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Published in: Archives of Gynecology and Obstetrics 6/2016

01-12-2016 | Maternal-Fetal Medicine

Using the angiogenic factors sFlt-1 and PlGF with Doppler ultrasound of the uterine artery for confirming preeclampsia

Authors: Franz Bahlmann, Ammar Al Naimi

Published in: Archives of Gynecology and Obstetrics | Issue 6/2016

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Abstract

Purpose

The aim of this study is to assess the value of the angiogenic factors for diagnosing preeclampsia and predicting the severity of manifestation. A secondary aim is assessing the combination of the uterine artery Doppler with the angiogenic factors for improving the diagnostic power.

Methods

This is a prospective single center study in a tertiary referral hospital. This study includes 728 individual patients. Inclusion criteria were singleton pregnancies, a referral to the hospital with suspicion of preeclampsia and any one or combination of the following symptoms: headache, upper abdominal pain, edema, and hypertension. Patients with complications that would affect the course of the pregnancy, such as placenta praevia, premature preterm rupture of membranes, breech presentation, and fetal chromosomal or structural anomalies, were excluded from the study. Blood samples collection and uterine artery Doppler ultrasound were performed at time of recruitment. The differences in sFlt-1, PlGF, and their quotient among normal collective and patients with preeclampsia were analyzed. Doppler ultrasound was performed by one of four highly qualified sonographers. Wilcoxon–Mann–Whitney U test, Spearman’s rank correlation, receiver operating characteristic curves, Chi-square test, and logistic regression were used in the analysis.

Results

A total of 1003 individual samples for the angiogenic factors were included in the analysis. 584 out of the recruited 728 patients had follow-up data with delivery information at the study hospital. Patients with preeclampsia show a significant increase in sFlt-1, which directly correlate with the increased severity of manifestation (Spearman’s ρ 0.49). The sFlt-1 cut-off value of 5424 pg/ml confirms preeclampsia with 83.7 % sensitivity, 68.1 % specificity, and 24 % misclassification rate. Preeclampsia patients also show a significant decrease in PlGF, which negatively correlates with the increased severity of manifestation (Spearman’s ρ −0.39). A PlGF cut-off value of 118 pg/ml confirms preeclampsia with 47.6 % sensitivity, 71.4 % specificity, and 27 % misclassification rate. Logistic regression shows that a combination of the quotient from sFlt-1/PlGF with notching and uterine artery PI provides a valid model for diagnosing preeclampsia with a diagnostic power of 74.4 %.

