title: Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models.
abstract: Unexpected clinical deterioration before 34 weeks gestation is an undesired course in early-onset pre-eclampsia. To safely prolong preterm gestation, accurate and timely prediction of complications is required.
  
  
  
  Women with confirmed early onset pre-eclampsia were recruited from 53 maternity units in the UK to a large prospective cohort study (PREP-946) for development of prognostic models for the overall risk of experiencing a complication using logistic regression (PREP-L), and for predicting the time to adverse maternal outcome using a survival model (PREP-S). External validation of the models were carried out in a multinational cohort (PIERS-634) and another cohort from the Netherlands (PETRA-216). Main outcome measures were C-statistics to summarise discrimination of the models and calibration plots and calibration slopes.
  
  
  
  A total of 169 mothers (18%) in the PREP dataset had adverse outcomes by 48 hours, and 633 (67%) by discharge. The C-statistics of the models for predicting complications by 48 hours and by discharge were 0.84 (95% CI, 0.81-0.87; PREP-S) and 0.82 (0.80-0.84; PREP-L), respectively. The PREP-S model included maternal age, gestation, medical history, systolic blood pressure, deep tendon reflexes, urine protein creatinine ratio, platelets, serum alanine amino transaminase, urea, creatinine, oxygen saturation and treatment with antihypertensives or magnesium sulfate. The PREP-L model included the above except deep tendon reflexes, serum alanine amino transaminase and creatinine. On validation in the external PIERS dataset, the reduced PREP-S model showed reasonable calibration (slope 0.80) and discrimination (C-statistic 0.75) for predicting adverse outcome by 48 hours. Reduced PREP-L model showed excellent calibration (slope: 0.93 PIERS, 0.90 PETRA) and discrimination (0.81 PIERS, 0.75 PETRA) for predicting risk by discharge in the two external datasets.
  
  
  
  PREP models can be used to obtain predictions of adverse maternal outcome risk, including early preterm delivery, by 48 hours (PREP-S) and by discharge (PREP-L), in women with early onset pre-eclampsia in the context of current care. They have a potential role in triaging high-risk mothers who may need transfer to tertiary units for intensive maternal and neonatal care.
  
  
  
  ISRCTN40384046 , retrospectively registered.
authors.affiliation: Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK.
authors.forename: Shakila
authors.initials: S
authors.lastname: Thangaratinam
authors.affiliation: Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. j.allotey@qmul.ac.uk.|Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK. j.allotey@qmul.ac.uk.
authors.forename: John
authors.identifier: 0000-0003-4134-6246
authors.initials: J
authors.lastname: Allotey
authors.affiliation: Pragmatic Clinical Trials Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK.
authors.forename: Nadine
authors.initials: N
authors.lastname: Marlin
authors.affiliation: Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Dodds
authors.affiliation: Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Cheong-See
authors.affiliation: Institute of Cardiovascular and Cell Sciences, St George's, University of London, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: von Dadelszen
authors.affiliation: Departments of Obstetrics and Gynecology, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Wessel
authors.initials: W
authors.lastname: Ganzevoort
authors.affiliation: Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Akkermans
authors.affiliation: Pragmatic Clinical Trials Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Kerry
authors.affiliation: The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.|The South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Ben W
authors.initials: BW
authors.lastname: Mol
authors.affiliation: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Karl G M
authors.initials: KG
authors.lastname: Moons
authors.affiliation: Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Riley
authors.affiliation: Women's Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Multidisciplinary Evidence Synthesis Hub (mEsh), Queen Mary University of London, London, UK.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Khan
mesh_terms: D000328:Adult; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D016015:Logistic Models; D011225:Pre-Eclampsia / Q000503:physiopathology*; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000592:standards*; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D006113:United Kingdom
keywords: Complications; Early-onset; Maternal; Pre-eclampsia; Prognostic models