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Emerging New Biomarkers of Preeclampsia

  • Srujana Polsani
    Affiliations
    From the Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine Bronx, NY; New York College of Osteopathic Medicine of New York Institute of Technology, Old Westbury, NY; and Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine Bronx, NY
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  • Elizabeth Phipps
    Affiliations
    From the Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine Bronx, NY; New York College of Osteopathic Medicine of New York Institute of Technology, Old Westbury, NY; and Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine Bronx, NY
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  • Belinda Jim
    Correspondence
    Address correspondence to Belinda Jim, MD, 1400 Pelham Parkway South, Bronx, NY 10461.
    Affiliations
    From the Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine Bronx, NY; New York College of Osteopathic Medicine of New York Institute of Technology, Old Westbury, NY; and Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine Bronx, NY
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      Preeclampsia continues to plague some of the most vulnerable women and fetuses. It is surprisingly prevalent in developing and developed nations. According to the World Health Organization, hypertension during pregnancy is a leading cause of maternal mortality in industrialized countries at 16% and up to 25% in developing countries. As the pathogenesis of this disease is being unraveled, we are afforded new opportunities to develop novel biomarkers for early identification and prevention of disease. The angiogenic markers including soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin have demonstrated to be the most promising, perhaps in conjunction with traditional markers such as plasma protein-13 and uterine artery Doppler studies. There is also increasing evidence that the podocyte is shed during the course of preeclampsia, which may be useful for diagnosis. Systems biology approaches to biomarker discovery such as proteomics and metabolomics are also gaining more attention and will most certainly open new avenues of research. In this review, we present the best studied biomarkers of preeclampsia to date.

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      References

        • Khan K.S.
        • Wojdyla D.
        • Say L.
        • Gulmezoglu A.M.
        • Van Look P.F.
        WHO analysis of causes of maternal death: a systematic review.
        Lancet. 2006; 367: 1066-1074
        • Xiong X.
        • Demianczuk N.N.
        • Buekens P.
        • Saunders L.D.
        Association of preeclampsia with high birth weight for age.
        Am J Obstet Gynecol. 2000; 183: 148-155
        • Friedman S.A.
        • Schiff E.
        • Kao L.
        • Sibai B.M.
        Neonatal outcome after preterm delivery for preeclampsia.
        Am J Obstet Gynecol. 1995; 172 (discussion 1788-1792): 1785-1788
        • Vestergaard M.
        • Basso O.
        • Henriksen T.B.
        • Ostergaard J.
        • Secher N.J.
        • Olsen J.
        Pre-eclampsia and febrile convulsions.
        Arch Dis Childhood. 2003; 88: 726-727
        • Bellamy L.
        • Casas J.P.
        • Hingorani A.D.
        • Williams D.J.
        Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.
        BMJ. 2007; 335: 974
        • Vikse B.E.
        • Irgens L.M.
        • Leivestad T.
        • Skjaerven R.
        • Iversen B.M.
        Preeclampsia and the risk of end-stage renal disease.
        N Engl J Med. 2008; 359: 800-809
        • Matthys L.A.
        • Coppage K.H.
        • Lambers D.S.
        • Barton J.R.
        • Sibai B.M.
        Delayed postpartum preeclampsia: an experience of 151 cases.
        Am J Obstet Gynecol. 2004; 190: 1464-1466
      1. Khalil A, Rezende J, Akolekar R, Syngelaki A, Nicolaides KH. Maternal racial origin and adverse pregnancy outcomes: a cohort study. Ultrasound Obstet Gynecol. doi:10.1002/uog.12313.2012.

        • Esplin M.S.
        • Fausett M.B.
        • Fraser A.
        • et al.
        Paternal and maternal components of the predisposition to preeclampsia.
        N Engl J Med. 2001; 344: 867-872
        • Robillard P.Y.
        • Hulsey T.C.
        • Perianin J.
