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Original Article

Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia

, , , , , , , , & show all
Pages 1187-1207 | Received 12 May 2011, Accepted 17 May 2011, Published online: 09 Aug 2011

References

  • Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: A systematic review. Lancet 2006;367:1066–1074.
  • Romero R, Lockwood C, Oyarzun E, Hobbins JC. Toxemia: New concepts in an old disease. Semin Perinatol 1988;12:302–323.
  • Sibai BM. Hypertensive disorders of pregnancy: The United States perspective. Curr Opin Obstet Gynecol 2008;20:102–106.
  • Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and severe obstetric morbidity in the United States. Obstet Gynecol 2009;113:1299–1306.
  • Berg CJ, Mackay AP, Qin C, Callaghan WM. Overview of maternal morbidity during hospitalization for labor and delivery in the United States: 1993-1997 and 2001-2005. Obstet Gynecol 2009;113:1075–1081.
  • Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011 Feb 16. E-pub ahead of print PMID 21333604.
  • Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592–1594.
  • Roberts JM, Gammill HS. Preeclampsia: Recent insights. Hypertension 2005;46:1243–1249.
  • von Dadelszen P, Menzies J, Magee LA. The complications of hypertension in pregnancy. Minerva Med 2005;96:287–302.
  • Ganzevoort W, Rep A, de Vries JI, Bonsel GJ, Wolf H; PETRA-investigators. Prediction of maternal complications and adverse infant outcome at admission for temporizing management of early-onset severe hypertensive disorders of pregnancy. Am J Obstet Gynecol 2006;195:495–503.
  • Sibai BM. Preeclampsia as a cause of preterm and late preterm (near-term) births. Semin Perinatol 2006;30:16–19.
  • Chappell LC, Enye S, Seed P, Briley AL, Poston L, Shennan AH. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: A prospective study. Hypertension 2008;51:1002–1009.
  • Witlin AG, Saade GR, Mattar F, Sibai BM. Predictors of neonatal outcome in women with severe preeclampsia or eclampsia between 24 and 33 weeks’ gestation. Am J Obstet Gynecol 2000;182:607–611.
  • Berends AL, de Groot CJ, Sijbrands EJ, Sie MP, Benneheij SH, Pal R, Heydanus R, et al. Shared constitutional risks for maternal vascular-related pregnancy complications and future cardiovascular disease. Hypertension 2008;51:1034–1041.
  • Hermes W, Franx A, van Pampus MG, Bloemenkamp KW, van der Post JA, Porath M, Ponjee G, et al. 10-Year cardiovascular event risks for women who experienced hypertensive disorders in late pregnancy: The HyRAS study. BMC Pregnancy Childbirth 2010;10:28.
  • Barden A. Pre-eclampsia: Contribution of maternal constitutional factors and the consequences for cardiovascular health. Clin Exp Pharmacol Physiol 2006;33:826–830.
  • Funai EF, Friedlander Y, Paltiel O, Tiram E, Xue X, Deutsch L, Harlap S. Long-term mortality after preeclampsia. Epidemiology 2005;16:206–215.
  • Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: Population based cohort study. BMJ 2001;323:1213–1217.
  • Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53:944–951.
  • Conde-Agudelo A, Romero R, Kusanovic JP, Hassan SS. Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: A systematic review and metaanalysis. Am J Obstet Gynecol 2011 Apr 27. E-pub ahead of print PMID 21529757.
  • Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS; ACTS Study Group. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006;354:1796–1806.
  • Rumbold A, Duley L, Crowther C, Haslam R. Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev 2008 Jan; 23(1):CD004227.
  • Villar J, Purwar M, Merialdi M, Zavaleta N, Thi Nhu Ngoc N, Anthony J, De Greeff A, et al.; WHO Vitamin C and Vitamin E trial group. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. BJOG 2009;116:780–788.
  • Spinnato JA 2nd, Freire S, Pinto E Silva JL, Cunha Rudge MV, Martins-Costa S, Koch MA, Goco N, et al. Antioxidant therapy to prevent preeclampsia: A randomized controlled trial. Obstet Gynecol 2007;110:1311–1318.
