Skip to main content

Advertisement

Log in

Diagnostic accuracy of the soluble Fms-like tyrosine kinase-1/placental growth factor ratio for preeclampsia: a meta-analysis based on 20 studies

  • Review
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

To investigate the accuracy of the soluble fms-like tyrosine kinase-1(sFlt-1)/placental growth factor (PlGF) ratio to predict preeclampsia (PE).

Methods

A search in the PubMed, Embase, and Cochrane Library was conducted for human studies without language restriction. We included the studies reported sufficient data to reconstruct the diagnostic 2 × 2 table of sFlt-1/PlGF with testing of PlGF and sFlt-1 in serum or plasma. Two reviewers independently screened the articles. Disagreements were resolved by a third reviewer. Unpublished data were requested from the authors of the study by email.

Results

Twenty studies with 28 groups of women with different gestational ages were included in our study. The pooled diagnostic sensitivity and specificity of sFlt-1/PlGF were 0.78 and 0.84 with the area under the SROC curve (AUC) of 0.88. In subgroup analyses, the diagnostic value of sFlt-1/PlGF for early-onset PE is highest with a pooled diagnostic odds ratio (DOR) of 241 and AUC of 0.98.

Conclusions

The accuracy of sFlt-1/PlGF ratio for screening PE was moderate and was high for early-onset PE. High-quality studies are needed to confirm their usefulness in prediction of PE in clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Schoofs K, Grittner U, Engels T, Pape J, Denk B, Henrich W, Verlohren S (2014) The importance of repeated measurements of the sFlt-1/PlGF ratio for the prediction of preeclampsia and intrauterine growth restriction. J Perinat Med 42(1):61–68

    CAS  PubMed  Google Scholar 

  2. Mackay AP, Berg C, Atrash H (2001) Pregnancy-Related Mortality From Preeclampsia and Eclampsia. Obstet Gynecol 97(4):533–538

    Article  CAS  PubMed  Google Scholar 

  3. Powe CE, Levine RJ, Karumanchi SA (2011) Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation 123(24):2856–2869. doi:10.1161/CIRCULATIONAHA.109.853127

    Article  PubMed  Google Scholar 

  4. Kar M (2014) Role of biomarkers in early detection of preeclampsia. J Clin Diagnostic Res 8(4):BE01-BE04

  5. Cerdeira AS, Karumanchi SA (2012) Angiogenic factors in preeclampsia and related disorders. Cold Spring Harbor perspectives in medicine. doi:10.1101/cshperspect.a006585

    PubMed Central  PubMed  Google Scholar 

  6. Rana S, Karumanchi SA, Lindheimer MD (2014) Angiogenic factors in diagnosis, management, and research in preeclampsia. Hypertension 63(2):198–202. doi:10.1161/hypertensionaha.113.02293

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Widmer M, Villar J, Benigni A, Conde-Agudelo A, Karumanchi SA, Lindheimer M (2007) Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol 109(1):168–180. doi:10.1097/01.AOG.0000249609.04831.7c

    Article  CAS  PubMed  Google Scholar 

  8. Kleinrouweler CE, Wiegerinck MMJ, Ris-Stalpers C, Bossuyt PMM, Van Der Post JAM, Von Dadelszen P, Mol BWJ, Pajkrt E (2012) 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 Int J Obstet Gynaecol 119(7):778–787

    Article  CAS  Google Scholar 

  9. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, vol 339. doi:10.1136/bmj.b2535

  10. Whiting PF, Rutjes AWS, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MMG, Sterne JAC, Bossuyt PMM (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536. doi:10.7326/0003-4819-155-8-201110180-00009

    Article  PubMed  Google Scholar 

  11. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH (2005) Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol 58(10):982–990. doi:10.1016/j.jclinepi.2005.02.022

    Article  PubMed  Google Scholar 

  12. Hellmich M, Lehmacher W (2005) A Ruler for interpreting diagnostic test results 44(1):126

  13. Kim SY, Ryu HM, Yang JH, Kim MY, Han JY, Kim JO, Chung JH, Park SY, Lee MH, Kim DJ (2007) Increased sFlt-1 to PlGF ratio in women who subsequently develop preeclampsia. J Korean Med Sci 22(5):873–877

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Stepan H, Unversucht A, Wessel N, Faber R (2007) Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion. Hypertension 49(4):818–824. doi:10.1161/01.HYP.0000258404.21552.a3

