OBSTETRICS An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia Stefan Verlohren, MD; Alberto Galindo, MD; Dietmar Schlembach, MD; Harald Zeisler, MD; Ignacio Herraiz, MD; Manfred G. Moertl, MD; Juliane Pape, MD; Joachim W. Dudenhausen, MD; Barbara Denk, PhD; Holger Stepan, MD OBJECTIVE: The angiogenic and antiangiogenic factors soluble fms- like tyrosine kinase (sFlt)-1 and placental growth factor (PIGF) have been implicated in the mechanisms of disease responsible for pre- eclampsia (PE). Moreover, it has been proposed that the concentrations of these markers in maternal serum/plasma may have predictive value. This study evaluates a newly developed Elecsys (Roche, Penzberg, Ger- many) assay for sFlt-1 and PIGF and tests the value of the sFlt-1/PIGF ratio in the assessment of PE. STUDY DESIGN: This multicenter case-control study included 351 pa- tients: 71 patients with PE and 280 gestational age-matched control subjects from 5 European study centers. A total of 595 serum samples were measured for sFlt-1 and PIGF using an automated platform. RESULTS: Maternal serum concentrations of sFlt-1 and PIGF significantly separated healthy women and women with PE. The sFlt-1/PIGF ratio had an area under the receiver operating characteristic curve of 0.95. The best per- formance was obtained in the identification of early-onset PE (area under the receiver operating characteristic curve of 0.97). CONCLUSION: Measurement of sFlt-1 and PIGF and calculation of sFlt- 1/PIGF ratio can be performed quickly and in a platform available in clin- ical laboratories. This is a substantial step forward in bringing the deter- mination of these analytes to clinical practice in obstetrics. We propose that sFlt-1, PIGF, and sFlt-1/PIGF ratio may be of value in the prediction of PE and in the differential diagnosis of patients with atypical presenta- tions of PE, and perhaps in the differential diagnosis of women with chronic hypertension suspected to develop superimposed PE. Key words: angiogenesis, antiangiogenic state, immunoassay and serum concentrations, placental growth factor, soluble vascular endothelial growth factor receptor-1, toxemia of pregnancy Cite this article as: Verlohren S, Galindo A, Schlembach D, 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.e1-11. P reeclampsia (PE) is still a leading cause of fetal and maternal morbid- ity and mortality 1 with an incidence of 3-5% worldwide. PE accounts for 42% of all maternal deaths per year and is asso- ciated with 15% of all preterm deliver- ies. 2,3 Despite intensive research efforts the pathogenesis of the disease is still un- known but it is likely to be multifactorial. The diagnosis of PE is based on the measurement of blood pressure and proteinuria. 3,4 However, sensitivity and specificity of these definitions are low regarding the prediction of adverse maternal and fetal outcomes. 5 The clinical presentation of the disease is variable, comprising severe and rap- idly progressing early-onset PE with the need to end pregnancy and deliver a preterm baby or mild forms of late- onset PE at term. 6 The reliable identification of high-risk PE patients is crucial as intensified mon- itoring and referral to specialized perina- tal care centers substantially reduces ma- ternal and fetal morbidity. Quick and reliable detection of the disease allows expeditious intervention with steroids for fetal lung maturity, 7 magnesium for seizure prophylaxis, 8 antihypertensive therapy, and bed rest. 9 Changes in the serum concentrations of angiogenic and antiangiogenic factors are implied in the pathogenesis of PE and have possible relevance in the diagnosis of the disease. Elevated serum concen- trations of the antiangiogenic soluble fms-like tyrosine kinase (sFlt)-1 recep- tors are involved in PE. 10-13 However, se- rum concentrations of the angiogenic placental growth factor (PIGF) are re- ported to be decreased in women with PE. 14-16 It was observed that sFlt-1 con- centrations increased beginning approx- imately 5 weeks before the onset of PE and PIGF expression declined already at 13-16 weeks of gestation suggesting pos- sible use as a screening parameter. 17-19 For this reason various investigators have examined the use of these factors as possible predictors for PE. 9,14,19-24 With accumulating evidence for sFlt-1 and PIGF as an aid in diagnosis as well as From the Department of Obstetrics (Drs Verlohren, Dudenhausen, and Pape), Campus Virchow-Clinic, Charité University Medicine, Berlin, Germany; the Department of Obstetrics and Gynecology (Drs Galindo and Herraiz), University Hospital “12 de Octubre,” Madrid, Spain; the Department of Obstetrics and Gynecology (Drs Schlembach and Moertl), Medical University of Graz, Austria; the Department of Obstetrics and Gynecology (Dr Zeisler), University of Vienna Medical School, Vienna, Austria; Roche Diagnostics, Clinical Trials Professional Diagnostics, Penzberg, Germany (Dr Denk); and the Department of Obstetrics (Dr Stepan), University Hospital Leipzig, Germany. Received March 17, 2009; revised Sept. 9, 2009; accepted Sept. 11, 2009. Reprints: Holger Stepan, MD, Department of Obstetrics, University Hospital Leipzig, Liebigstr. 20a, D-04103 Leipzig, Germany. holger.stepan@medizin.uni-leipzig.de. This study was sponsored by Roche, Penzberg, Germany. 0002-9378/$36.00 • © 2010 Published by Mosby, Inc. • doi: 10.1016/j.ajog.2009.09.016 Research www. AJOG.org FEBRUARY 2010 American Journal of Obstetrics & Gynecology 161.e1