title: A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d.
abstract: BACKGROUND
  Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth.
  
  
  RESULTS
  This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti-HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29-28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60-21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42-114.66) were associated with preterm labor and delivery.
  
  
  CONCLUSIONS
  A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions.
authors.affiliation: Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
authors.forename: JoonHo
authors.initials: J
authors.lastname: Lee
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Vanessa
authors.initials: V
authors.lastname: Topping
authors.forename: Wonsuk
authors.initials: W
authors.lastname: Yoo
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Yoon
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood; D002821:Chorioamnionitis / Q000097:blood / Q000209:etiology / Q000276:immunology*; D002908:Chronic Disease; D015935:Complement C4b / Q000032:analysis; D003430:Cross-Sectional Studies; D005260:Female; D005333:Fetus / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D054502:Histocompatibility, Maternal-Fetal / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange / Q000276:immunology; D010446:Peptide Fragments / Q000032:analysis / Q000097:blood*; D011247:Pregnancy; D047928:Premature Birth / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000276:immunology*
chemical_list: D000906:Antibodies; D006680:HLA Antigens; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d