        • Janky E.
        • Miri E.H.
        • Papiernik E.
        Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception.
        Lancet. 1994; 344: 973-975
        • Skjaerven R.
        • Wilcox A.J.
        • Lie R.T.
        The interval between pregnancies and the risk of preeclampsia.
        N Engl J Med. 2002; 346: 33-38
        • England L.
        • Zhang J.
        Smoking and risk of preeclampsia: a systematic review.
        Front Biosci. 2007; 12: 2471-2483
        • Mehendale R.
        • Hibbard J.
        • Fazleabas A.
        • Leach R.
        Placental angiogenesis markers sFlt-1 and PlGF: response to cigarette smoke.
        Am J Obstet Gynecol. 2007; 197: e361-e365
        • Schutte J.M.
        • Schuitemaker N.W.
        • van Roosmalen J.
        • Steegers E.A.
        • Dutch Maternal Mortality Committee
        Substandard care in maternal mortality due to hypertensive disease in pregnancy in the Netherlands.
        BJOG. 2008; 115: 732-736
        • Reslan O.M.
        • Khalil R.A.
        Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia.
        Cardiovasc Hematol Agents Med Chem. 2010; 8: 204-226
        • Levine R.J.
        • Lam C.
        • Qian C.
        • et al.
        Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
        N Engl J Med. 2006; 355: 992-1005
        • Levine R.J.
        • Maynard S.E.
        • Qian C.
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683
        • Rana S.
        • Karumanchi S.A.
        • Levine R.J.
        • et al.
        Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia.
        Hypertension. 2007; 50: 137-142
        • Moore Simas T.A.
        • Crawford S.L.
        • Solitro M.J.
        • Frost S.C.
        • Meyer B.A.
        • Maynard S.E.
        Angiogenic factors for the prediction of preeclampsia in high-risk women.
        Am J Obstet Gynecol. 2007; 197: e241-e248
        • Su Y.N.
        • Lee C.N.
        • Cheng W.F.
        • Shau W.Y.
        • Chow S.N.
        • Hsieh F.J.
        Decreased maternal serum placenta growth factor in early second trimester and preeclampsia.
        Obstet Gynecol. 2001; 97: 898-904
        • Tjoa M.L.
        • van Vugt J.M.
        • Mulders M.A.
        • Schutgens R.B.
        • Oudejans C.B.
        • van Wijk I.J.
        Plasma placenta growth factor levels in midtrimester pregnancies.
        Obstet Gynecol. 2001; 98: 600-607
        • Polliotti B.M.
        • Fry A.G.
        • Saller D.N.
        • Mooney R.A.
        • Cox C.
        • Miller R.K.
        Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia.
        Obstet Gynecol. 2003; 101: 1266-1274
        • 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: 1702-1703
        • Krauss T.
        • Pauer H.U.
        • Augustin H.G.
        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
        • Bersinger N.A.
        • Odegard R.A.
        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
        • Park C.W.
        • Park J.S.
        • Shim S.S.
        • Jun J.K.
        • Yoon B.H.
        • Romero R.
        An elevated maternal plasma, but not amniotic fluid, soluble fms-like tyrosine kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis is a risk factor for preeclampsia.
        Am J Obstet Gynecol. 2005; 193: 984-989
        • Vatten L.J.
        • Eskild A.
        • Nilsen T.I.
        • Jeansson S.
        • Jenum P.A.
        • Staff A.C.
        Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia.
        Am J Obstet Gynecol. 2007; 196: e231-e236
        • Smith G.C.
        • Crossley J.A.
        • Aitken D.A.
        • 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
        • Vaisbuch E.
        • Whitty J.E.
        • Hassan S.S.
        • et al.
        Circulating angiogenic and antiangiogenic factors in women with eclampsia.
        Am J Obstet Gynecol. 2011; 204: e151-e159
        • Noori M.
        • Donald A.E.
