Evaluation of Serum Biomarkers and Other Diagnostic Modalities for Early Diagnosis of Preeclampsia

  • Angela Felicia Sunjaya Faculty of Medicine, Tarumanagara University, Jakarta, Indonesia
  • Anthony Paulo Sunjaya Mail Faculty of Medicine, Tarumanagara University, Jakarta, Indonesia
Preeclampsia, Early Diagnosis, Biomarkers, Doppler Ultrasonography, Diagnostic Model


Objective: Preeclampsia (PE) is a multi-systemic complication of pregnancy often characterised with theonset of hypertension and proteinuria after 20 weeks of gestation. Today, PE is the leading cause ofmaternal and perinatal morbidity and mortality worldwide. An early detection of PE would allow a chanceto plan the appropriate monitoring and for clinical management to be immediately done following earlydetection thus making prophylactic strategies much more effective.Materials and methods: This systematic review aims to evaluate the potential of the various serumbiomarkers and diagnostic modalities (uterine artery Doppler, MAP, and maternal history) available forearly prediction of PE with articles included and obtained through MEDLINE Full Text, Pubmed, ScienceDirect, ProQuest, SAGE, Taylor and Francis Online, Google Scholar, HighWire and Elsevier ClinicalKey.Results: Ninety-five articles were found that fulfilled all of our inclusion criteria. Placental growth factor(PlGF), pregnancy associated plasma protein A (PAPP-A), soluble fms-like tyrosine kinase (sFLT) andplacental protein 13 (PP-13) were the most commonly studied biomarkers. Whereas uterine Dopplerscanning and Mean Arterial Pressure (MAP) were the most commonly studied out of other modalities.Conclusion: Current evidence shows serum biomarkers such as PIGF, PP-13 and sFlt yielded the bestresults for a single biomarker with others having conflicting results. However, a combination model withother diagnostic modalities performed better than a single biomarker. In the future, new techniques willhopefully provide sets of multiple markers, which will lead to a screening program with clinically relevantperformance. However further studies are required to improve current methods.


1. World Health Organization (WHO). WHO Recommendations for Prevention and Treatment of pre-eclampsia and eclampsia. World Health Organization (WHO), Department of Reproductive Health and Research, 2011.
2. Savaj S, Nosratolah D Vaziri. An overview of recent advances in pathogenesis and diagnosis of preeclampsia. Iranian Journal of Kidney Diseases 2012; 6: 334-8.
3. Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and severe obstetric morbidity in the United States. Obstet Gynecol 2009; 113:1299-306.
4. Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004. Am J Hypertens 2008; 21: 521-6.
5. Kuc S, Wortelboer EJ, van Rijn BB, Franx A, Visser GH, Schielen PC. Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review. Obstet Gynecol Surv 2011; 66: 225-39.
6. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;33:130-7.
7. WHO, UNICEF, UNFPA and The World Bank. Maternal Mortality in 2005. Geneva: WHO, UNICEF, UNFPA and The World Bank, Department of Reproductive Health and Research, 2007.
8. Jeyabalan A. Epidemiology of preeclampsia: impact of obesity. Nutr Rev 2013; 71 Suppl 1: S18-25.
9. Noris M, Perico N, Remuzzi G. Mechanisms of disease: Pre-eclampsia. Nat Clin Pract Nephrol 2005;1: 98-114.
10. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008; 156: 918-30.
11. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008;359: 61-73.
12. Zhong Y, Zhu F, Ding Y. Serum screening in first trimester to predict pre-eclampsia, small for gestational age and preterm delivery: systematic review and meta-analysis. BMC Pregnancy Childbirth 2015; 15: 191.
13. Costa Fda S, Murthi P, Keogh R, Woodrow N. Early screening for preeclampsia. Rev Bras Ginecol Obstet 2011; 33: 367-75.
14. Pedrosa AC, Matias A. Screening for pre-eclampsia: a systematic review of tests combining uterine artery Doppler with other markers. J Perinat Med 2011; 39: 619-35.
15. Thilaganathan B, Wormald B, Zanardini C, Sheldon J, Ralph E, Papageorghiou AT. Early-pregnancy multiple serum markers and second-trimester uterine artery Doppler in predicting preeclampsia. Obstet Gynecol 2010; 115: 1233-8.
