Multicenter prospective clinical study to evaluate the prediction of short-term outcome in pregnant women with suspected preeclampsia (PROGNOSIS): study protocol

BMC Pregnancy and Childbirth

Holger Stepan²  Wilma Verhagen-Kamerbeek³  Peter Dilba¹  Maria Schoedl¹  Deirdre Allegranza³  Martin Hund³ 

[1] Roche Diagnostics GmbH, Penzberg, Germany;Department of Obstetrics, University of Leipzig, Leipzig, Germany;Roche Diagnostics International Ltd, Forrenstrasse 2, CH-6343 Rotkreuz, Switzerland

关键词: Neonatal outcome;    Maternal outcome;    PlGF;    sFlt-1;    Antiangiogenic factors;    Angiogenic factors;    Predictive markers;    Eclampsia;    HELLP syndrome;    Preeclampsia;   

Others  :  1125469
DOI  :  10.1186/1471-2393-14-324

 received in 2014-02-26, accepted in 2014-09-01,  发布年份 2014

【 摘 要 】

Background

Preeclampsia is defined as new onset of hypertension and proteinuria at gestational week 20 or after. However, use of these measures to predict preeclampsia before its clinical onset is unreliable, and evidence suggests that preeclampsia, eclampsia, or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome may develop without hypertension or proteinuria being evident. Because of its unpredictability, varying clinical presentation and potential adverse outcomes, pregnant women with suspected preeclampsia require intensive monitoring or hospitalization. Beyond preeclampsia diagnosis, there is a high unmet medical need for more reliable predictive markers for preeclampsia to improve maternal and fetal outcomes and reduce unnecessary hospital admissions. An imbalance of circulating angiogenic and antiangiogenic factors, including raised soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF), has been found in women diagnosed with preeclampsia and before clinical onset of the disease. The PRediction of short-term Outcome in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) was designed to investigate the use of the sFlt-1/PlGF ratio in the short-term prediction of preeclampsia.

Methods/Design

This global, multicenter, prospective, double-blind, non-interventional study aims to derive and validate cutoffs for the sFlt-1/PlGF ratio, to rule out (for 1 week) or rule in (within 4 weeks) the occurrence of preeclampsia/eclampsia/HELLP syndrome. Eligible participants are women presenting at 24 to <37 weeks’ gestation with clinical suspicion of, but not manifest preeclampsia/eclampsia/HELLP syndrome. Clinical assessments, maternal serum sFlt-1/PlGF sampling and documentation of maternal/neonatal outcomes are performed at regular intervals, using strict diagnostic criteria for preeclampsia-related conditions and outcomes. Serum sFlt-1 and PlGF analysis will be performed using fully automated Elecsys® immunoassays. Investigators and participants will remain blinded to the results. Target recruitment is 1000 participants. Health economic analysis is also planned.

Discussion

The results of PROGNOSIS will provide the most comprehensive evidence to date on the accuracy of the sFlt-1/PlGF ratio for short-term prediction of preeclampsia/eclampsia/HELLP syndrome. Adoption of the sFlt-1/PlGF test in clinical practice has the potential to reduce the frequency of adverse pregnancy outcomes for both mother and fetus, and decrease healthcare costs associated with unnecessary hospitalization of women with suspected preeclampsia.

