title: Imbalance of Amniotic Fluid Activin-A and Follistatin in Intraamniotic Infection, Inflammation, and Preterm Birth.
abstract: Microbial invasion of the amniotic fluid (AF) cavity stimulates an inflammatory response that involves activin-A, a pleiotropic mediator member of the TGFβ superfamily involved in connective tissue remodeling. The role of AF follistatin, a natural inhibitor of activin-A, in inflammation-induced preterm birth (PTB), has yet to be determined.
  
  
  
  The objective of the study was to investigate the relationships between AF activin-A and follistatin in physiological gestation and in pregnancies complicated by PTB and to evaluate a possible role played by the activin-A-follistatin balance in processes leading to PTB and preterm premature rupture of membranes (PPROM).
  
  
  
  The AF levels of total activin-A and follistatin were immunoassayed in 168 women with a normal pregnancy outcome or PTB with and without intraamniotic inflammation or PPROM. The impact of the activin-A-follistatin imbalance on PTB terminal effector pathways (prostaglandins [prostaglandin E2, prostaglandin F2α] and matrix metalloproteinases [MMP-1, MMP-2, MMP-3, and MMP-9]) was investigated in an amniochorion explant system challenged with lipopolysaccharide (LPS) to mimic inflammation.
  
  
  
  AF follistatin and the activin-A to follistatin ratio varied with gestational age, both decreasing toward term (P < .001). Activin-A was up-regulated in AF infection (>2-fold elevation in activin-A to follistatin ratio) correlating directly with severity of inflammation (both P < .001). Activin-A increased prostaglandins, MMP-1, and MMP-9 released by amniochorion (P < .05) to LPS-equivalent levels. Follistatin effectively blunted the prostaglandin response to activin-A and LPS and that of MMPs after activin-A but not after LPS challenge.
  
  
  
  Activin-A and follistatin are part of the complex inflammatory response of the gestational sac to infection and modulate effector pathways leading to PTB. The activin-A to follistatin ratio may play a role in determining the clinical phenotype of PTB as preterm labor or PPROM.
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: John T
authors.initials: JT
authors.lastname: Hardy
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Buhimschi
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: Megan E
authors.initials: ME
authors.lastname: McCarthy
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: Guomao
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Laky
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: Lydia L
authors.initials: LL
authors.lastname: Shook
authors.affiliation: Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210.
authors.forename: Catalin S
authors.initials: CS
authors.lastname: Buhimschi
mesh_terms: D028341:Activins / Q000032:analysis / Q000378:metabolism*; D000328:Adult; D000653:Amniotic Fluid / Q000737:chemistry / Q000378:metabolism*; D002821:Chorioamnionitis / Q000378:metabolism*; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000378:metabolism; D038681:Follistatin / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000150:complications / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000378:metabolism; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000378:metabolism*; D011256:Pregnancy Outcome; D047928:Premature Birth / Q000209:etiology / Q000378:metabolism*
chemical_list: D038681:Follistatin; C422405:activin A; D028341:Activins