title: A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
abstract: BACKGROUND
  Accumulating evidence suggests that an imbalance between pro-angiogenic (i.e., vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) and anti-angiogenic factors (i.e., soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1)) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor beta, and its soluble form has recently been implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies and those destined to develop PE (preterm and term) or to deliver a small for gestational age (SGA) neonate.
  
  
  METHODS
  This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n = 46); (2) patients who delivered an SGA neonate but did not develop PE (n = 56); and (3) patients who developed PE (n = 42). Longitudinal samples were collected at each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1, and PlGF were determined by specific and sensitive ELISA.
  
  
  RESULTS
  (1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; (2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p < 0.036 and for term PE: p = 0.002); (3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with a normal pregnancy throughout gestation, and the maternal plasma concentration of this analyte became detectable later among patients with pregnancy complications, compared to normal pregnant women; (4) there were no significant differences in the plasma concentrations of sVEGFR-1 between patients destined to deliver an SGA neonate and those with normal pregnancies; (5) patients destined to develop preterm and term PE had a significantly higher plasma concentration of sVEGFR-1 at 26 and 29 weeks of gestation than controls (p = 0.009 and p = 0.0199, respectively); and (6) there was no significant difference in the increment of sVEGFR-1 between control patients and those who delivered an SGA neonate (p = 0.147 at 25 weeks and p = 0.8285 at 40 weeks).
  
  
  CONCLUSIONS
  (1) Changes in the maternal plasma concentration of s-Eng, sVEGFR-1, and PlGF precede the clinical presentation of PE, but only changes in s-Eng and PlGF precede the delivery of an SGA neonate; and (2) differences in the profile of angiogenic and anti-angiogenic response to intrauterine insults may determine whether a patient will deliver an SGA neonate, develop PE, or both.
authors.affiliation: Perinatology Research Branch, National Institute of Child Health and Human Development, NIH/DHHS, Bethesda, MD 20892, USA. prbchiefstaff@med.wayne.edu
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Jyh Kae
authors.initials: JK
authors.lastname: Nien
authors.forename: Jimmy
authors.initials: J
authors.lastname: Espinoza
authors.forename: David
authors.initials: D
authors.lastname: Todem
authors.forename: Wenjiang
authors.initials: W
authors.lastname: Fu
authors.forename: Hwan
authors.initials: H
authors.lastname: Chung
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Francesca
authors.initials: F
authors.lastname: Gotsch
authors.forename: Offer
authors.initials: O
authors.lastname: Erez
authors.forename: Shali
authors.initials: S
authors.lastname: Mazaki-Tovi
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gomez
authors.forename: Sam
authors.initials: S
authors.lastname: Edwin
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levine
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D015415:Biomarkers; D016022:Case-Control Studies; D000071063:Endoglin; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000502:physiology; D008137:Longitudinal Studies; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D047928:Premature Birth / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1