title: 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.
abstract: OBJECTIVE
  Changes in the maternal plasma concentrations of angiogenic (placental growth factor (PlGF) and vascular endothelial growth factor (VEGF)) and anti-angiogenic factors (sEng and vascular endothelial growth factor receptor-1 (sVEGFR-1)) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng, and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.
  
  
  METHODS
  This longitudinal cohort study included 1622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6-15 weeks) and midtrimester (20-25 weeks). Maternal plasma PlGF, sEng, and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm, and early-onset preeclampsia. Receiving operating characteristic curves, sensitivity, specificity, positive and negative likelihood ratios, and multivariable logistic regression were applied. A p-value of <0.05 was considered significant.
  
  
  RESULTS
  (1) The prevalence of preeclampsia, term, preterm, (<37 weeks) and early-onset preeclampsia (<34 weeks) was 3.8 (62/1622), 2.5 (40/1622), 1.4 (22/1622) and 0.6% (9/1622), respectively; (2) Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes; (3) Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole; in particular, they perform poorly in the prediction of term preeclampsia; (4) In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98-99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia.
  
  
  CONCLUSIONS
  (1) The PlGF/sEng ratio and its delta and slope had an excellent predictive performance for the prediction of early-onset preeclampsia, with very high likelihood ratios for a positive test result and very low likelihood ratios for a negative test result; and (2) Although the positive likelihood ratios are high and the positive predictive values low, the number of patients needed to be closely followed is 4:1 for the PlGF/sEng ratio and 3:1 for the slope of PlGF/sEng.
authors.affiliation: Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, USA. jkusanov@med.wayne.edu
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Offer
authors.initials: O
authors.lastname: Erez
authors.forename: Pooja
authors.initials: P
authors.lastname: Mittal
authors.forename: Edi
authors.initials: E
authors.lastname: Vaisbuch
authors.forename: Shali
authors.initials: S
authors.lastname: Mazaki-Tovi
authors.forename: Francesca
authors.initials: F
authors.lastname: Gotsch
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Edwin
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomez
authors.forename: Lami
authors.initials: L
authors.lastname: Yeo
authors.forename: Agustin
authors.initials: A
authors.lastname: Conde-Agudelo
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood*; D001783:Blood Flow Velocity; D000071063:Endoglin; D005260:Female; D006801:Humans; D016015:Logistic Models; D008137:Longitudinal Studies; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood* / Q000175:diagnosis; D011247:Pregnancy / Q000097:blood*; D011257:Pregnancy Proteins / Q000097:blood*; D011261:Pregnancy Trimester, First / Q000097:blood; D011262:Pregnancy Trimester, Second / Q000097:blood; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000097:blood*; D012680:Sensitivity and Specificity; D014463:Ultrasonography; D055988:Uterine Artery / Q000000981:diagnostic imaging; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1