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

 

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Abstract

Background: Aim of the study was a critical assessment of the clinical validity of the prenatal determination of sFlt-1/PlGF for preeclampsia (PE), pregnancy-induced hypertension (PIH), and proteinuria. Our analysis was based on a specificity of 95 % and a sensitivity of 82 % for the prediction of preeclampsia, as described by Elecsys (Roche). Methods: In this retrospective study the ratio of the prenatal antiangiogenic factor sFlt-1 (soluble fms-like tyrosine kinase-1) to the proangiogenic factor PIGF (placental growth factor) was analyzed using the electrochemiluminescence immunoassay of Elecsys (Roche Diagnostics, Mannheim, Germany) in 173 pregnant women. Sixty-three women with PE, 34 women with PIH and 6 women with proteinuria were compared to 72 controls. On average, the sFlt-1/PlGF ratio was determined 8 (controls), 2.4 (PE), 3.2 (PIH) and 4.1 (proteinuria) weeks before delivery. The PE and PIH cases were further subdivided into early (< 34 weeks of gestation) and late (≥ 34 weeks of gestation) onset groups. Statistical data analysis was done using the usual descriptive statistics and logistic regression analysis. ROC curves were calculated, and the sensitivity, specificity, and negative and positive predictive value (NPV, PPV) were estimated for a threshold of 85. Results: Although the specificity of the sFlt-1/PlGF ratio was high for PE, the sensitivity was low (only 59.4 %), thus giving unsatisfying results for PE. The sensitivity only increased to 62.5 % for the early-onset PE group. Intriguingly, a high ratio was detected for the combination of IUGR (intrauterine growth restriction) and PE in the early-onset PE group (8 cases). In the control group, 4 cases exceeded the cut-off value of 85 but showed no clinical signs of PE and the birth was unremarkable. In summary, we found that the sFlt-1/PIGF ratio could not be used as a predictive test for preeclampsia but rather as an indicator for the development and estimation of the severity of PE. Thus, the test is less suitable for the reliable exclusion of PE in routine clinical practice. Recommendation: The determination of the sFlT-1/PlGF ratio is only one element for PE diagnosis in addition to the measurement of blood pressure, proteinuria, ultrasound and Doppler.

Zusammenfassung

Fragestellung: Kritische Begutachtung der klinischen Validität der vorgeburtlichen Bestimmung der sFlt-1/PlGF-Ratio bei Präeklampsie, schwangerschaftsinduzierter Hypertonie (SIH) und Proteinurie. Zugrunde gelegt wurde die von Elecsys (Roche) publizierte Spezifität von 95 % und Sensitivität von 82 % für die Vorhersage einer Präeklampsie. Material und Methodik: Durchgeführt wurde eine retrospektive Analyse der sFlt-1/PlGF-Ratio mittels Electrochemiluminescence Immunoassay von Elecsys (Roche Diagnostics, Mannheim, Deutschland) bei 173 Schwangeren. 63 Frauen mit Präeklampsie, 34 Frauen mit SIH und 6 Frauen mit Proteinurie wurden mit 72 Kontrollen verglichen. Im Mittel wurde die Ratio bei den Kontrollen 8, bei den Präeklampsien 2,4, bei SIH 3,2 und bei Proteinurien 4,1 Wochen vor Geburt bestimmt. Die Präeklampsien sowie die SIH-Fälle wurden nochmals in Early-Onset- (< 34 SSW) und Late-Onset-Gruppen (≥ 34 SSW) unterteilt. Zur statistischen Auswertung wurde der Fisher-Exact- und Wilcoxon-Rangsummen-Test durchgeführt, zudem erfolgte eine logistische Regressionsanalyse, die Kalkulation von ROC-Kurven und bei einem Cut-off-Wert von 85 eine Abschätzung von Sensitivität, Spezifität, PPV („positive predictive value“) und NPV („negative predictive value“). Ergebnisse: Wenngleich bei PE eine hohe Spezifität für sFlt-1/PlGF vorliegt, konnte eine Sensitivität von nur 59,4 % und somit nicht zufriedenstellende Ergebnisse für PE ermittelt werden. Lediglich beim „Early Onset“-PE-Kollektiv (< 34. SSW) steigt die Sensibilität auf 62,5 % an. Auffällig war die hohe Ratio bei der Kombination intrauterine Wachstumsretardierung und Präeklampsie im „Early Onset“-Kollektiv (8 Fälle). Im Kontrollkollektiv überschritten 4 Fälle den Cut-off-Wert von 85, die klinisch keine Präeklampsie bis zur Geburt entwickelten. Insgesamt konnte die sFlt-1/PlGF-Ratio nicht zur Prädiktion, sondern eher zur Entwicklung und Schweregradeinschätzung einer Präeklampsie verwendet werden, Der Test ist daher weniger zum sicheren Ausschluss einer Präeklampsie im klinischen Alltag geeignet. Empfehlung: Die Bestimmung der sFlT-1/PlGF-Ratio ist ein Mosaikbaustein bei der PE-Diagnostik neben Messung von Blutdruck und Eiweißausscheidung sowie Ultraschall und Doppler-Messung.