16. Yu CK, Khouri O, Onwudiwe N, Spiliopoulos Y, Nicolaides KH; Fetal medicine foundation second-trimester screening group. Prediction of pre-eclampsia by uterine artery Doppler imaging: relationship to gestational age at delivery and small-for-gestational age. Ultrasound Obstet Gynecol 2008; 31: 310-3.
17. Park HJ, Shim SS, Cha DH. Combined screening for early detection of pre-eclampsia. Int J Mol Sci 2015; 16:17952-74.
18. Borzychowski AM, Sargent IL, Redman CW. Inflammation and pre-eclampsia. Semin Fetal Neonatal Med 2006; 11: 309-16.
19. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592-4.
20. Visser N, van Rijn BB, Rijkers GT, Franx A, Bruinse HW. Inflammatory changesin preeclampsia: current understanding of the maternal innate and adaptive immune response. Obstet Gynecol Surv 2007; 62:191-201.
21. Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD. Advances in thepathophysiology of pre-eclampsia and related podocyte injury. Kidney Int 2014; 86:275-85.
22. Wibowo N, Irwinda R, Frisdianty E. Pedoman Nasional Pelayanan Kedokteran Diagnosis dan tatalaksana pre-eklampsia: Indonesian Society of Obstetrician and Gynecologists; Ministry of Health Republic of Indonesia, 2010.
23. Royal College of Obstetricians and Gynaecologists. Hypertension in pregnancy: the management of hypertensive disorders during pregnancy London: Royal College of Obstetricians and Gynaecologists, 2011.
24. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116: 402-14.
25. Roberge S, Villa P, Nicolaides K, Giguère Y, Vainio M, Bakthi A, et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther 2012; 31: 141-6.
26. Roberge S, Guguere Y, Villa P, Nicolaides K, Vainio M, Forest JC, et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Fetal Diagnosis and Therapy 2012; 31: 141–6.
27. Committee Opinion No. 638: First-trimester risk assessment for early-onset preeclampsia. Obstet Gynecol 2015; 126: e25-7.
28. Kenny LC, Black MA, Poston L, Taylor R, Myers JE, Baker PN, et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints(SCOPE) international cohort study. Hypertension 2014; 64:644-52.
29. Wright D, Akolekar R, Syngelaki A, Poon LC, Nicolaides KH. A competing risks model in early screening for preeclampsia. Fetal Diagn Ther 2012; 32: 171-8.
30. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther 2013; 33: 8-15.
31. Odibo AO, Zhong Y, Goetzinger KR, Odibo L, Bick JL, Bower CR, 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.
32. Kuc S, Koster MP, Franx A, Schielen PC, Visser GH. Maternal characteristics,mean arterial pressure and serum markers in early prediction of preeclampsia. PLoS One 2013; 8:e63546.
33. Di Lorenzo G, Ceccarello M, Cecotti V, Ronfani L, Monasta L, Vecchi Brumatti L, et al. First trimester maternal serum PIGF, free β-hCG, PAPP-A, PP-13, uterine artery Doppler and maternal history for the prediction of preeclampsia. Placenta 2012; 33: 495-501.
34. Goetzinger KR, Singla A, Gerkowicz S, Dicke JM, Gray DL, Odibo AO. Predicting the risk of pre-eclampsia between 11 and 13 weeks' gestation by combining maternal characteristics and serum analytes, PAPP-A and free β-hCG. Prenat Diagn 2010; 30: 1138-42.
35. Myers JE, Kenny LC, McCowan LM, Chan EH,
Dekker GA, Poston L, et al; SCOPE consortium. Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study. BJOG 2013; 120: 1215-23.
36. D'Antonio F, Rijo C, Thilaganathan B, Akolekar R, Khalil A, Papageourgiou A,et al. Association between first-trimester maternal serum pregnancy-associated plasma protein-A and obstetric complications. Prenat Diagn 2013; 33:839-47.
37. Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol 2012; 119: 1234-42.
38. Youssef A, Righetti F, Morano D, Rizzo N, Farina A. Uterine artery Doppler and biochemical markers (PAPP-A, PIGF, sFlt-1, P-selectin, NGAL) at 11 + 0 to 13 + 6 weeks in the prediction of late (> 34 weeks) pre-eclampsia. Prenat Diagn 2011; 31: 1141-6.