  • Beazley D, Ahokas R, Livingston J, Griggs M, Sibai BM. Vitamin C and E supplementation in women at high risk for preeclampsia: A double-blind, placebo-controlled trial. Am J Obstet Gynecol 2005;192:520–521.
  • Xu H, Perez-Cuevas R, Xiong X, Reyes H, Roy C, Julien P, Smith G, et al.; INTAPP study group. An international trial of antioxidants in the prevention of preeclampsia (INTAPP). Am J Obstet Gynecol 2010;202:239.e1–239.e10.
  • Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, Paul RH, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213–1218.
  • Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, VanDorsten P, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701–705.
  • Rotchell YE, Cruickshank JK, Gay MP, Griffiths J, Stewart A, Farrell B, Ayers S, et al. Barbados Low Dose Aspirin Study in Pregnancy (BLASP): A randomised trial for the prevention of pre-eclampsia and its complications. Br J Obstet Gynaecol 1998;105:286–292.
  • Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguère Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol 2010;116:402–414.
  • Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E, Tamarkin M, Barkai G, et al. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. N Engl J Med 1989;321:351–356.
  • Imperiale TF, Petrulis AS. A meta-analysis of low-dose aspirin for the prevention of pregnancy-induced hypertensive disease. JAMA 1991;266:260–264.
  • Brennecke SP, Brown MA, Crowther CA, Hague WM, King J, McCowan L, Morris J, et al. Aspirin and prevention of preeclampsia. Position statement of the use of low-dose aspirin in pregnancy by the Australasian Society for the Study of Hypertension in Pregnancy. Aust N Z J Obstet Gynaecol 1995;35:38–41.
  • Kyle PM, Buckley D, Kissane J, de Swiet M, Redman CW. The angiotensin sensitivity test and low-dose aspirin are ineffective methods to predict and prevent hypertensive disorders in nulliparous pregnancy. Am J Obstet Gynecol 1995;173:865–872.
  • Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, DerSimonian R, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–76.
  • Crowther CA, Hiller JE, Pridmore B, Bryce R, Duggan P, Hague WM, Robinson JS. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: An Australian randomized trial. FRACOG and the ACT Study Group. Aust N Z J Obstet Gynaecol 1999;39:12–18.
  • Bailey DJ, Walton SM. Routine investigations might be useful in pre-eclampsia, but not in gestational hypertension. Aust N Z J Obstet Gynaecol 2005;45:144–147.
  • Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 1998;105:1177–1184.
  • Milne F, Redman C, Walker J, Baker P, Black R, Blincowe J, Cooper C, et al.; PRECOG II Group. Assessing the onset of pre-eclampsia in the hospital day unit: Summary of the pre-eclampsia guideline (PRECOG II). BMJ 2009;339:b3129.
  • 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.
  • Romero R, Mazor M, Lockwood CJ, Emamian M, Belanger KP, Hobbins JC, Duffy T. Clinical significance, prevalence, and natural history of thrombocytopenia in pregnancy-induced hypertension. Am J Perinatol 1989;6:32–38.
  • Romero R, Vizoso J, Emamian M, Duffy T, Riely C, Halford T, Oyarzun E, et al. Clinical significance of liver dysfunction in pregnancy-induced hypertension. Am J Perinatol 1988;5:146–151.
  • Anumba DO, Lincoln K, Robson SC. Predictive value of clinical and laboratory indices at first assessment in women referred with suspected gestational hypertension. Hypertens Pregnancy 2010;29:163–179.
  • Bell SC, Halligan AW, Martin A, Ashmore J, Shennan AH, Lambert PC, Taylor DJ. The role of observer error in antenatal dipstick proteinuria analysis. Br J Obstet Gynaecol 1999;106:1177–1180.
  • Thangaratinam S, Ismail KM, Sharp S, Coomarasamy A, Khan KS; Tests in Prediction of Pre-eclampsia Severity review group. Accuracy of serum uric acid in predicting complications of pre-eclampsia: A systematic review. BJOG 2006;113:369–378.