        • Angelakopoulou A.
        • Hingorani A.D.
        • Williams D.J.
        Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
        Circulation. 2010; 122: 478-487
        • Levine R.J.
        • Thadhani R.
        • Qian C.
        • et al.
        Urinary placental growth factor and risk of preeclampsia.
        JAMA. 2005; 293: 77-85
        • Thadhani R.
        • Mutter W.P.
        • 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: 770-775
        • Levine R.J.
        • Qian C.
        • Maynard S.E.
        • Yu K.F.
        • Epstein F.H.
        • Karumanchi S.A.
        Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women.
        Am J Obstet Gynecol. 2006; 194: 1034-1041
        • De Vivo A.
        • Baviera G.
        • Giordano D.
        • Todarello G.
        • Corrado F.
        • D'Anna R.
        Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia.
        Acta Obstet Gynecol Scand. 2008; 87: 837-842
        • McElrath T.F.
        • Lim K.H.
        • Pare E.
        • et al.
        Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy.
        Am J Obstet Gynecol. 2012; 207: 407.e1-407.e7
        • 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: e41-e47
        • Kusanovic J.P.
        • Romero R.
        • Chaiworapongsa T.
        • 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
        • Aggarwal P.K.
        • Jain V.
        • Sakhuja V.
        • Karumanchi S.A.
        • Jha V.
        Low urinary placental growth factor is a marker of pre-eclampsia.
        Kidney Int. 2006; 69: 621-624
        • Savvidou M.D.
        • Akolekar R.
        • Zaragoza E.
        • Poon L.C.
        • Nicolaides K.H.
        First trimester urinary placental growth factor and development of pre-eclampsia.
        BJOG. 2009; 116: 643-647
        • Buhimschi C.S.
        • Baumbusch M.A.
        • Dulay A.T.
        • et al.
        The role of urinary soluble endoglin in the diagnosis of pre-eclampsia: comparison with soluble fms-like tyrosine kinase 1 to placental growth factor ratio.
        BJOG. 2010; 117: 321-330
        • Perni U.
        • Sison C.
        • Sharma V.
        • et al.
        Angiogenic factors in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during pregnancy.
        Hypertension. 2012; 59: 740-746
        • Rolfo A.
        • Attini R.
        • Nuzzo A.M.
        • et al.
        Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers.
        Kidney Int. 2013; 83: 177-181
        • Masuyama H.
        • Nobumoto E.
        • Okimoto N.
        • Inoue S.
        • Segawa T.
        • Hiramatsu Y.
        Superimposed preeclampsia in women with chronic kidney disease.
        Gynecol Obstet Invest. 2012; 74: 274-281
        • Chafetz I.
        • Kuhnreich I.
        • Sammar M.
        • et al.
        First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction.
        Am J Obstet Gynecol. 2007; 197: e31-e37
        • Huppertz B.
        • Sammar M.
        • Chefetz I.
        • Neumaier-Wagner P.
        • Bartz C.
        • Meiri H.
        Longitudinal determination of serum placental protein 13 during development of preeclampsia.
        Fetal Diagn Ther. 2008; 24: 230-236
        • Romero R.
        • Kusanovic J.P.
        • Than N.G.
        • et al.
        First-trimester maternal serum PP13 in the risk assessment for preeclampsia.
        Am J Obstet Gynecol. 2008; 199: 122.e1-122.e11
        • Stamatopoulou A.
        • Cowans N.J.
        • Matwejew E.
        • von Kaisenberg C.
        • Spencer K.
        Placental protein-13 and pregnancy-associated plasma protein-A as first trimester screening markers for hypertensive disorders and small for gestational age outcomes.
        Hypertens Pregnancy. 2011; 30: 384-395
        • Akolekar R.
        • Syngelaki A.
        • Beta J.
        • Kocylowski R.
        • Nicolaides K.H.
        Maternal serum placental protein 13 at 11-13 weeks of gestation in preeclampsia.