39. Chafetz I, Kuhnreich I, Sammar M, Tal Y, Gibor Y, Meiri H, et al.First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol 2007; 197:35.e1-7.
40. Vandenberghe G, Mensink I, Twisk JW, Blankenstein MA, Heijboer AC, van Vugt JM. First trimester screening for intra-uterine growth restriction and early-onset pre-eclampsia. Prenat Diagn 2011; 31: 955-61.
41. Gonen R, Shahar R, Grimpel YI, Chefetz I, Sammar M, Meiri H, et al. Placental protein 13 as an early marker for pre-eclampsia: a prospective longitudinal study. BJOG 2008; 115: 1465-72.
42. 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: 1021–38.
43. Poon LC, Stratieva V, Piras S, Piri S, Nicolaides KH. Hypertensive disorders in pregnancy: combined screening by uterine artery Doppler, blood pressure and serum PAPP-A at 11-13 weeks. Prenat Diagn 2010; 30: 216-23.
44. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension 2009; 53: 812-8.
45. Ranta JK, Raatikainen K, Romppanen J, Pulkki K, Heinonen S. Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption. Eur J Obstet Gynecol Reprod Biol 2011; 157: 48-52.
46. Poon LC, Nicolaides KH. Early prediction of preeclampsia. Obstet Gynecol Int 2014; 2014: 297397.
47. 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.
48. Lockwood CJ, Krikun G, Caze R, Rahman M, Buchwalder LF, Schatz F. Decidual cell-expressed tissue factor in human pregnancy and its involvement in hemostasis and preeclampsia-related angiogenesis. Ann N Y Acad Sci 2008; 1127: 67-72.
49. Milkat B, Gellhaus A, Wagner N, Birdir C, Kimmig R, Koninger A. Early detection of maternal risk for preeclampsia. ISRN Obstet Gynecol 2012; 2012: 172808.
50. 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: 303-9.
51. Foidart JM, Munaut C, Chantraine F, Akolekar R, Nicolaides KH. Maternal plasmasoluble endoglin at 11-13 weeks' gestation in pre-eclampsia. Ultrasound Obstet Gynecol 2010; 35: 680-7.
52. Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, et al. The change in concentrations of angiogenic and anti angiogenic factors inmaternal 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; 21:279-87.
53. Vatten LJ, Eskild A, Nilsen TI, Jeansson S, Jenum PA, Staff AC. Changes incirculating level of angiogenic factors from the first to second trimester aspredictors of preeclampsia. Am J Obstet Gynecol 2007; 196: 239.e1-6.
54. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) andanti-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.
55. Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction ofearly, intermediate and late pre-eclampsia from maternal factors, biophysical andbiochemical markers at 11-13 weeks. Prenat Diagn 2011; 31: 66-74.
56. Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC, Visser GH. First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia. BJOG 2010; 117: 1384-9.
57. Tayyar A, Garcia-Tizon Larroca S, Poon LC, Wright D, Nicolaides KH. Competing risk model in screening for pre-eclampsia by mean arterial pressure and uterine artery pulsatility index at 30–33 weeks’gestation. Fetal Diagn Ther 2014; 36: 18-27.
58. Mikat B, Zeller A, Scherag A, Drommelschmidt K, Kimmig R, Schmidt M. βhCG and PAPP-A in first trimester: predictive factors for preeclampsia. Hypertens Pregnancy 2012; 31: 261-7.
59. 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.
60. Sekizawa A, Purwosunu Y, Yoshimura S, Nakamura M, Shimizu H,Okai T, et al. PP13 mRNA expression in trophoblasts from preeclamptic placentas. Reproductive Sciences 2009; 16: 408-13.
61. Than NG, Romero R, Kim CJ, McGowen MR, Papp Z, Wildman DE. Galectins: guardians of eutherian pregnancy at the maternal-fetal interface. Trends Endocrinol Metab 2012; 23:23-31.
62. Than NG, Romero R, Goodman M, Weckle A, Xing J, Dong Z, et al. A primate subfamily of galectins expressed at thematernal-fetal interface that promote immune cell death. Proc Natl Acad Sci U SA 2009; 106:9731-6.
