title: A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study.
abstract: OBJECTIVE
  An imbalance between angiogenic and anti-angiogenic factors in maternal blood has been observed in several obstetrical syndromes including preeclampsia, pregnancies with fetal growth restriction and fetal death. Vascular lesions have been identified in a subset of patients with spontaneous preterm labor (PTL). It is possible that PTL may be one of the manifestations of an anti-angiogenic state. The aim of this study was to determine if patients prior to the clinical diagnosis of PTL leading to preterm delivery had plasma concentrations of angiogenic and anti-angiogenic factors different from normal pregnant women.
  
  
  METHODS
  This longitudinal nested case-control study included normal pregnant women (n = 208) and patients with PTL leading to preterm delivery (n = 52). Maternal blood samples were collected at 6 gestational age intervals from 6 to 36.9 weeks of gestation. The end point (time of diagnosis) of the study, 'True PTL', was defined as patients presenting with PTL and delivered within 1 day. Plasma concentrations of sVEGFR-1, sVEGFR-2, sEng and PlGF were determined by ELISA. Analysis was performed with both cross-sectional and longitudinal (mixed effects model) approaches.
  
  
  RESULTS
  (1) Plasma sEng concentration in patients destined to develop PTL was higher than that in normal pregnant women from 15-20 weeks of gestation. The difference became statistical significant at 28 weeks of gestation, or approximately 5-10 weeks prior to the diagnosis of 'true PTL'. (2) Backward analysis suggests that plasma concentrations of PlGF and sVEGFR-2 were lower, and those of sVEGFR-1 were higher in patients with PTL than in normal pregnant women less than 5 weeks prior to the diagnosis of 'true PTL'; and (3) Plasma concentrations of sEng and sVEGFR-1 were higher and those of PlGF and sVEGFR-2 were lower in patients diagnosed with PTL and delivery within 1 day than in normal pregnant women who delivered at term.
  
  
  CONCLUSIONS
  The changes in sEng are demonstrable several weeks prior to the onset of preterm parturition. In contrast, the changes in the other angiogenic proteins are present close to the onset of PTL and delivery. This observation supports the view that an imbalance of angiogenic factors participates in the pathophysiology of spontaneous preterm parturition.
authors.affiliation: Perinatology Research Branch, NICHD/NIH/DHHS, Detroit, Michigan, USA.
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Adi
authors.initials: A
authors.lastname: Tarca
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Pooja
authors.initials: P
authors.lastname: Mittal
authors.forename: Sun Kwon
authors.initials: SK
authors.lastname: Kim
authors.forename: Francesca
authors.initials: F
authors.lastname: Gotsch
authors.forename: Offer
authors.initials: O
authors.lastname: Erez
authors.forename: Edi
authors.initials: E
authors.lastname: Vaisbuch
authors.forename: Shali
authors.initials: S
authors.lastname: Mazaki-Tovi
authors.forename: Percy
authors.initials: P
authors.lastname: Pacora
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ogge
authors.forename: Zhong
authors.initials: Z
authors.lastname: Dong
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Lami
authors.initials: L
authors.lastname: Yeo
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood*; D042501:Angiogenic Proteins / Q000097:blood*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D055442:Metabolome / Q000502:physiology; D009035:Mothers; D007752:Obstetric Labor, Premature / Q000097:blood* / Q000145:classification / Q000209:etiology* / Q000503:physiopathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood; D011296:Prenatal Diagnosis / Q000379:methods; D012189:Retrospective Studies
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D011257:Pregnancy Proteins