  • Menzies J, Magee LA, Macnab YC, Ansermino JM, Li J, Douglas MJ, Gruslin A, et al. Current CHS and NHBPEP criteria for severe preeclampsia do not uniformly predict adverse maternal or perinatal outcomes. Hypertens Pregnancy 2007;26:447–462.
  • Gazmararian JA, Petersen R, Jamieson DJ, Schild L, Adams MM, Deshpande AD, Franks AL. Hospitalizations during pregnancy among managed care enrollees. Obstet Gynecol 2002;100:94–100.
  • Bacak SJ, Callaghan WM, Dietz PM, Crouse C. Pregnancy-associated hospitalizations in the United States, 1999-2000. Am J Obstet Gynecol 2005;192:592–597.
  • Callaghan WM, Mackay AP, Berg CJ. Identification of severe maternal morbidity during delivery hospitalizations, United States, 1991-2003. Am J Obstet Gynecol 2008;199:133.e1–133.e8.
  • Liu S, Heaman M, Sauve R, Liston R, Reyes F, Bartholomew S, Young D, Kramer MS; Maternal Health Study Group of the Canadian Perinatal Surveillance System. An analysis of antenatal hospitalization in Canada, 1991-2003. Matern Child Health J 2007;11:181–187.
  • Brooten D, Kaye J, Poutasse SM, Nixon-Jensen A, McLean H, Brooks LM, Groden S, et al. Frequency, timing, and diagnoses of antenatal hospitalizations in women with high-risk pregnancies. J Perinatol 1998;18:372–376.
  • Hadker N, Garg S, Costanzo C, Miller JD, Foster T, van der Helm W, Creeden J. Financial impact of a novel pre-eclampsia diagnostic test versus standard practice: A decision-analytic modeling analysis from a UK healthcare payer perspective. J Med Econ 2010;13:728–737.
  • Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, 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;111:649–658.
  • Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12:642–649.
  • Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672–683.
  • Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee Kim Y, Gonçalves LF, Gomez R, Edwin S. 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;190:1541–7; discussion 1547.
  • Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, et al.; CPEP Study Group. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006;355:992–1005.
  • Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, Takeda S, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 2003;88:2348–2351.
  • 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.
  • Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin Reprod Endocrinol 1998;16:17–31.
  • 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;179:1539–1544.
  • Clark DE, Smith SK, He Y, Day KA, Licence DR, Corps AN, Lammoglia R, Charnock-Jones DS. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod 1998;59:1540–1548.
  • Charnock-Jones DS, Sharkey AM, Boocock CA, Ahmed A, Plevin R, Ferrara N, Smith SK. Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol Reprod 1994;51:524–530.
  • Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, Schaaps JP, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: Pathophysiological consequences. J Clin Endocrinol Metab 2003;88:5555–5563.
  • Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, 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.
  • Ahmad S, Ahmed A. Antiangiogenic effect of soluble vascular endothelial growth factor receptor-1 in placental angiogenesis. Endothelium 2005;12:89–95.
  • Bujold E, Romero R, Chaiworapongsa T, Kim YM, Kim GJ, Kim MR, Espinoza J, Gonçalves LF, Edwin S, Mazor M. Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin. J Matern Fetal Neonatal Med. 2005;18:9–16.
  • Chaiworapongsa T, Romero R, Tarca AL, Kusanovic JP, Gotsch F, Mittal P, Kim SK, et al. A decrease in maternal plasma concentrations of sVEGFR-2 precedes the clinical diagnosis of preeclampsia. Am J Obstet Gynecol 2010;202:550.e1–550.10.
  • Lindheimer MD, Romero R. Emerging roles of antiangiogenic and angiogenic proteins in pathogenesis and prediction of preeclampsia. Hypertension 2007;50:35–36.
  • Masuyama H, Suwaki N, Nakatsukasa H, Masumoto A, Tateishi Y, Hiramatrsu Y. Circulating angiogenic factors in preeclampsia, gestational proteinuria, and preeclampsia superimposed on chronic glomerulonephritis. Am J Obstet Gynecol 2006;194:551–556.
  • McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004;191:1240–1246.
  • Nagamatsu T, Fujii T, Kusumi M, Zou L, Yamashita T, Osuga Y, Momoeda M, et al. Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: An implication for the placental vascular development and the pathophysiology of preeclampsia. Endocrinology 2004;145:4838–4845.
  • Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran M, Sudhakar A, Kalluri R. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 2003;278:12605–12608.
  • Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 2004;89:770–775.
  • Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vaisbuch E, Mazaki-Tovi S, 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.
  • Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, Bujold E, 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.
  • Crispi F, Llurba E, Domínguez C, Martín-Gallán P, Cabero L, Gratacós E. Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol 2008;31:303–309.
  • 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.
  • 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.e1–40.e7.
  • Ohkuchi A, Hirashima C, Matsubara S, Suzuki H, Takahashi K, Arai F, Watanabe T, 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;30:151–159.
  • Moore Simas TA, Crawford SL, Solitro MJ, Frost SC, Meyer BA, Maynard SE. Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet Gynecol 2007;197:244.e1–244.e8.
  • Akolekar R, Zaragoza E, Poon LC, Pepes S, Nicolaides KH. Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol 2008;32:732–739.
  • Stepan H, Geipel A, Schwarz F, Krämer T, Wessel N, Faber R. Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion. Am J Obstet Gynecol 2008;198:175.e1–175.e6.
  • Smith GC, Crossley JA, Aitken DA, Jenkins N, Lyall F, Cameron AD, Connor JM, Dobbie R. 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.
  • Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV, Martins-Costa S, Bartz J, 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;199:268.e1–268.e9.
  • Powers RW, Jeyabalan A, Clifton RG, Van Dorsten P, Hauth JC, Klebanoff MA, Lindheimer MD, et al.; Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network. Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies. PLoS ONE 2010;5:e13263.
  • Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–168.
  • Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM, Goldenberg RL, Joffe G. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 1997;177:1003–1010.
  • Oggè G, Romero R, Kusanovic JP, Chaiworapongsa T, Dong Z, Mittal P, Vaisbuch E, et al. Serum and plasma determination of angiogenic and anti-angiogenic factors yield different results: The need for standardization in clinical practice. J Matern Fetal Neonatal Med 2010;23:820–827.
  • He X, Fu B, Fung WK. Median regression for longitudinal data. Stat Med 2003;22:3655–3669.
  • Yücesoy G, Ozkan S, Bodur H, Tan T, Caliskan E, Vural B, Corakçi A. Maternal and perinatal outcome in pregnancies complicated with hypertensive disorder of pregnancy: A seven year experience of a tertiary care center. Arch Gynecol Obstet 2005;273:43–49.
  • von DP, Payne B, Li J, Ansermino JM, Broughton PF, Cote AM, et al. Prediction of adverse maternal outcomes in pre-eclampsia: Development and validation of the fullPIERS model. Lancet 2011;377:219–227.
  • Fatemeh T, Marziyeh G, Nayereh G, Anahita G, Samira T. Maternal and perinatal outcome in nulliparious women complicated with pregnancy hypertension. J Pak Med Assoc 2010;60:707–710.
  • Erdemoglu M, Kuyumcuoglu U, Kale A, Akdeniz N. Factors affecting maternal and perinatal outcomes in HELLP syndrome: Evaluation of 126 cases. Clin Exp Obstet Gynecol 2010;37:213–216.
  • Buchbinder A, Sibai BM, Caritis S, Macpherson C, Hauth J, Lindheimer MD, Klebanoff M, et al.; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol 2002;186:66–71.
  • Chaiworapongsa T, Espinoza J, Gotsch F, Kim YM, Kim GJ, Goncalves LF, Edwin S, 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;21:25–40.