63. Huppertz B, Abe E, Murthi P, Nagamatsu T, Szukiewicz D, Salafia C. Placental angiogenesis, maternal and fetal vessels--a workshop report. Placenta 2007; 28: S94-6.
64. Spencer K, Cowans NJ, Chefetz I, Tal J, Meiri H. First-trimester maternalserum PP-13, PAPP-A and second-trimester uterine artery Doppler pulsatility indexas markers of pre-eclampsia. Ultrasound Obstet Gynecol 2007; 29:128-34.
65. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Harrington K. First trimester maternal serum placental protein 13 for the prediction of pre-eclampsia in women with a priori high risk. Prenat Diagn 2009; 29: 781-9.
66. Kar M. Role of biomarkers in early detection of preeclampsia. J Clin Diagn Res 2014; 8: BE01-4.
67. Aggarwal PK, Chandel N, Jain V, Jha V. The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia. J Hum Hypertens 2012; 26: 236-41.
68. Wu P, van den Berg C, Alfirevic Z, O'Brien S, Röthlisberger M, Baker PN, et al. Early pregnancy biomarkers in pre-eclampsia: A systematic review and meta-analysis. Int J Mol Sci 2015; 16: 23035-56.
69. Boucoiran I, Thissier-Levy S, Wu Y, Wei SQ, Luo ZC, Delvin E, et al. MIROS study group. Risks for preeclampsia and small for gestational age: predictive values of placental growth factor, soluble fms-like tyrosine kinase-1, and inhibin A in singleton and multiple-gestation pregnancies. Am J Perinatol 2013; 30: 607-12.
70. Bills VL, Varet J, Millar A, Harper SJ, Soothill PW, Bates DO. Failure toup-regulate VEGF165b in maternal plasma is a first trimester predictive markerfor pre-eclampsia. Clin Sci (Lond) 2009; 116:265-72.
71. Giguère Y, Massé J, Thériault S, Bujold E, Lafond J, Rousseau F, et al. Screening for pre-eclampsia early in pregnancy: performance of a multivariable model combining clinical characteristics and biochemical markers. BJOG 2015; 122: 402-10.
72. Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol 2010;8:102.
73. Cohen JL, Smilen KE, Bianco AT, Moshier EL, Ferrara LA, Stone JL. Predictive value of combined serum biomarkers for adverse pregnancy outcomes. Eur J Obstet Gynecol Reprod Biol 2014; 181: 89-94.
74. Audibert F, Boucoiran I, An N, Aleksandrov N, Delvin E, Bujold E, et al. Screening for preeclampsia using first-trimester serum markers and uterine artery Doppler in nulliparous women. Am J Obstet Gynecol 2010; 203: 383.e1-8.
75. Brameld KJ, Dickinson JE, O'Leary P, Bower C, Goldblatt J, Hewitt B, et al. First trimester predictors of adverse pregnancy outcomes. Aust N Z J Obstet Gynaecol 2008; 48: 529-35.
76. Spencer K, Yu CK, Cowans NJ, Otigbah C, Nicolaides KH. Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler. Prenat Diagn 2005; 25: 949-53.
77. Canini S, Prefumo F, Pastorino D, Crocetti L, Afflitto CG, Venturini PL, et al. Association between birth weight and first-trimester free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Fertil Steril 2008; 89: 174-8.
78. Zwahlen M, Gerber S, Bersinger NA. First trimester markers for pre-eclampsia: placental vs. non-placental protein serum levels. Gynecol Obstet Invest 2007; 63: 15-21.
79. Muttukrishna S, Knight PG, Groome NP, Redman CW, Ledger WL. Activin A and inhibin A as possible endocrine markers for pre-eclampsia. Lancet 1997; 349:1285-8.
80. Akolekar R, Minekawa R, Veduta A, Romero XC, Nicolaides KH. Maternal plasma inhibin A at 11-13 weeks of gestation in hypertensive disorders of pregnancy. Prenat Diagn 2009; 29: 753-60.
81. Akolekar R, Etchegaray A, Zhou Y, Maiz N, Nicolaides KH. Maternal serum activin a at 11-13 weeks of gestation in hypertensive disorders of pregnancy. Fetal Diagn Ther 2009; 25: 320-7.