Conclusions

The study confirms the use of the sFlt-1 and PlGF for diagnosing preeclampsia. It also shows their significance in differentiating between different categories of preeclampsia according to severity. This study shows that the use of angiogenic factors in combination with ultrasound findings provides valid models for confirming preeclampsia.
Literature
1.
go back to reference Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM (2001) The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20:IX–XIVCrossRefPubMed Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM (2001) The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20:IX–XIVCrossRefPubMed
2.
go back to reference Högberg U (2005) The World Health Report 2005: “make every mother and child count”—including Africans. Scand J Public Health 33:409–411CrossRefPubMed Högberg U (2005) The World Health Report 2005: “make every mother and child count”—including Africans. Scand J Public Health 33:409–411CrossRefPubMed
4.
go back to reference Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, Vercruysse L, van Assche A (1991) Placental beed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol 98:648–655CrossRefPubMed Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, Vercruysse L, van Assche A (1991) Placental beed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol 98:648–655CrossRefPubMed
5.
go back to reference Carbillon L, Challier JC, Alouini S, Uzan M, Uzan S (2001) Uteroplacental circulation development: Doppler assessment and clinical importance. Placenta 22:795–799CrossRefPubMed Carbillon L, Challier JC, Alouini S, Uzan M, Uzan S (2001) Uteroplacental circulation development: Doppler assessment and clinical importance. Placenta 22:795–799CrossRefPubMed
6.
go back to reference Talbert DG (1995) Uterine flow velocity waveform shape as an indicator of maternal and placental development failure mechanisms: a model-based synthesizing approach. Ultrasound Obstet Gynecol 6:261–271CrossRefPubMed Talbert DG (1995) Uterine flow velocity waveform shape as an indicator of maternal and placental development failure mechanisms: a model-based synthesizing approach. Ultrasound Obstet Gynecol 6:261–271CrossRefPubMed
7.
go back to reference Papageorghiou AT, Yu CK, Bindra R, Pandis G, Nicolaides KH, Fetal Medicine Foundation Second Trimester Screening Group (2001) Multicenter screening for pre-eclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 18:441–449CrossRefPubMed Papageorghiou AT, Yu CK, Bindra R, Pandis G, Nicolaides KH, Fetal Medicine Foundation Second Trimester Screening Group (2001) Multicenter screening for pre-eclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 18:441–449CrossRefPubMed
8.
go back to reference Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ (2002) Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 160:1405–1423CrossRefPubMedPubMedCentral Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ (2002) Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 160:1405–1423CrossRefPubMedPubMedCentral
9.
go back to reference Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658CrossRefPubMedPubMedCentral Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658CrossRefPubMedPubMedCentral
10.
go back to reference Ahmad S, Ahmed A (2004) Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 95:884–891CrossRefPubMed Ahmad S, Ahmed A (2004) Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 95:884–891CrossRefPubMed
11.
go back to reference 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. N Engl J Med 350:672–683CrossRefPubMed 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. N Engl J Med 350:672–683CrossRefPubMed
12.
go back to reference Krauss T, Pauer HU, Augustin HG (2004) Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy 23:101–111CrossRefPubMed Krauss T, Pauer HU, Augustin HG (2004) Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy 23:101–111CrossRefPubMed
13.
go back to reference Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA (2003) Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 188:177–182CrossRefPubMed Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA (2003) Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 188:177–182CrossRefPubMed
14.
go back to reference Bahlmann F, Fittschen M, Reinhard I, Wellek S, Steiner E (2012) Reference values for blood flow velocity in the uterine artery in normal pregnancies from 18 weeks to 42 weeks of gestation calculated by automatic Doppler waveform analysis. Ultraschall Med 33:258–264CrossRefPubMed Bahlmann F, Fittschen M, Reinhard I, Wellek S, Steiner E (2012) Reference values for blood flow velocity in the uterine artery in normal pregnancies from 18 weeks to 42 weeks of gestation calculated by automatic Doppler waveform analysis. Ultraschall Med 33:258–264CrossRefPubMed
17.
go back to reference Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA, CPEP Study Group (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005CrossRefPubMed Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA, CPEP Study Group (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005CrossRefPubMed
18.
go back to reference Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936–943CrossRefPubMed Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P (2003) Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936–943CrossRefPubMed
19.
go back to reference Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS (2001) Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 184:1267–1272CrossRefPubMed Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS (2001) Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 184:1267–1272CrossRefPubMed
20.
go back to reference Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ (1998) Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 179:1539–1544CrossRefPubMed Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ (1998) Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 179:1539–1544CrossRefPubMed
21.
go back to reference Mundim GJ, Paschoini MC, Araujo Júnior E, Da Silva Costa F, Rodrigues Júnior V (2016) Assessment of angiogenesis modulators in pregnant women with pre-eclampsia: a case-control study. Arch Gynecol Obstet 293:369–375CrossRefPubMed Mundim GJ, Paschoini MC, Araujo Júnior E, Da Silva Costa F, Rodrigues Júnior V (2016) Assessment of angiogenesis modulators in pregnant women with pre-eclampsia: a case-control study. Arch Gynecol Obstet 293:369–375CrossRefPubMed
22.
go back to reference Lim JH, Kim SY, Park SY, Yang JH, Kim MY, Ryu HM (2008) Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors. Obstet Gynecol 111:1403–1409CrossRefPubMed Lim JH, Kim SY, Park SY, Yang JH, Kim MY, Ryu HM (2008) Effective prediction of preeclampsia by a combined ratio of angiogenesis-related factors. Obstet Gynecol 111:1403–1409CrossRefPubMed
23.
go back to reference Liu Y, Zhao Y, Yu A, Zhao B, Gao Y, Niu H (2015) 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 292:507–518CrossRefPubMed Liu Y, Zhao Y, Yu A, Zhao B, Gao Y, Niu H (2015) 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 292:507–518CrossRefPubMed
24.
go back to reference 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. Am J Obstet Gynecol 202:161.e1–161.e11CrossRef 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. Am J Obstet Gynecol 202:161.e1–161.e11CrossRef
25.
go back to reference Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S (2016) Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 374:13–22CrossRefPubMed Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S (2016) Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 374:13–22CrossRefPubMed
26.
go back to reference Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H (2012) The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 206:58.e1–8CrossRefPubMed Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H (2012) The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 206:58.e1–8CrossRefPubMed
27.
go back to reference Fischer T, Schneider MP, Schobel HP, Heusser K, Langenfeld M, Schmieder RE (2000) Vascular reactivity in patients with preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 183:1489–1494CrossRefPubMed Fischer T, Schneider MP, Schobel HP, Heusser K, Langenfeld M, Schmieder RE (2000) Vascular reactivity in patients with preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 183:1489–1494CrossRefPubMed
28.
go back to reference Verlohren S, Herraiz I, Lapaire O, Schlembach D, Zeisler H, Calda P, Sabria J, Markfeld-Erol F, Galindo A, Schoofs K, Denk B, Stepan H (2014) New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension 63:346–352CrossRefPubMed Verlohren S, Herraiz I, Lapaire O, Schlembach D, Zeisler H, Calda P, Sabria J, Markfeld-Erol F, Galindo A, Schoofs K, Denk B, Stepan H (2014) New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension 63:346–352CrossRefPubMed
Metadata
Title
Using the angiogenic factors sFlt-1 and PlGF with Doppler ultrasound of the uterine artery for confirming preeclampsia
Authors
Franz Bahlmann
Ammar Al Naimi
Publication date
01-12-2016
Publisher
Springer Berlin Heidelberg
Published in
Archives of Gynecology and Obstetrics / Issue 6/2016
Print ISSN: 0932-0067
Electronic ISSN: 1432-0711
DOI
https://doi.org/10.1007/s00404-016-4128-4

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