FMS-Like Tyrosine Kinase-1 and Placenta Growth Factor Ratio in Prediction of Preeclampsia: The SaPPPhirE Study. Hypertension. 2018;71:306–316. doi:10.1161/HYPERTENSIONAHA.117.10182

    Article  CAS  Google Scholar 

  96. Stepan H, Hund M, Dilba P, Sillman J, Schlembatch D. Elecsys® and Kryptor immunoassays for the measurement of sFlt-1 and PlGF to aid preeclampsia diagnosis: are they comparable? Clin Chem Lab Med. 2019;57:1139–1348. https://doi.org/10.1515/cclm-2018-1228

    Article  CAS  Google Scholar 

  97. Stepan H, Hund M, Andraczek T. Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome. Hypertension. 2020;75:918–926. doi: 10.1161/HYPERTENSIONAHA.119.13763

    Article  CAS  Google Scholar 

  98. Wadhwani NS, Sundrani DP, Wagh GN, Mehendale SS, Tipnis MM, Joshi PC, et al. The REVAMP study: research exploring various aspects and mechanisms in preeclampsia: study protocol. BMC Pregnancy Childbirth. 2019;19:308 https://doi.org/10.1186/s12884-019-2450-0

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the Indian Council of Medical Research (ICMR) for funding the REVAMP (Research Exploring Various Aspects and Mechanisms in Preeclampsia) study (5/7/1069/13-RCH). Author AS thanks the Indian Council of Medical Research (ICMR), Government of India, for providing her the ‘RA fellowship’ (RBMH/FW/2019/17).

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Deshpande, J.S., Sundrani, D.P., Sahay, A.S. et al. Unravelling the potential of angiogenic factors for the early prediction of preeclampsia. Hypertens Res 44, 756–769 (2021). https://doi.org/10.1038/s41440-021-00647-9

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