82. Spencer K, Cowans NJ, Nicolaides KH. Maternal serum inhibin-A and activin-A levels in the first trimester of pregnancies developing pre-eclampsia. Ultrasound Obstet Gynecol 2008; 32: 622-6.
83. Oujo B, Perez-Barriocanal F, Bernabeu C, Lopez-Novoa JM. Membrane and soluble forms of endoglin in preeclampsia. Curr Mol Med 2013; 13: 1345-57.
84. Mutter WP, Karumanchi SA. Molecular mechanisms of preeclampsia. Microvasc Res 2008; 75: 1-8.
85. 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.
86. 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: 642-9.
87. 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: 137-42.
88. Robinson CJ, Johnson DD. Soluble endoglin as a second-trimester marker for preeclampsia. Am J Obstet Gynecol 2007; 197:174.e1-5.
89. Staff AC, Braekke K, Johnsen GM, Karumanchi SA, Harsem NK. Circulating concentrations of soluble endoglin (CD105) in fetal and maternal serum and in amniotic fluid in preeclampsia. Am J Obstet Gynecol 2007; 197: 176.e1-6.
90. 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; 111:1403-9.
91. 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.e1-6.
92. 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: 837-42.
93. Salahuddin S, Lee Y, Vadnais M, Sachs BP, Karumanchi SA, Lim KH. Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Am J Obstet Gynecol 2007; 197: 28.e1-6.
94. Gack S, Marmé A, Marmé F, Wrobel G, Vonderstrass B, Bastert G, et al. Preeclampsia: increased expression of soluble ADAM12. J Mol Med (Berl) 2005; 83:887-96.
95. Wortelboer EJ, Koster MP, Cuckle HS, Stoutenbeek PH, Schielen PC, Visser GH. First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia. BJOG 2010; 117: 1384-9.
96. Spencer K, Cowans NJ, Stamatopoulou A. ADAM12s in maternal serum as a potential marker of pre-eclampsia. Prenat Diagn 2008; 28: 212-6.
97. Laigaard J, Sørensen T, Placing S, Holck P, Fröhlich C, Wøjdemann KR, et al. Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia. Obstet Gynecol 2005; 106:144-9.
98. Poon LC, Chelemen T, Granvillano O, Pandeva I, Nicolaides KH. First-trimester maternal serum a disintegrin and metalloprotease 12 (ADAM12) and adverse pregnancy outcome. Obstet Gynecol 2008; 112: 1082-90.
99. Cuckle HS. Screening for pre-eclampsia--lessons from aneuploidy screening. Placenta 2011; 32 Suppl:S42-8.
100. Parra-Cordero M, Rodrigo R, Barja P, Bosco C, Rencoret G, Sepúlveda-Martinez A, et al. Prediction of early and late pre-eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy. Ultrasound Obstet Gynecol 2013; 41: 538-44.
101. Herraiz I, Arbués J, Camaño I, Gómez-Montes E, Grañeras A, Galindo A. Application of a first-trimester prediction model for pre-eclampsia based on uterine arteries and maternal history in high-risk pregnancies. Prenat Diagn 2009; 29: 1123-9.
102. Scazzocchio E, Figueras F, Crispi F, Meler E, Masoller N, Mula R, et al. Performance of a first-trimester screening of preeclampsia in a routine care low-risk setting. Am J Obstet Gynecol 2013; 208: 203.e1-203.e10.
103. Baschat AA, Magder LS, Doyle LE, Atlas RO, Jenkins CB, Blitzer MG. Prediction of preeclampsia utilizing the first trimester screening examination. Am J Obstet Gynecol 2014; 211: 514.e1-7.
104. Caradeux J, Serra R, Nien JK, Pérez-Sepulveda A, Schepeler M, Guerra F, et al.First trimester prediction of early onset preeclampsia using demographic,clinical, and sonographic data: a cohort study. Prenat Diagn 2013; 33:732-6.
105. Baschat AA. First-trimester screening for pre-eclampsia: moving from personalized risk prediction to prevention. Ultrasound Obstet Gynecol 2015; 45: 119-29.
