title: Longitudinal reference ranges for maternal plasma laeverin, and its role as a potential biomarker of preeclampsia.
abstract: Laeverin is a placenta-specific membrane-bound aminopeptidase. In this study we wanted to: 1) serially measure plasma levels of laeverin in healthy women during the second half of pregnancy and postpartum, 2) determine whether laeverin is differently expressed at 22-24 weeks in women who later develop preeclampsia compared to controls, 3) compare laeverin protein expression in placenta and umbilical vein serum in healthy and preeclamptic pregnancies at birth.
  
  
  
  Plasma was obtained serially, approximately every 4-weeks, from 53 healthy women with uncomplicated pregnancies during 22+0to 39+6weeks of gestation, and at 22-24 weeks from 15 women who later developed preeclampsia. Enzyme-linked immunosorbent assay was used to measure laeverin protein concentration. Serum from healthy non-pregnant premenopausal women (n = 10), menopausal women (n = 10) and men (n = 11) were used as negative controls. Protein extracts from placental tissue were obtained after birth from healthy- (n = 11) and preeclamptic women (n = 13). Paired umbilical artery and vein serum samples from the neonates (n = 10) of healthy mothers were also analyzed. Multilevel modeling was used to determine the reference centiles. Differences between groups were analyzed using Student's t-test.
  
  
  
  Healthy pregnant women at term (37-40 weeks) had significantly higher plasma levels of laeverin (mean 4.95 ± 0.32 ng/mL; p < 0.0001) compared to men (mean 0.18 ± 0.31 ng/mL), non-pregnant premenopausal women (mean 0.77 ± 0.26 ng/mL) and postmenopausal women (mean 0.57 ± 0.40 ng/mL). Maternal plasma laeverin levels decreased with advancing gestation, from 6.96 ± 0.32 ng/mL at 22-24 weeks to 4.95 ± 0.32 ng/mL at term (p < 0.0001) in uncomplicated pregnancies. Half of the women who developed preeclampsia had plasma laeverin levels below the 5thpercentile at 22-24 weeks gestation. However, laeverin levels were 1.6 fold higher in preeclamptic compared to healthy placentas (p = 0.0071). Umbilical venous samples of healthy neonates (n = 38) had higher (p = 0.001) mean levels of laeverin (16.63 ± 0.73 ng/mL), compared to neonates of preeclamptic (n = 14) mothers (12.02 ± 1.00 ng/mL). Postpartum plasma levels of laeverin decreased in healthy and preeclamptic women with a half-life of 3 and 5 days, respectively.
  
  
  
  Maternal plasma levels of laeverin decrease with advancing gestation during the second half of normal pregnancy and lower levels measured at 22-24 weeks might be associated with the development of preeclampsia later in gestation.
authors.affiliation: Women's Health and Perinatology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway and Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway. mona.nystad@unn.no.
authors.forename: Mona
authors.initials: M
authors.lastname: Nystad
authors.affiliation: Institute of Clinical Medicine, University of Oslo, and Department of Obstetrics, Fetal Medicine Unit, Akershus and Oslo University Hospital, Oslo, Norway.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Sitras
authors.affiliation: Women's Health and Perinatology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway and Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Flo
authors.affiliation: Women's Health and Perinatology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway and Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Widnes
authors.affiliation: Women's Health and Perinatology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway and Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway.
authors.forename: Åse
authors.initials: Å
authors.lastname: Vårtun
authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway.
authors.forename: Tom
authors.initials: T
authors.lastname: Wilsgaard
authors.affiliation: Women's Health and Perinatology Research Group, Department of Clinical Medicine, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway and Department of Obstetrics and Gynecology, University Hospital of North Norway, Tromsø, Norway.|Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Acharya
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D062145:Maternal Serum Screening Tests / Q000379:methods / Q000706:statistics & numerical data*; D045726:Metalloproteases / Q000097:blood*; D011225:Pre-Eclampsia / Q000175:diagnosis*; D011247:Pregnancy; D011264:Pregnancy Trimesters / Q000097:blood*; D012016:Reference Values; D055815:Young Adult
chemical_list: D015415:Biomarkers; C482089:LVRN protein, human; D045726:Metalloproteases
keywords: Aminopeptidase-Q; ELISA; Laeverin; Plasma; Preeclampsia