【 授权许可】

   
2014 Hund et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM: 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:IX-XIV.
• [2]Milne F, Redman C, Walker J, Baker P, Bradley J, Cooper C, de Swiet M, Fletcher G, Jokinen M, Murphy D, Nelson-Piercy C, Osgood V, Robson S, Shennan A, Tuffnell A, Twaddle S, Waugh J: The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community. BMJ 2005, 330:576-580.
• [3]Lim K-H: Preeclampsia. [Medscape Reference Diseases and Conditions article] Updated 18 November 2013. [ http://emedicine.medscape.com/article/1476919-overview#aw2aab6b3 webcite] (Accessed 11 December 2013)
• [4]Polsani S, Phipps E, Jim B: Emerging new biomarkers of preeclampsia. Adv Chronic Kidney Dis 2013, 20:271-279.
• [5]NICE clinical guideline 107: Hypertension in Pregnancy. [Last modified: January 2011] [ http://www.nice.org.uk/nicemedia/live/13098/50418/50418.pdf webcite] (Accessed 25 November 2013).
• [6]Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R: Pre-eclampsia. Lancet 2010, 376:631-644.
• [7]Scazzocchio E, Figueras F: Contemporary prediction of preeclampsia. Curr Opin Obstet Gynecol 2011, 23:65-71.
• [8]Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, Roberts TE, Mol BW, van der Post JA, Leeflang MM, Barton PM, Hyde CJ, Gupta JK, Khan KS: Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess 2008., 12(6) [ http://www.journalslibrary.nihr.ac.uk/__data/assets/pdf_file/0019/64621/FullReport-hta12060.pdf webcite] (Accessed 6 December 2013)
• [9]Liu A, Wen SW, Bottomley J, Walker MC, Smith G: Utilization of health care services of pregnant women complicated by preeclampsia in Ontario. Hypertens Pregnancy 2009, 28:76-84.
• [10]Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF: WHO analysis of causes of maternal death: a systematic review. Lancet 2006, 367:1066-1074.
• [11]Wang A, Rana S, Karumanchi SA: Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology 2009, 24:147-158.
• [12]Soto E, Romero R, Kusanovic JP, Ogge G, Hussein Y, Yeo L, Hassan SS, Kim CJ, Chaiworapongsa T: Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion. J Matern Fetal Neonatal Med 2012, 25:498-507.
• [13]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: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004, 350:672-683.
• [14]Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG, Pape J, Dudenhausen JW, Denk B, Stepan H: 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.
• [15]Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H, Calda P, Holzgreve W, Galindo A, Engels T, Denk B, Stepan H: 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.
• [16]Villa PM, Hämäläinen E, Mäki A, Räikkönen K, Pesonen AK, Taipale P, Kajantie E, Laivuori H: Vasoactive agents for the prediction of early- and late-onset preeclampsia in a high-risk cohort. BMC Pregnancy Childbirth 2013, 13:110. BioMed Central Full Text
• [17]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: 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 2014, 63:346-352.
• [18]Schneider E, Gleixner A, Hänel R, Leyhe Y, Kleinschmidt C, Beck G, Steinberg M, Denk B, Gassner D: Technical performance of the first fully automated assays for human soluble fms-like tyrosine kinase 1 and human placental growth factor. Z Geburtshilfe Neonatol 2009, 213:A8. [ https://www.thieme-connect.com/ejournals/abstract/10.1055/s-0029-1216308 webcite]. (Accessed 25 November 2013).
• [19]Schiettecatte J, Russcher H, Anckaert E, Mees M, Leeser B, Tirelli AS, Fiedler GM, Luthe H, Denk B, Smitz J: Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia. Clin Biochem 2010, 43:768-770.
• [20]ACOG Committee on Practice Bulletins–Obstetrics: ACOG Practice Bulletin: diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 2002, 99:159-167.