    Article  CAS  PubMed  Google Scholar 

  15. De Vivo A, Baviera G, Giordano D, Todarello G, Corrado F, D’Anna R (2008) Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia. Acta Obstet Gynecol Scand 87(8):837–842. doi:10.1080/00016340802253759

    Article  PubMed  Google Scholar 

  16. Diab AE, El-Behery MM, Ebrahiem MA, Shehata AE (2008) Angiogenic factors for the prediction of pre-eclampsia in women with abnormal midtrimester uterine artery Doppler velocimetry. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet 102(2):146–151. doi:10.1016/j.ijgo.2008.02.016

    Article  CAS  Google Scholar 

  17. Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV, Martins-Costa S, Bartz J, de Barros Santos C, Cecatti JG, Costa R, Ramos JG, Spinnato JA 2nd (2008) 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 199(3):268.e261–e269. doi:10.1016/j.ajog.2008.06.071

  18. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vaisbuch E, Mazaki-Tovi S, Gotsch F, Edwin SS, Gomez R, Yeo L, Conde-Agudelo A, Hassan SS (2009) 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 Mater-Fetal Neonatal Med Off J Euro Assoc Perinatal Med Fed Asia Oceania Perinatal Soc Int Soc Perinatal Obstet 22(11):1021–1038. doi:10.3109/14767050902994754

    Article  CAS  Google Scholar 

  19. Molvarec A, Szarka A, Walentin S, Szucs E, Nagy B, Rigo J Jr (2010) Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia. Hypertension research Off J Japan Soc Hypert 33(9):892–898. doi:10.1038/hr.2010.92

    Article  CAS  Google Scholar 

  20. Ohkuchi A, Hirashima C, Suzuki H, Takahashi K, Yoshida M, Matsubara S, Suzuki M (2010) Evaluation of a new and automated electrochemiluminescence immunoassay for plasma sFlt-1 and PlGF levels in women with preeclampsia. Hypert Res Off J Japan Soc Hypert 33(5):422–427. doi:10.1038/hr.2010.15

    Article  CAS  Google Scholar 

  21. Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG, Pape J, Dudenhausen JW, Denk B, Stepan H (2010) An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. American journal of obstetrics and gynecology 202(2):161.e161–161.e111. doi:10.1016/j.ajog.2009.09.016

  22. McElrath TF, Lim KH, Pare E, Rich-Edwards J, Pucci D, Troisi R, Parry S (2012) Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy. American journal of obstetrics and gynecology 207(5):407.e401–407.e407. doi:10.1016/j.ajog.2012.08.010

  23. Chen G, Zhang L, Jin X, Zhou Y, Niu J, Chen J, Gu Y (2013) Effects of angiogenic factors, antagonists, and podocyte injury on development of proteinuria in preeclampsia. Reproductive sciences (Thousand Oaks, Calif) 20(5):579–588. doi:10.1177/1933719112459227

  24. Park HJ, Kim SH, Jung YW, Shim SS, Kim JY, Cho YK, Farina A, Zanello M, Lee KJ, Cha DH (2014) Screening models using multiple markers for early detection of late-onset preeclampsia in low-risk pregnancy. BMC Pregnancy Childbirth 14:35

    Article  PubMed Central  PubMed  Google Scholar 

  25. Lehnen H, Mosblech N, Reineke T, Puchooa A, Menke-Mollers I, Zechner U, Gembruch U (2013) Prenatal clinical assessment of sFlt-1 (Soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio as a diagnostic tool for preeclampsia, pregnancy-induced hypertension, and proteinuria. Geburtshilfe Frauenheilkd 73(5):440–445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Odibo AO, Rada CC, Cahill AG, Goetzinger KR, Tuuli MG, Odibo L, Macones GA, England SK (2013) First-trimester serum soluble fms-like tyrosine kinase-1, free vascular endothelial growth factor, placental growth factor and uterine artery Doppler in preeclampsia. J Perinatol Off J California Perinatal Assoc 33(9):670–674. doi:10.1038/jp.2013.33

    Article  CAS  Google Scholar 

  27. Villa PM, Hamalainen E, Maki A, Raikkonen K, Pesonen AK, Taipale P, Kajantie E, Laivuori H (2013) Vasoactive agents for the prediction of early- and late-onset preeclampsia in a high-risk cohort. BMC Pregnancy Childbirth 13:110. doi:10.1186/1471-2393-13-110

    Article  PubMed Central  PubMed  Google Scholar 

  28. Hanita O, Alia NN, Zaleha AM, Nor Azlin MI (2014) Serum soluble FMS-like tyrosine kinase 1 and placental growth factor concentration as predictors of preeclampsia in high risk pregnant women. Malays J Pathol 36(1):19–26