        Prenatal Diagn. 2009; 29: 1103-1108
        • Odibo A.O.
        • Zhong Y.
        • Goetzinger K.R.
        • et al.
        First-trimester placental protein 13, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of pre-eclampsia.
        Placenta. 2011; 32: 598-602
        • Steel S.A.
        • Pearce J.M.
        • Chamberlain G.
        Doppler ultrasound of the uteroplacental circulation as a screening test for severe pre-eclampsia with intra-uterine growth retardation.
        Eur J Obstet Gynecol Reprod Biol. 1988; 28: 279-287
        • Aardema M.W.
        • De Wolf B.T.
        • Saro M.C.
        • Oosterhof H.
        • Fidler V.
        • Aarnoudse J.G.
        Quantification of the diastolic notch in Doppler ultrasound screening of uterine arteries.
        Ultrasound Obstet Gynecol. 2000; 16: 630-634
        • Papageorghiou A.T.
        • Leslie K.
        Uterine artery Doppler in the prediction of adverse pregnancy outcome.
        Curr Opin Obstet Gynecol. 2007; 19: 103-109
        • Espinoza J.
        • Romero R.
        • Nien J.K.
        • 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: 326.e1-326.e13
        • 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
        • Cnossen J.S.
        • Morris R.K.
        • ter Riet G.
        • et al.
        Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis.
        CMAJ. 2008; 178: 701-711
        • Barton J.R.
        • Sibai B.M.
        Prediction and prevention of recurrent preeclampsia.
        Obstet Gynecol. 2008; 112: 359-372
        • Poon L.C.
        • Kametas N.A.
        • Maiz N.
        • Akolekar R.
        • Nicolaides K.H.
        First-trimester prediction of hypertensive disorders in pregnancy.
        Hypertension. 2009; 53: 812-818
        • 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: 707-716
        • Garovic V.D.
        • Wagner S.J.
        • Petrovic L.M.
        • et al.
        Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia.
        Nephrol Dial Transpl. 2007; 22: 1136-1143
        • Garovic V.D.
        • Wagner S.J.
        • Turner S.T.
        • et al.
        Urinary podocyte excretion as a marker for preeclampsia.
        Am J Obstet Gynecol. 2007; 196: 320.e1-320.e7
        • Zhao S.
        • Gu X.
        • Groome L.J.
        • Wang Y.
        Decreased nephrin and GLEPP-1, but increased VEGF, Flt-1, and nitrotyrosine, expressions in kidney tissue sections from women with preeclampsia.
        Reprod Sci. 2009; 16: 970-979
        • Collino F.
        • Bussolati B.
        • Gerbaudo E.
        • et al.
        Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells.
        Am J Physiol Renal Physiol. 2008; 294: F1185-F1194
        • Aita K.
        • Etoh M.
        • Hamada H.
        • et al.
        Acute and transient podocyte loss and proteinuria in preeclampsia.
        Nephron Clin Pract. 2009; 112: c65-c70
        • Jim B.
        • Jean-Louis P.
        • Qipo A.
        • et al.
        Podocyturia as a diagnostic marker for preeclampsia amongst high-risk pregnant patients.
        J Pregnancy. 2012; 2012: 984630
        • Wang Y.
        • Zhao S.
        • Loyd S.
        • Groome L.J.
        Increased urinary excretion of nephrin, podocalyxin, and betaig-h3 in women with preeclampsia.
        Am J Physiol Ren Physiol. 2012; 302: F1084-F1089
        • Kelder T.P.
        • Penning M.E.
        • Uh H.W.
        • et al.
        Quantitative polymerase chain reaction-based analysis of podocyturia is a feasible diagnostic tool in preeclampsia.
        Hypertension. 2012; 60: 1538-1544
        • Greene C.S.
        • Troyanskaya O.G.
        Integrative systems biology for data-driven knowledge discovery.
