title: Placental C4d deposition is a feature of defective placentation: observations in cases of preeclampsia and miscarriage.
abstract: Placental C4d deposition is frequent in preeclampsia, and shallow placentation is a characteristic of both preeclampsia and miscarriage. This study was conducted to determine the relationship among placental C4d, maternal human leukocyte antigen (HLA) antibodies, and placental pathology in preeclampsia and miscarriage cases. The patient population (N = 104) included those with (1) preterm preeclampsia with fetal growth restriction (PE-FGR; n = 21), (2) preterm preeclampsia (PE; n = 20), (3) spontaneous preterm delivery (sPTD; n = 39), and (4) miscarriage (n = 24). C4d immunohistochemistry was performed, and the presence of maternal plasma HLA antibodies was examined. C4d staining of the syncytiotrophoblast was more frequent in PE-FGR patients (76.2 %) than in PE (10.0 %; p < 0.001) and sPTD (2.6 %; p < 0.001) patients. Maternal HLA antibody-positive rate was not different among the study groups. There was a significant correlation between C4d immunoreactivity and placental pathology consistent with maternal vascular underperfusion (p < 0.001) but not with maternal HLA antibody status. In miscarriages, the positive rates of C4d, HLA class I, and HLA class II antibodies were 58.3, 25.0, and 12.5 %, respectively. There was no correlation between the presence of maternal HLA class I or II antibodies and placental C4d immunoreactivity. This study confirms frequent placental C4d deposition in preeclampsia with fetal growth restriction and miscarriage. The association between placental C4d deposition and pathological findings of maternal vascular underperfusion suggests that C4d staining of the syncytiotrophoblast is a consequence of defective placentation rather than of a specific maternal immune response against fetal HLA. The study also demonstrates the usefulness of C4d as a biomarker of placentas at risk.
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea.
authors.forename: Eun Na
authors.initials: EN
authors.lastname: Kim
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Yoon
authors.forename: Joong Yeup
authors.initials: JY
authors.lastname: Lee
authors.forename: Doyeong
authors.initials: D
authors.lastname: Hwang
authors.forename: Ki Chul
authors.initials: KC
authors.lastname: Kim
authors.forename: JoonHo
authors.initials: J
authors.lastname: Lee
authors.forename: Jae-Yoon
authors.initials: JY
authors.lastname: Shim
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
mesh_terms: D000022:Abortion, Spontaneous / Q000209:etiology / Q000473:pathology*; D000328:Adult; D003181:Complement C4; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000473:pathology; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D010920:Placenta / Q000473:pathology; D010922:Placenta Diseases / Q000473:pathology*; D010929:Placentation / Q000502:physiology*; D011225:Pre-Eclampsia / Q000209:etiology / Q000473:pathology*; D011247:Pregnancy; D046888:Tissue Array Analysis
chemical_list: D003181:Complement C4; D006680:HLA Antigens
references.citation: Transplantation. 2012 May 15;93(9):867-73
references.pmid: 22361472
references.citation: Placenta. 2008 Mar;29 Suppl A:S86-91
references.pmid: 17950457
references.citation: J Heart Lung Transplant. 2013 Apr;32(4):410-7
references.pmid: 23498162
references.citation: J Exp Med. 1996 May 1;183(5):2343-8
references.pmid: 8642343
references.citation: N Engl J Med. 2013 Sep 26;369(13):1215-26
references.pmid: 24066742
references.citation: Am J Reprod Immunol. 2010 Jun;63(6):534-43
references.pmid: 20331588
references.citation: Placenta. 2005 Feb-Mar;26(2-3):114-23
references.pmid: 15708112
references.citation: J Soc Gynecol Investig. 2004 Sep;11(6):342-52
references.pmid: 15350246
references.citation: Mol Immunol. 1999 Sep-Oct;36(13-14):957-63
references.pmid: 10698350
references.citation: J Matern Fetal Neonatal Med. 2014 Jan;27(2):132-44
references.pmid: 23687930
references.citation: Semin Neonatol. 2004 Aug;9(4):255-63
references.pmid: 15251142
references.citation: PLoS One. 2011 Feb 04;6(2):e16806
references.pmid: 21326865
references.citation: Am J Obstet Gynecol. 2002 Nov;187(5):1416-23
references.pmid: 12439541
references.citation: Am J Obstet Gynecol. 2013 Apr;208(4):287.e1-287.e15
references.pmid: 23333542
references.citation: Virchows Arch. 2014 May;464(5):613-20
references.pmid: 24671647
references.citation: BMC Pediatr. 2003 Dec 16;3:13
references.pmid: 14678563
references.citation: Hypertension. 2008 Apr;51(4):970-5
references.pmid: 18259009
references.citation: Am J Transplant. 2004 Oct;4(10):1562-6
references.pmid: 15367210
references.citation: Placenta. 2005 Apr;26 Suppl A:S114-7
references.pmid: 15837060
references.citation: Am J Obstet Gynecol. 2011 Mar;204(3):193-201
references.pmid: 21094932
references.citation: Semin Perinatol. 2012 Feb;36(1):56-9
references.pmid: 22280867
references.citation: Am J Obstet Gynecol. 2011 Feb;204(2):152.e1-9
references.pmid: 21062661
references.citation: Hypertension. 2012 Nov;60(5):1332-7
references.pmid: 23006730
references.citation: Pediatr Dev Pathol. 2013 Jan-Feb;16(1):7-13
references.pmid: 23137164
references.citation: Pregnancy Hypertens. 2011 Jan;1(1-2):72-8
references.pmid: 22242213
references.citation: Br J Obstet Gynaecol. 1986 Oct;93(10):1049-59
references.pmid: 3790464
references.citation: Mod Pathol. 2010 Jul;23(7):1000-11
references.pmid: 20348884
references.citation: J Reprod Immunol. 2009 Nov;82(2):119-25
references.pmid: 19665237
references.citation: BMJ. 2005 Mar 12;330(7491):576-80
references.pmid: 15760998
references.citation: Am J Obstet Gynecol. 2000 Jul;183(1):S1-S22
references.pmid: 10920346
references.citation: Am J Pathol. 2000 Dec;157(6):2111-22
references.pmid: 11106583
references.citation: J Am Soc Nephrol. 2002 Mar;13(3):779-87
references.pmid: 11856785
references.citation: Pathol Int. 2013 Mar;63(3):150-7
references.pmid: 23530559
references.citation: Am J Transplant. 2014 Feb;14(2):255-71
references.pmid: 24401076
references.citation: Am J Transplant. 2009 Apr;9(4):812-9
references.pmid: 19344468
references.citation: Placenta. 2013 May;34(5):432-5
references.pmid: 23481222
references.citation: Am J Obstet Gynecol. 2005 Jan;192(1):264-71
references.pmid: 15672035
references.citation: Lancet. 2010 Aug 21;376(9741):631-44
references.pmid: 20598363
references.citation: Am J Obstet Gynecol. 2007 Feb;196(2):167.e1-5
references.pmid: 17306667
references.citation: J Exp Med. 2006 Sep 4;203(9):2165-75
references.pmid: 16923853
references.citation: Lancet. 2001 Jan 6;357(9249):53-6
references.pmid: 11197372
references.citation: Placenta. 2009 Jun;30(6):473-82
references.pmid: 19375795