    CAS  PubMed  Google Scholar 

  29. Doherty A, Carvalho JC, Drewlo S, El-Khuffash A, Downey K, Dodds M, Kingdom J (2014) Altered hemodynamics and hyperuricemia accompany an elevated sFlt-1/PlGF ratio before the onset of early severe preeclampsia. J Obstet Gynaecol Canada JOGC J D’obstetrique et gynecologie du Canada JOGC 36(8):692–700

    Google Scholar 

  30. Moore Simas TA, Crawford SL, Bathgate S, Yan J, Robidoux L, Moore M, Maynard SE (2014) Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women. J Maternal-Fetal Neonatal Med 27(10):1038–1048

    Article  CAS  Google Scholar 

  31. Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA, Hodges-Savola C (2010) Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study. Am J Obstet Gynecol 202(1):40.e41-47. doi:10.1016/j.ajog.2009.07.025

  32. Stubert J, Ullmann S, Bolz M, Kulz T, Dieterich M, Richter DU, Reimer T (2014) Prediction of preeclampsia and induced delivery at <34 weeks gestation by sFLT-1 and PlGF in patients with abnormal midtrimester uterine Doppler velocimetry: a prospective cohort analysis. BMC Pregnancy Childbirth 14(1):292

    Article  PubMed Central  PubMed  Google Scholar 

  33. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. New England J Med 355(10):992–1005. doi:10.1056/NEJMoa055352

    Article  CAS  Google Scholar 

  34. Moore Simas TA, Crawford SL, Solitro MJ, Frost SC, Meyer BA, Maynard SE (2007) Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet Gynecol 197(3):244.e241–244.e248. doi:10.1016/j.ajog.2007.06.030

  35. Deeks JJ (2001) Systematic reviews in health care: Systematic reviews of evaluations of diagnostic and screening tests. BMJ 323(7305):157–162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Oudejans CB, van Dijk M, Oosterkamp M, Lachmeijer A, Blankenstein MA (2007) Genetics of preeclampsia: paradigm shifts. Hum Genet 120(5):607–612. doi:10.1007/s00439-006-0259-1

    Article  PubMed  Google Scholar 

  37. Mignini LE, Latthe PM, Villar J, Kilby MD, Carroli G, Khan KS (2005) Mapping the theories of preeclampsia: the role of homocysteine. Obstet Gynecol 105(2):411–425. doi:10.1097/01.AOG.0000151117.52952.b6

    Article  CAS  PubMed  Google Scholar 

  38. James JL, Whitley GS, Cartwright JE (2010) Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces. J Pathol 221(4):363–378. doi:10.1002/path.2719

    Article  CAS  PubMed  Google Scholar 

  39. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2004) Circulating angiogenic factors and the risk of preeclampsia. New England J Med 350(7):672–683. doi:10.1056/NEJMoa031884

    Article  CAS  Google Scholar 

  40. Karumanchi SA, Lindheimer MD (2008) Preeclampsia pathogenesis: “triple a rating”-autoantibodies and antiangiogenic factors. Hypertension 51(4):991–992. doi:10.1161/HYPERTENSIONAHA.107.100735

    Article  CAS  PubMed  Google Scholar 

  41. Gu Y, Lewis DF, Wang Y (2008) Placental productions and expressions of soluble endoglin, soluble fms-like tyrosine kinase receptor-1, and placental growth factor in normal and preeclamptic pregnancies. J Clin Endocrinol Metabol 93(1):260–266. doi:10.1210/jc.2007-1550

    Article  CAS  Google Scholar 

  42. Mutter WP, Karumanchi SA (2008) Molecular mechanisms of preeclampsia. Microvasc Res 75(1):1–8. doi:10.1016/j.mvr.2007.04.009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service, and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Diagnostic Accuracy of the Soluble Fms-like Tyrosine Kinase-1/Placental Growth Factor Ratio for Preeclampsia: a Meta-analysis based on 20 Studies.” We have full control of all primary data and we agree to allow the Journal to review our data if requested.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yufang Gao or Haitao Niu.

Additional information

Y. Liu and Y. Zhao contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Zhao, Y., Yu, A. et al. Diagnostic accuracy of the soluble Fms-like tyrosine kinase-1/placental growth factor ratio for preeclampsia: a meta-analysis based on 20 studies. Arch Gynecol Obstet 292, 507–518 (2015). https://doi.org/10.1007/s00404-015-3671-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-015-3671-8

Keywords

Navigation