  • Chaiworapongsa T, Romero R, Kusanovic JP, Mittal P, Kim SK, Gotsch F, Than NG, et al. Plasma soluble endoglin concentration in pre-eclampsia is associated with an increased impedance to flow in the maternal and fetal circulations. Ultrasound Obstet Gynecol 2010;35:155–162.
  • Schlembach D, Wallner W, Sengenberger R, Stiegler E, Mörtl M, Beckmann MW, Lang U. 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;29:407–413.
  • Robinson CJ, Johnson DD, Chang EY, Armstrong DM, Wang W. Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet Gynecol 2006;195:255–259.
  • 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;29:464–470.
  • Maynard SE, Moore Simas TA, Bur L, Crawford SL, Solitro MJ, Meyer BA. Soluble endoglin for the prediction of preeclampsia in a high risk cohort. Hypertens Pregnancy 2010;29:330–341.
  • Staff AC, Harsem NK, Braekke K, Hyer M, Hoover RN, Troisi R. Maternal, gestational and neonatal characteristics and maternal angiogenic factors in normotensive pregnancies. Eur J Obstet Gynecol Reprod Biol 2009;143:29–33.
  • 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;111:1403–1409.
  • Troisi R, Braekke K, Harsem NK, Hyer M, Hoover RN, Staff AC. Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclamptic and uncomplicated pregnancies. Am J Obstet Gynecol 2008;199:653.e1–653.10.
  • Signore C, Mills JL, Qian C, Yu K, Lam C, Epstein FH, Karumanchi SA, Levine RJ. Circulating angiogenic factors and placental abruption. Obstet Gynecol 2006;108:338–344.
  • Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, Gotsch F, 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.
  • Stepan H, Unversucht A, Wessel N, Faber R. Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion. Hypertension 2007;49:818–824.
  • Vatten LJ, Eskild A, Nilsen TI, Jeansson S, Jenum PA, Staff AC. Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia. Am J Obstet Gynecol 2007;196:239.e1–239.e6.
  • Lindheimer MD, Kanter D. Interpreting abnormal proteinuria in pregnancy: The need for a more pathophysiological approach. Obstet Gynecol 2010;115:365–375.
  • Newman MG, Robichaux AG, Stedman CM, Jaekle RK, Fontenot MT, Dotson T, Lewis DF. Perinatal outcomes in preeclampsia that is complicated by massive proteinuria. Am J Obstet Gynecol 2003;188:264–268.
  • Thangaratinam S, Coomarasamy A, O’Mahony F, Sharp S, Zamora J, Khan KS, Ismail KM. Estimation of proteinuria as a predictor of complications of pre-eclampsia: A systematic review. BMC Med 2009;7:10.
  • Schiff E, Friedman SA, Kao L, Sibai BM. The importance of urinary protein excretion during conservative management of severe preeclampsia. Am J Obstet Gynecol 1996;175:1313–1316.
  • Price CP, Newall RG, Boyd JC. Use of protein: Creatinine ratio measurements on random urine samples for prediction of significant proteinuria: A systematic review. Clin Chem 2005;51:1577–1586.
  • Côté AM, Brown MA, Lam E, von Dadelszen P, Firoz T, Liston RM, Magee LA. Diagnostic accuracy of urinary spot protein: Creatinine ratio for proteinuria in hypertensive pregnant women: Systematic review. BMJ 2008;336:1003–1006.
  • Lindow SW, Davey DA. The variability of urinary protein and creatinine excretion in patients with gestational proteinuric hypertension. Br J Obstet Gynaecol 1992;99:869–872.
  • 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;33:422–427.
  • Bergmann A, Ahmad S, Cudmore M, Gruber AD, Wittschen P, Lindenmaier W, Christofori G, et al. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J Cell Mol Med 2010;14:1857–1867.
  • Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707–716.
  • Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998;273:30336–30343.
  • Wang A, Rana S, Karumanchi SA. Preeclampsia: The role of angiogenic factors in its pathogenesis. Physiology (Bethesda) 2009;24:147–158.
  • Eremina V, Cui S, Gerber H, Ferrara N, Haigh J, Nagy A, Ema M, et al. Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol 2006;17:724–735.
