title: Early Pregnancy Biomarkers in Pre-Eclampsia: A Systematic Review and Meta-Analysis.
abstract: Pre-eclampsia (PE) complicates 2%-8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39-0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE.
authors.affiliation: Institute for Science and Technology in Medicine-Keele University, Guy Hilton Research Centre, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB, UK. p.wu@keele.ac.uk.|Academic Unit of Obstetrics and Gynaecology, Royal Stoke University Hospital, Maternity Centre, Newcastle Road, Hartshill, Stoke-on-Trent ST4 6QG, UK. p.wu@keele.ac.uk.
authors.forename: Pensée
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Subdivision of Obstetrics and Prenatal Medicine, Erasmus MC-University Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands. c.vandenberg@erasmusmc.nl.
authors.forename: Caroline
authors.initials: C
authors.lastname: van den Berg
authors.affiliation: Department of Women's and Children's Health, The University of Liverpool, Liverpool L8 7SS, UK. zarko@liverpool.ac.uk.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Alfirevic
authors.affiliation: Institute for Science and Technology in Medicine-Keele University, Guy Hilton Research Centre, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB, UK. brien@uhns.nhs.uk.|Academic Unit of Obstetrics and Gynaecology, Royal Stoke University Hospital, Maternity Centre, Newcastle Road, Hartshill, Stoke-on-Trent ST4 6QG, UK. brien@uhns.nhs.uk.
authors.forename: Shaughn
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital of Cologne, 50931 Cologne, Germany. maria.roethlisberger@uk-koeln.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Röthlisberger
authors.affiliation: College of Medicine, Biological Sciences and Psychology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK. philip.baker@le.ac.uk.
authors.forename: Philip Newton
authors.initials: PN
authors.lastname: Baker
authors.affiliation: Department of Obstetrics and Gynaecology, Cork University Maternity Hospital (5th Floor), Cork University Hospital, Wilton, Cork T12 YE02, Ireland. l.kenny@ucc.ie.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Kenny
authors.affiliation: Karolinska Institutet, Centre for Gender Medicine, Institutions of Medicine and Clinical Science, Intervention and Technology, Department Ob/Gyn, Karolinska University Hospital, 14186 Stockholm, Sweden. karolina.kublickiene@ki.se.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kublickiene
authors.affiliation: Academic Unit of Obstetrics and Gynaecology, Royal Stoke University Hospital, Maternity Centre, Newcastle Road, Hartshill, Stoke-on-Trent ST4 6QG, UK. j.j.duvekot@erasmusmc.nl.
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: Duvekot
mesh_terms: D051722:ADAM Proteins / Q000032:analysis; D000072199:ADAM12 Protein; D015415:Biomarkers / Q000032:analysis; D005260:Female; D037161:Galectins / Q000032:analysis; D006801:Humans; D007265:Inhibins / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000175:diagnosis*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000032:analysis; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis
chemical_list: D015415:Biomarkers; D037161:Galectins; C038195:LGALS13 protein, human; D008565:Membrane Proteins; C000608036:PGF protein, human; D011257:Pregnancy Proteins; C422362:inhibin A; D000072483:Placenta Growth Factor; D007265:Inhibins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D011266:Pregnancy-Associated Plasma Protein-A
keywords: early pregnancy biomarkers; meta-analysis; pre-eclampsia