• References

• 1 Brown MA, Lindheimer MD, de Swiet M et al. 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 2001; 20: XI-XIV
  PubMedGoogle Scholar
• 2 American College of Obstetricians and Gynecologists, Committee on Obstetric Practice. Diagnosis and management of preeclampsia and eclampsia: ACOG practice bulletin, No. 33. Int J Gynecol Obstet 2002; 77: 67-75
  CrossrefPubMedGoogle Scholar
• 3 Koopmans CM, Bijlenga D, Groen H et al. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeksʼ gestation (HYPITAT): a multicenter, open-label randomized controlled trial. Lancet 2009; 374: 979-988
  CrossrefPubMedGoogle Scholar
• 4 Magee LA, Yong J, Espinosa V et al. Expectant management of severe preeclampsia remote from term: a structured systematic review. Hypertens Pregnancy 2009; 28: 312-347
  CrossrefPubMedGoogle Scholar
• 5 Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368-4380
  CrossrefPubMedGoogle Scholar
• 6 Karumanchi SA, Lim KH, August P. Pathogenesis of preeclampsia. Up to date, last literature review version 19.3 Sept 2011.
  PubMedGoogle Scholar
• 7 Levine RJ, Maynard SE, Qian C et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672-683
  CrossrefPubMedGoogle Scholar
• 8 Verlohren S, Galindo A, Schlembach D et al. An automated method for the determination of the sFlt-1/PlGF ratio in the assessment of preeclampsia. Am J Obstet Gynecol 2010; 202: 161.e1-161.e11
  CrossrefPubMedGoogle Scholar
• 9 Elecsys, Penzberg, Germany. http://www.roche.de/diagnostics/labor/serumarbeitsplatz/praeeklampsie.htm
  PubMedGoogle Scholar
• 10 Maynard SE, Min JY, Merchan J et al. Express placental soluble fms-like tyrosine kinase-1 (sFLT-1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111: 649-658
  CrossrefPubMedGoogle Scholar
• 11 Chaiworapongsa T, Romero R, Espinoza J et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Am J Obstet Gynecol 2004; 190: 1541-1547
  CrossrefPubMedGoogle Scholar
• 12 Mehendale R, Hibbard J, Fazleabas A et al. Placental angiogenesis markers sFlt-1 and PlGF: response to cigarette smoke. Am J Obstet Gynecol 2007; 197: 363.e1-363.e5
  CrossrefPubMedGoogle Scholar
• 13 Widmer M, Villar J, Benigni A et al. Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol 2007; 109: 168-180
  CrossrefPubMedGoogle Scholar
• 14 Tallarek A-C, Huppetz B, Stepan H. Preeclampsia – aetiology, current diagnostics and clinical management, new therapy options and future perspectives. Geburtsh Frauenheilk 2012; 72: 1099-1106
  Article in Thieme ConnectPubMedGoogle Scholar
• 15 Verlohren S, Herraiz I, Lapaire O et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 2012; 206: 58.e1-58.e8
  CrossrefPubMedGoogle Scholar
• 16 Rana S, Hacker MR, Modest AM et al. Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia. Hypertension 2012; 60: 451-458
  CrossrefPubMedGoogle Scholar
• 17 Rana S, Powe CE, Salahuddin S et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012; 125: 911-919
  CrossrefPubMedGoogle Scholar
• 18 Espinoza J, Romero R, Nien JK 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 Obstet Gynecol 2007; 196: 326.e1-326.e13
  PubMedGoogle Scholar
• 19 Benton SJ, Hu Y, Xie F et al. Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays. Am J Obstet Gynecol 2011; 205: 469-471
  PubMedGoogle Scholar
• 20 De Oliveira L, Camara NOS, Peracoli JC et al. SFlt-1 and IP-10 in women with early-onset preeclampsia. Pregnancy Hypertension 2011; 1: 129-131
  PubMedGoogle Scholar
• 21 Knudsen UB, Kronborg CS, von Dadelszen P et al. A single rapid point-of-care placental growth factor determination as an aid in the diagnosis of preeclampsia. Pregnancy Hypertension 2012; 2: 8-15
  PubMedGoogle Scholar
• 22 Ghosh SK, Raheja S, Tuli A et al. Can maternal serum placental growth factor estimation in early second trimester predict the occurrence of early onset preeclampsia and/or early onset intrauterine growth restriction? A prospective cohort study. J Obstet Gynaecol Res 2013; Mar 17 [Epub ahead of print]
  PubMedGoogle Scholar