title: Placental growth factor (alone or in combination with soluble fms-like tyrosine kinase 1) as an aid to the assessment of women with suspected pre-eclampsia: systematic review and economic analysis.
abstract: Pre-eclampsia (PE) prediction based on blood pressure, presence of protein in the urine, symptoms and laboratory test abnormalities can result in false-positive diagnoses. This may lead to unnecessary antenatal admissions and preterm delivery. Blood tests that measure placental growth factor (PlGF) or the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to PlGF could aid prediction of PE if either were added to routine clinical assessment or used as a replacement for proteinuria testing.
  
  
  
  To evaluate the diagnostic accuracy and cost-effectiveness of PlGF-based tests for patients referred to secondary care with suspected PE in weeks 20-37 of pregnancy.
  
  
  
  Systematic reviews and an economic analysis.
  
  
  
  Bibliographic databases including MEDLINE, EMBASE, Web of Science and The Cochrane Library and Database of Abstracts of Reviews of Effects were searched up to July 2015 for English-language references. Conferences, websites, systematic reviews and confidential company submissions were also accessed.
  
  
  
  Systematic reviews of test accuracy and economic studies were conducted to inform an economic analysis. Test accuracy studies were required to include women with suspected PE and report quantitatively the accuracy of PlGF-based tests; their risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. The economic studies review had broad eligibility criteria to capture any types of economic analysis; critical appraisal employed standard checklists consistent with National Institute for Health and Care Excellence criteria. Study selection, critical appraisal and data extraction in both reviews were performed by two reviewers.
  
  
  
  An independent economic analysis was conducted based on a decision tree model, using the best evidence available. The model evaluates costs (2014, GBP) from a NHS and Personal Social Services perspective. Given the short analysis time horizon, no discounting was undertaken.
  
  
  
  Four studies were included in the systematic review of test accuracy: two on Alere's Triage®PlGF test (Alere, Inc., San Diego, CA, USA) for predicting PE requiring delivery within a specified time and two on Roche Diagnostics' Elecsys®sFlt-1 to PlGF ratio test (Roche Diagnostics GmbH, Mannheim, Germany) for predicting PE within a specified time. Three studies were included in the systematic review of economic studies, and two confidential company economic analyses were assessed separately. Study heterogeneity precluded meta-analyses of test accuracy or cost-analysis outcomes, so narrative syntheses were conducted to inform the independent economic model. The model predicts that, when supplementing routine clinical assessment for rule-out and rule-in of PE, the two tests would be cost-saving in weeks 20-35 of gestation, and marginally cost-saving in weeks 35-37, but with minuscule impact on quality of life. Length of neonatal intensive care unit stay was the most influential parameter in sensitivity analyses. All other sensitivity analyses had negligible effects on results.
  
  
  
  No head-to-head comparisons of the tests were identified. No studies investigated accuracy of PlGF-based tests when used as a replacement for proteinuria testing. Test accuracy studies were found to be at high risk of clinical review bias.
  
  
  
  The Triage and Elecsys tests would save money if added to routine clinical assessment for PE. The magnitude of savings is uncertain, but the tests remain cost-saving under worst-case assumptions. Further research is required to clarify how the test results would be interpreted and applied in clinical practice.
  
  
  
  This study is registered as PROSPERO CRD42015017670.
  
  
  
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Southampton Health Technology Assessments Centre, University of Southampton, Southampton, UK.
authors.forename: Geoff K
authors.initials: GK
authors.lastname: Frampton
authors.affiliation: Southampton Health Technology Assessments Centre, University of Southampton, Southampton, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jones
authors.affiliation: Southampton Health Technology Assessments Centre, University of Southampton, Southampton, UK.
authors.forename: Micah
authors.initials: M
authors.lastname: Rose
authors.affiliation: Southampton Health Technology Assessments Centre, University of Southampton, Southampton, UK.
authors.forename: Liz
authors.initials: L
authors.lastname: Payne
mesh_terms: D015415:Biomarkers; D003362:Cost-Benefit Analysis; D003663:Decision Trees; D005260:Female; D005865:Gestational Age; D006801:Humans; D007363:Intensive Care Units, Neonatal / Q000706:statistics & numerical data; D007902:Length of Stay / Q000706:statistics & numerical data; D008403:Mass Screening / Q000191:economics* / Q000379:methods*; D017059:Models, Econometric; D000072483:Placenta Growth Factor / Q000097:blood*; D011225:Pre-Eclampsia / Q000097:blood* / Q000175:diagnosis*; D011247:Pregnancy; D011788:Quality of Life; D012680:Sensitivity and Specificity; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
chemical_list: D015415:Biomarkers; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1