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. 2011 Nov;59(5):928-38.
doi: 10.1111/j.1365-2559.2011.04038.x.

Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies

JoonHo Lee  1 , Roberto Romero, Zhong Dong, Yi Xu, Faisal Qureshi, Suzanne Jacques, Wonsuk Yoo, Tinnakorn Chaiworapongsa, Pooja Mittal, Sonia S Hassan, Chong Jai Kim
Affiliations

Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies

JoonHo Lee et al. Histopathology. 2011 Nov.

Abstract

Aims: Chronic chorioamnionitis is a histological manifestation of maternal anti-fetal cellular rejection. As failure of graft survival is the most catastrophic event in organ transplantation, we hypothesized that fetal death could be a consequence of maternal rejection. The aim of this study was to assess whether there is evidence of cellular and antibody-mediated rejection in fetal death.

Methods and results: Placental histology was reviewed for the presence of chronic chorioamnionitis in unexplained preterm fetal death (n=30) and preterm live birth (n=103). Amniotic fluid CXCL10 concentrations were measured with a specific immunoassay. Chronic chorioamnionitis was more frequent in fetal death than in live birth (60.0% versus 37.9%; P<0.05) and fetal death had a higher median amniotic fluid CXCL10 concentration than live birth (2.0 versus 1.8 ng/ml, P<0.05), after adjusting for gestational age at amniocentesis. Maternal anti-human leucocyte antigen class II panel-reactive seropositivity determined by flow cytometry was higher in fetal death compared to live birth (35.7% versus 10.9%; P<0.05).

Conclusions: Chronic chorioamnionitis is a common pathologic feature in unexplained preterm fetal death. This novel finding suggests that cellular and antibody-mediated anti-fetal rejection of the mother is associated with fetal death (graft failure) in human pregnancy.

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Figures

Figure 1
Figure 1
Immunohistological features of chronic chorioamnionitis in preterm live birth and fetal death cases. T cell infiltrates are largely composed of CD8+ T cells. A, A preterm live birth case showing infiltration of CD8+ T cells into the chorionic trophoblast layer. B, A preterm live birth case with destruction and thinning of chorionic trophoblast layer by infiltrating CD8+ T cells. C, Infiltration of CD8+ T cells into the chorionic connective tissue layer in a case of fetal death. D, A fetal death case shows margination of CD8+ T cells at the choriodecidual interface with foci of scattered lymphocytic infiltration into the chorionic trophoblast layer.
Figure 2
Figure 2
Comparisons of frequencies of placental lesions between preterm live birth cases and preterm fetal death cases. Chronic chorioamnionitis is more frequent in fetal death cases (A, P<0.05), while acute chorioamnionitis is more frequent in live birth cases (B, P =0.001). Conversely, no difference was noted in the findings consistent with maternal vascular underperfusion (C) and fetal vascular thrombo-occlusive disease (D). CCA: chronic chorioamnionitis; ACA: acute chorioamnionitis; MVU: maternal vascular underperfusion; FVTOD: fetal vascular thrombo-occlusive disease; NS: not significant.
Figure 3
Figure 3
Amniotic fluid (AF) concentrations of interleukin (IL)-6 and CXCL10 in live birth and fetal death cases and in acute and chronic chorioamnionitis cases. A, AF IL-6 concentration is not different between cases with live birth and fetal death. B, The presence of acute chorioamnionitis, regardless of chronic chorioamnionitis, is associated with a robust increase in IL-6. C, Fetal death cases have a higher median AF CXCL10 concentration than live birth cases (P<0.05). D, Median AF CXCL10 concentrations are elevated in cases with isolated chronic chorioamnionitis and cases with concomitant acute and chronic chorioamnionitis, compared to cases without chorioamnionitis (P<0.05, for each). All comparisons of AF IL-6 and CXCL10 concentrations are performed after adjusting for gestational age at amniocentesis. *P<0.05; **P<0.01; ***P<0.001. AF: amniotic fluid; CCA: chronic chorioamnionitis; ACA: acute chorioamnionitis.
Figure 4
Figure 4
Panel-reactive anti-human leucocyte antigen (HLA) antibodies in maternal sera. A, Flow cytometric analysis clearly shows anti-HLA class I (left) and anti-HLA-class II (right) antibodies in maternal sera of a fetal death case. B, Seropositivity for anti-HLA class II but not anti-HLA class I antibodies is significantly higher in mothers with fetal death compared to those who gave preterm live births (P<0.05). NS: not significant.
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