  • 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.
  • Masuda Y, Shimizu A, Mori T, Ishiwata T, Kitamura H, Ohashi R, Ishizaki M, et al. Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Am J Pathol 2001;159:599–608.
  • Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis. Am J Kidney Dis 2007;49:186–193.
  • Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol 2011;204:193–201.
  • DiGiulio DB, Gervasi M, Romero R, Mazaki-Tovi S, Vaisbuch E, Kusanovic JP, Seok KS, et al. Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods. J Perinat Med 2010;38:503–513.
  • Mazaki-Tovi S, Vaisbuch E, Romero R, Kusanovic JP, Chaiworapongsa T, Kim SK, Nhan-Chang CL, et al. Maternal and neonatal circulating visfatin concentrations in patients with pre-eclampsia and a small-for-gestational age neonate. J Matern Fetal Neonatal Med 2010;23:1119–1128.
  • Mazaki-Tovi S, Romero R, Kim SK, Vaisbuch E, Kusanovic JP, Erez O, Chaiworapongsa T, et al. Could alterations in maternal plasma visfatin concentration participate in the phenotype definition of preeclampsia and SGA? J Matern Fetal Neonatal Med 2010;23:857–868.
  • Soto E, Romero R, Richani K, Espinoza J, Chaiworapongsa T, Nien JK, Edwin SS, et al. Preeclampsia and pregnancies with small-for-gestational age neonates have different profiles of complement split products. J Matern Fetal Neonatal Med 2010;23:646–657.
  • Illanes S, Parra M, Serra R, Pino K, Figueroa-Diesel H, Romero C, Arraztoa JA, et al. Increased free fetal DNA levels in early pregnancy plasma of women who subsequently develop preeclampsia and intrauterine growth restriction. Prenat Diagn 2009;29:1118–1122.
  • Erez O, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Kusanovic JP, Kim CJ, Chaiworapongsa T, et al. Evidence of maternal platelet activation, excessive thrombin generation, and high amniotic fluid tissue factor immunoreactivity and functional activity in patients with fetal death. J Matern Fetal Neonatal Med 2009;22:672–687.
  • Vaisbuch E, Romero R, Mazaki-Tovi S, Erez O, Kim SK, Chaiworapongsa T, Gotsch F, et al. Retinol binding protein 4–a novel association with early-onset preeclampsia. J Perinat Med 2010;38:129–139.
  • Erez O, Romero R, Vaisbuch E, Mazaki-Tovi S, Kusanovic JP, Chaiworapongsa T, Than NG, et al. Maternal anti-protein Z antibodies in pregnancies complicated by pre-eclampsia, SGA and fetal death. J Matern Fetal Neonatal Med 2009;22:662–671.
  • Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Erez O, Gotsch F, Chaiworapongsa T, et al. Maternal serum adiponectin multimers in preeclampsia. J Perinat Med 2009;37:349–363.
  • Than NG, Abdul Rahman O, Magenheim R, Nagy B, Fule T, Hargitai B, Sammar M, et al. Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome. Virchows Arch 2008;453:387–400.
  • Than NG, Romero R, Erez O, Kusanovic JP, Tarca AL, Edwin SS, Kim JS, et al. A role for mannose-binding lectin, a component of the innate immune system in pre-eclampsia. Am J Reprod Immunol 2008;60:333–345.
  • Gotsch F, Romero R, Kusanovic JP, Chaiworapongsa T, Dombrowski M, Erez O, Than NG, et al. Preeclampsia and small-for-gestational age are associated with decreased concentrations of a factor involved in angiogenesis: Soluble Tie-2. J Matern Fetal Neonatal Med 2008;21:389–402.
  • Romero R, Kusanovic JP, Than NG, Erez O, Gotsch F, Espinoza J, Edwin S, et al. First-trimester maternal serum PP13 in the risk assessment for preeclampsia. Am J Obstet Gynecol 2008;199:122.e1–122.e11.