        Semin Nephrol. 2010; 30: 443-454
        • Barratt J.
        • Topham P.
        Urine proteomics: the present and future of measuring urinary protein components in disease.
        CMAJ. 2007; 177: 361-368
        • Buhimschi I.A.
        • Zhao G.
        • Funai E.F.
        • et al.
        Proteomic profiling of urine identifies specific fragments of SERPINA1 and albumin as biomarkers of preeclampsia.
        Am J Obstet Gynecol. 2008; 199: 551.e1-551.e16
        • Bergman D.
        • Kadner S.S.
        • Cruz M.R.
        • et al.
        Synthesis of alpha 1-antichymotrypsin and alpha 1-antitrypsin by human trophoblast.
        Pediatr Res. 1993; 34: 312-317
        • Linja-Aho A.
        • Mazur W.
        • Toljamo T.
        • et al.
        Distribution and levels of alpha-1-antitrypsin in the lung and plasma in smokers and chronic obstructive pulmonary disease.
        APMIS. 2013; 121: 11-21
        • Engstrom G.
        • Janzon L.
        • Berglund G.
        • et al.
        Blood pressure increase and incidence of hypertension in relation to inflammation-sensitive plasma proteins.
        Arterioscler Thromb Vasc Biol. 2002; 22: 2054-2058
        • Chen G.
        • Zhang Y.
        • Jin X.
        • et al.
        Urinary proteomics analysis for renal injury in hypertensive disorders of pregnancy with iTRAQ labeling and LC-MS/MS.
        Proteomics Clin Appl. 2011; 5: 300-310
        • Carty D.M.
        • Siwy J.
        • Brennand J.E.
        • et al.
        Urinary proteomics for prediction of preeclampsia.
        Hypertension. 2011; 57: 561-569
        • Kottgen A.
        • Glazer N.L.
        • Dehghan A.
        • et al.
        Multiple loci associated with indices of renal function and chronic kidney disease.
        Nat Genet. 2009; 41: 712-717
        • Wishart D.S.
        • Knox C.
        • Guo A.C.
        • et al.
        HMDB: a knowledgebase for the human metabolome.
        Nucleic Acids Res. 2009; 37: D603-D610
        • Odibo A.O.
        • Goetzinger K.R.
        • Odibo L.
        • et al.
        First-trimester prediction of preeclampsia using metabolomic biomarkers: a discovery phase study.
        Prenatal Diagn. 2011; 31: 990-994
        • Bahado-Singh R.O.
        • Akolekar R.
        • Mandal R.
        • et al.
        Metabolomics and first-trimester prediction of early-onset preeclampsia.
        J Matern Fetal Neonatal Med. 2012; 25: 1840-1847
        • 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: 940-950
        • Duckitt K.
        • Harrington D.
        Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.
        BMJ. 2005; 330: 565
        • Davies A.M.
        • Czaczkes J.W.
        • Sadovsky E.
        • Prywes R.
        • Weiskopf P.
        • Sterk V.V.
        Toxemia of pregnancy in Jerusalem. I. Epidemiological studies of a total community.
        Isr J Med Sci. 1970; 6: 253-266
        • Kleinrouweler C.E.
        • Wiegerinck M.M.
        • Ris-Stalpers C.
        • et al.
        Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis.
        BJOG. 2012; 119: 778-787
        • Lim J.H.
        • Kim S.Y.
        • Park S.Y.
        • et al.
        Soluble endoglin and transforming growth factor-beta1 in women who subsequently developed preeclampsia.
        Prenatal Diagn. 2009; 29: 471-476
        • Stepan H.
        • Geipel A.
        • Schwarz F.
        • Kramer 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
        • Tidwell S.C.
        • Ho H.N.
        • Chiu W.H.
        • Torry R.J.
        • Torry D.S.
        Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia.
        Am J Obstet Gynecol. 2001; 184: 1267-1272