• [21]Magann EF, Martin NJ: Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol 1999, 42:532-550.
• [22]Von Dadelszen P, Magee LA, Roberts JM: Subclassification of preeclampsia. Hypertens Pregnancy 2003, 22:143-148.
• [23]Simhan HN, Caritis SN: Prevention of preterm delivery. N Engl J Med 2007, 357:477-487.
• [24]Stepan H: Intrauterine Wachstumsretardierung. In Therapiehandbuch Gynäkologie und Geburtshilfe. Edited by Wacker J, Bastert G, Sillem M, Beckmann MW. Heidelberg: Springer Medizin; 2007:45-50.
• [25]Perinatal Institute for Maternal and Child Health Fetal Growth Customised Charts. [ http://www.perinatal.org.uk/FetalGrowth/fetalgrowth.aspx webcite] (Accessed 08 Aug 2013)
• [26]Roche Diagnostics GmbH: Elecsys/cobas PlGF immunoassay. [Package insert. 2013-08, V 5] [ http://www.rochecanada.com/fmfiles/re7234008/package_inserts/05144671190_PLGF_EN_PI_V5.pdf webcite] (Accessed 10 December 2013)
• [27]Roche Diagnostics GmbH: Elecsys/cobas sFlt-1 immunoassay. [Package insert. 2013-08, V 5] [ http://www.rochecanada.com/fmfiles/re7234008/package_inserts/sFlt-1-05109523190-English-CAN-V5.pdf webcite] (Accessed 10 December 2013)
• [28]Pepe MS: The Statistical Evaluation of Medical Tests for Classification and Prediction. Oxford, UK: Oxford University Press; 2003.
• [29]Hund M, Allegranza D, Schoedl M, Verhagen-Kamerbeek WDJ: PROGNOSIS Study: Prediction of Short-Term Outcome in Pregnant Women With Suspected Preeclampsia Study Using the Angiogenic Biomarkers sFlt-1/PlGF. Vienna, Austria: Presented at the 18th World Congress on Controversies in Obstetrics, Gynecology and Infertility (COGI); 2013.
• [30]Xu Q, Liang Y: Monte Carlo cross validation. Chemometr Intell Lab Syst 2001, 56:1-11.
• [31]Xu Q, Liang Y, Du Y: Monte Carlo cross validation for selecting a model and estimating the prediction error in multivariate calibration. J Chemom 2004, 18:112-120.
• [32]Rana S, Hacker MR, Modest AM, Salahuddin S, Lim KH, Verlohren S, Perschel FH, Karumanchi SA: Circulating angiogenic factors and risk of adverse maternal and perinatal outcomes in twin pregnancies with suspected preeclampsia. Hypertension 2012, 60:451-458.
• [33]Maynard SE, Crawford SL, Bathgate S, Yan J, Robidoux L, Moore M, Moore Simas TA: Gestational angiogenic biomarker patterns in high risk preeclampsia groups. Am J Obstet Gynecol 2013, 209:53.e1-53.e9.
• [34]World Health Organization: WHO Recommendations for Prevention and Treatment of Pre-eclampsia and Eclampsia. Geneva; 2011. [ http://whqlibdoc.who.int/publications/2011/9789241548335_eng.pdf webcite] (Accessed 13 December 2013)
• [35]Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, Lim KH, Wenger JB, Thadhani R, Karumanchi SA: Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125:911-919.
• [36]Myers JE, Kenny LC, McCowan LM, Chan EH, Dekker GA, Poston L, Simpson NA, North RA, SCOPE consortium: Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study. BJOG 2013, 120:1215-1223.
• [37]Chappell LC, Duckworth S, Seed PT, Griffin M, Myers J, Mackillop L, Simpson N, Waugh J, Anumba D, Kenny LC, Redman CW, Shennan AH: Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation 2013, 128:2121-2131.
• [38]Chaiworapongsa T, Romero R, Korzeniewski SJ, Cortez JM, Pappas A, Tarca AL, Chaemsaithong P, Dong Z, Yeo L, Hassan SS: Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study. J Matern Fetal Neonatal Med 2014, 27(2):132-144.
• [39]DGGG: Diagnostik und Therapie hypertensiver Schwangerschaftserkrankungen. [ http://www.awmf.org/leitlinien/detail/ll/015-018.html webcite] (Accessed 14 January 2013)
• [40]ACOG Task Force on Hypertension in Pregnancy: Hypertension in Pregnancy. 2013. [American College of Obstetricians and Gynecologists] [ http://www.acog.org/~/media/Task%20Force%20and%20Work%20Group%20Reports/HypertensioninPregnancy.pdf webcite] (Accessed 11 December 2013)