  • Nien JK, Mazaki-Tovi S, Romero R, Erez O, Kusanovic JP, Gotsch F, Pineles BL, et al. Adiponectin in severe preeclampsia. J Perinat Med 2007;35:503–512.
  • Gotsch F, Romero R, Friel L, Kusanovic JP, Espinoza J, Erez O, Than NG, et al. CXCL10/IP-10: A missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern Fetal Neonatal Med 2007;20:777–792.
  • Kusanovic JP, Romero R, Hassan SS, Gotsch F, Edwin S, Chaiworapongsa T, Erez O, et al. Maternal serum soluble CD30 is increased in normal pregnancy, but decreased in preeclampsia and small for gestational age pregnancies. J Matern Fetal Neonatal Med 2007;20:867–878.
  • Erez O, Hoppensteadt D, Romero R, Espinoza J, Goncalves L, Nien JK, Kusanovic JP, et al. Preeclampsia is associated with low concentrations of protein Z. J Matern Fetal Neonatal Med 2007;20:661–667.
  • Mittal P, Espinoza J, Hassan S, Kusanovic JP, Edwin SS, Nien JK, Gotsch F, et al. Placental growth hormone is increased in the maternal and fetal serum of patients with preeclampsia. J Matern Fetal Neonatal Med 2007;20:651–659.
  • Ho JT, Lewis JG, O’Loughlin P, Bagley CJ, Romero R, Dekker GA, Torpy DJ. Reduced maternal corticosteroid-binding globulin and cortisol levels in pre-eclampsia and gamete recipient pregnancies. Clin Endocrinol (Oxf) 2007;66:869–877.
  • Pineles BL, Romero R, Montenegro D, Tarca AL, Han YM, Kim YM, Draghici S, et al. Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am J Obstet Gynecol 2007;196:261.e1–261.e6.
  • Goddard KA, Tromp G, Romero R, Olson JM, Lu Q, Xu Z, Parimi N, et al. Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes. Hum Hered 2007;63:1–16.
  • Armant DR, Kilburn BA, Petkova A, Edwin SS, Duniec-Dmuchowski ZM, Edwards HJ, Romero R, Leach RE. Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor. Development 2006;133:751–759.
  • Kim YM, Romero R, Oh SY, Kim CJ, Kilburn BA, Armant DR, Nien JK, et al. Toll-like receptor 4: A potential link between “danger signals,” the innate immune system, and preeclampsia? Am J Obstet Gynecol 2005;193:921–927.
  • Bianchi DW, Romero R. Biological implications of bi-directional fetomaternal cell traffic: A summary of a National Institute of Child Health and Human Development-sponsored conference. J Matern Fetal Neonatal Med 2003;14:123–129.
  • Neale D, Demasio K, Illuzi J, Chaiworapongsa T, Romero R, Mor G. Maternal serum of women with pre-eclampsia reduces trophoblast cell viability: Evidence for an increased sensitivity to Fas-mediated apoptosis. J Matern Fetal Neonatal Med 2003;13:39–44.
  • Chaiworapongsa T, Yoshimatsu J, Espinoza J, Kim YM, Berman S, Edwin S, Yoon BH, Romero R. Evidence of in vivo generation of thrombin in patients with small-for-gestational-age fetuses and pre-eclampsia. J Matern Fetal Neonatal Med 2002;11:362–367.
  • Chaiworapongsa T, Gervasi MT, Refuerzo J, Espinoza J, Yoshimatsu J, Berman S, Romero R. Maternal lymphocyte subpopulations (CD45RA+ and CD45RO+) in preeclampsia. Am J Obstet Gynecol 2002;187:889–893.
  • Arias F, Romero R, Joist H, Kraus FT. Thrombophilia: A mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern Fetal Med 1998;7:277–286.
  • Huppertz B, Frank HG, Reister F, Kingdom J, Korr H, Kaufmann P. Apoptosis cascade progresses during turnover of human trophoblast: Analysis of villous cytotrophoblast and syncytial fragments in vitro. Lab Invest 1999;79:1687–1702.
