title: Maternal soluble fms-like tyrosine kinase-1, placental growth factor, plasminogen activator inhibitor-2, and folate concentrations and early fetal size: the Generation R study.
abstract: OBJECTIVE
  Fetal growth is dependent on adequate development of the placenta. Impaired angiogenesis and vasculogenesis in early pregnancy compromises placental and embryonic development. The proteins soluble fms-like tyrosine kinase (sFlt)-1, placental growth factor (PlGF), and plasminogen activator inhibitor (PAI)-2, and the B vitamin folate are determinants of placental development. This study aims to identify associations between these maternal biomarkers and early fetal size.
  
  
  METHODS
  From a prospective birth cohort study in The Netherlands, 1491 pregnant women were selected for this study. At a mean gestational age (GA) of 12.4 weeks (SD 0.8) maternal venous blood samples were obtained to determine the concentrations of sFlt-1, PlGF, PAI-2, and folate. Early fetal size was assessed with measurement of the crown-to-rump length (CRL) at a mean of 12.4 weeks' GA (SD 0.8). Analyses were performed using multivariable linear regression analyses with the biomarkers (continuous, quintiles) as regressors and CRL as main outcome measure.
  
  
  RESULTS
  Linear trend analysis showed positive associations between maternal sFlt-1 (P < .001), PlGF (P = .042), PAI-2 (P < .001), and folate (P = .039) and CRL. These associations were independent of GA, maternal age, height, body mass index, ethnicity, fetal sex, parity, educational level, smoking, and folic acid supplement use (folate not adjusted).
  
  
  CONCLUSIONS
  sFlt-1, PlGF, PAI-2, and folate are positively associated with first-trimester fetal size.
authors.affiliation: Generation R study, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marieke I
authors.initials: MI
authors.lastname: Bouwland-Both
authors.forename: Eric A P
authors.initials: EA
authors.lastname: Steegers
authors.forename: Jan
authors.initials: J
authors.lastname: Lindemans
authors.forename: Henk
authors.initials: H
authors.lastname: Russcher
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Anneke J
authors.initials: AJ
authors.lastname: Geurts-Moespot
authors.forename: Fred C G J
authors.initials: FC
authors.lastname: Sweep
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.forename: Régine P M
authors.initials: RP
authors.lastname: Steegers-Theunissen
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D047109:Fetal Development; D005492:Folic Acid / Q000097:blood*; D006801:Humans; D000072483:Placenta Growth Factor; D010929:Placentation; D017396:Plasminogen Activator Inhibitor 2 / Q000097:blood*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood*; D011261:Pregnancy Trimester, First; D011446:Prospective Studies; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
chemical_list: C000608036:PGF protein, human; D017396:Plasminogen Activator Inhibitor 2; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D005492:Folic Acid; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: cohort study; early fetal size; folate; placental development; placental growth factor; plasminogen activator inhibitor-2; soluble fms-like tyrosine kinase-1