106. North RA, McCowan LM, Dekker GA, Poston L, Chan EH, Stewart AW, et al. Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort. BMJ 2011; 342: d1875.
107. Onwudiwe N, Yu CK, Poon LC, Spiliopoulos I, Nicolaides KH. Prediction ofpre-eclampsia by a combination of maternal history, uterine artery Doppler andmean arterial pressure. Ultrasound Obstet Gynecol 2008; 32:877-83.
108. National Collaborating Centre for Women's and Children's Health (UK).Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. London: RCOG Press, 2010.
109. Poon LC, Kametas NA, Chelemen T, Leal A, Nicolaides KH. Maternal risk factors for hypertensive disorders in pregnancy: a multivariate approach. J Hum Hypertens 2010; 24: 104-10.
110. Harris LK, Keogh RJ, Wareing M, Baker PN, Cartwright JE, Aplin JD, et al.Invasive trophoblasts stimulate vascular smooth muscle cell apoptosis by a fasligand-dependent mechanism. Am J Pathol 2006; 169:1863-74.
111. Cnossen JS, Vollebregt KC, de Vrieze N, ter Riet G, Mol BW, Franx A, et al. Accuracy of mean arterial pressure and blood pressure measurements in predicting pre-eclampsia: systematic review and meta-analysis. BMJ 2008; 336:1117-20.
112. Kumar M, Gupta U, Bhattacharjee J, Singh R, Singh S, Goel M, et al. Early prediction of hypertension during pregnancy in a low-resource setting. Int J Gynaecol Obstet 2016; 132:159-64.
113. Poon LC, Staboulidou I, Maiz N, Plasencia W, Nicolaides KH. Hypertensive disorders in pregnancy: screening by uterine artery Doppler at 11-13 weeks. Ultrasound Obstet Gynecol 2009; 34: 142-8.
114. Gallo D, Poon LC, Fernandez M, Wright D, Nicolaides KH. Prediction of preeclampsia by mean arterial pressure at 11-13 and 20-24 weeks' gestation. Fetal Diagn Ther 2014; 36:28-37.
115. Spencer K, Cowans NJ, Chefetz I, Tal J, Meiri H. First-trimester maternal serum PP-13, PAPP-A and second-trimester uterine artery Doppler pulsatility index as markers of pre-eclampsia. Ultrasound Obstet Gynecol 2007; 29: 128-34.
116. Keogh RJ, Harris LK, Freeman A, Baker PN, Aplin JD, Whitley GS, et al. Fetal-derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand to induce smooth muscle cell death. Circ Res 2007; 100: 834-41.
117. Cetin I, Huppertz B, Burton G, Cuckle H, Gonen R, Lapaire O, et al. Pregenesys pre-eclampsia markers consensus meeting: What do we require frommarkers, risk assessment and model systems to tailor preventive strategies? Placenta 2011; 32 Suppl: S4-16.
118. Plasencia W, Maiz N, Bonino S, Kaihura C, Nicolaides KH. Uterine artery Doppler at 11 + 0 to 13 + 6 weeks in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol 2007; 30: 742-9.
119. Velauthar L, Plana MN, Kalidindi M, Zamora J, Thilaganathan B, Illanes SE,et al. First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta-analysis involving 55,974 women. Ultrasound Obstet Gynecol 2014; 43:500-7.
120. Harrington K. Early screening for pre-eclampsia and intrauterine growthrestriction. Ultrasound Obstet Gynecol 2011; 37:623-4.
121. Stepan H, Herraiz I, Schlembach D, Verlohren S, Brennecke S, Chantraine F, et al.Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis ofpre-eclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol 2015; 45:241-6.
122. Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, et al. The sFlt-1/PlGF ratio indifferent types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 2012; 206:58.e1-8.
123. Benton SJ, Hu Y, Xie F, Kupfer K, Lee SW, Magee LA, et al. Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays. Am J Obstet Gynecol 2011; 205: 469.e1-8.
124. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risksmodel in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther 2013; 33:8-15.
How to Cite
Sunjaya A, Sunjaya A. Evaluation of Serum Biomarkers and Other Diagnostic Modalities for Early Diagnosis of Preeclampsia. J Fam Reprod Health. 13(2):56-69.
Review Articles