  • Leach RE, Romero R, Kim YM, Chaiworapongsa T, Kilburn B, Das SK, Dey SK, et al. Pre-eclampsia and expression of heparin-binding EGF-like growth factor. Lancet 2002;360:1215–1219.
  • Lamarca B. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. Minerva Ginecol 2010;62:105–120.
  • Redman CW, Sacks GP, Sargent IL. Preeclampsia: An excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 1999;180:499–506.
  • Sagol S, Ozkinay E, Ozsener S. Impaired antioxidant activity in women with pre-eclampsia. Int J Gynaecol Obstet 1999;64:121–127.
  • Gervasi MT, Chaiworapongsa T, Pacora P, Naccasha N, Yoon BH, Maymon E, Romero R. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gynecol 2001;185:792–797.
  • Romero R, Chaiworapongsa T, Erez O, Tarca AL, Gervasi MT, Kusanovic JP, Mittal P, et al. An imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: Results of a longitudinal study. J Matern Fetal Neonatal Med 2010;23:1384–1399.
  • Espinoza J, Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Nien JK, Kusanovic JP, et al. Unexplained fetal death: Another anti-angiogenic state. J Matern Fetal Neonatal Med 2007;20:495–507.
  • Chaiworapongsa T, Romero R, Kusanovic JP, Savasan ZA, Kim SK, Mazaki-Tovi S, Vaisbuch E, et al. Unexplained fetal death is associated with increased concentrations of anti-angiogenic factors in amniotic fluid. J Matern Fetal Neonatal Med 2010;23:794–805.
  • Chaiworapongsa T, Kusanovic JP, Savasan ZA, Mazaki-Tovi S, Kim SK, Vaisbuch E, Tarca AL, et al. Fetal death: A condition with a dissociation in the concentrations of soluble vascular endothelial growth factor receptor-2 between the maternal and fetal compartments. J Matern Fetal Neonatal Med 2010;23:960–972.
  • Kusanovic JP, Romero R, Espinoza J, Nien JK, Kim CJ, Mittal P, Edwin S, et al. Twin-to-twin transfusion syndrome: An antiangiogenic state? Am J Obstet Gynecol 2008;198:382.e1–382.e8.
  • Stepan H, Faber R. Cytomegalovirus-induced mirror syndrome associated with elevated levels of angiogenic factors. Obstet Gynecol 2007;109:1205–6; author reply 1206.
  • Rana S, Venkatesha S, DePaepe M, Chien EK, Paglia M, Karumanchi SA. Cytomegalovirus-induced mirror syndrome associated with elevated levels of circulating antiangiogenic factors. Obstet Gynecol 2007;109:549–552.
  • Espinoza J, Romero R, Nien JK, Kusanovic JP, Richani K, Gomez R, Kim CJ, et al. A role of the anti-angiogenic factor sVEGFR-1 in the ‘mirror syndrome’ (Ballantyne’s syndrome). J Matern Fetal Neonatal Med 2006;19:607–613.
  • Chaiworapongsa T, Romero R, Tarca A, Kusanovic JP, Mittal P, Kim SK, Gotsch F, et al. A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: Evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study. J Matern Fetal Neonatal Med 2009;22:1122–1139.
  • Schiettecatte J, Russcher H, Anckaert E, Mees M, Leeser B, Tirelli AS, Fiedler GM, et al. Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia. Clin Biochem 2010;43:768–770.
  • Molvarec A, Szarka A, Walentin S, Szucs E, Nagy B, Rigó J Jr. Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia. Hypertens Res 2010;33:892–898.
  • Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG, Pape J, 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.
  • Wolf M, Shah A, Lam C, Martinez A, Smirnakis KV, Epstein FH, Taylor RN, et al. Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies. Am J Obstet Gynecol 2005;193:16–22.
  • Mijal RS, Holzman CB, Rana S, Karumanchi SA, Wang J, Sikorskii A. Midpregnancy levels of angiogenic markers in relation to maternal characteristics. Am J Obstet Gynecol 2011;204:244.e1–244.12.

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