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Statistically, patients with severe pregnancy complications are at risk of recurrent complications, but it is less understood if patients present with similar or different placental pathologies in subsequent pregnancies. In this case report, we describe 2 consecutive adverse pregnancies in the same woman 4 years apart. The first pregnancy was diagnosed as early-onset preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, with placental maternal vascular malperfusion features, such as syncytial knots and accelerated villous maturity. In contrast, the second pregnancy was associated with normotensive fetal growth restriction and placental "immunological" lesions, such as massive perivillous fibrin deposition and chronic intervillositis. However, based on the expression of FLT1, LIMCH1, and TAP1 by quantitative polymerase chain reaction, the placentas from both pregnancies were found to exhibit an "immunological" transcriptional signature. This suggests that this small panel of gene expression markers may be able to predict the future reoccurrence of an immunological placental pathology despite no histological evidence within the first pregnancy. These results call for more studies looking at paired pregnancies of individuals with recurrent obstetric complications and confirm the importance of assessing matched transcriptional and histopathological placental information.

Eosinophilic/T-cell chorionic vasculitis (ETCV) is an idiopathic placental lesion characterized by chorionic vasculitis composed predominantly of eosinophils and CD3+ T lymphocytes. It usually presents as a unifocal lesion, but a subset have multifocal involvement. We report 4 Di-Di and 2 Di-Mo twins sharing fused placental discs with discordant circulatory involvement by multifocal ETCV. The findings are difficult to explain by sampling alone. The limitation of ETCV to 1 fetus's vascular territory in monozygotic twin pregnancies is difficult to explain but could provide insights into the fetal immune system and the etiology of ETCV.

Numerous conditions, including placental vascular compromise, can lead to small-for-gestational-age (SGA) infants. As few studies have investigated primarily term placentas from SGA infants, we compared placentas from 67 SGA infants to placentas from 67 infants with appropriate weights for gestational age (AGA) in this population, matched for gestational age and gender. Placental histology was reviewed and electronic records were queried for maternal and fetal birth data, infant morbidities, and infant follow-up weights. Comparison of these 2 cohorts showed that placentas from SGA infants were more likely to have smaller weights and thinner umbilical cords than those from AGA infants. SGA placentas had a significant increase in another uteroplacental malperfusion feature: single and multiple infarctions. Rates of preeclampsia, infant cardiac anomalies, and infant genetic abnormalities were not statistically different between groups. Fetal and maternal inflammatory responses, nongestational diabetes, and gestational hypertension were more common in the controls, but these are common indications for placental examination. No statistical differences were present for decidual vasculopathy, chronic villitis, intervillous thrombi, or meconium. More SGA neonates had hypoglycemia compared to their AGA counterparts. SGA infants tended to have decreased weights up to 7 months of age; however, the low number of infants with follow-up limited the statistical significance. This study confirms that small placental size and select features of uteroplacental malperfusion are more common in SGA versus AGA term placentas. The lack of other significant differences may be due to the inclusion of only term infants, with more severe pathology leading to preterm delivery.

Eosinophilic/T-cell chorionic vasculitis (ETCV) is an inflammatory lesion of placental fetal vessels. In contrast to acute chorionic vasculitis, inflammation in ETCV is seen in chorionic vessel walls opposite the amnionic surface. It is not known whether inflammation in ETCV consists of maternal cells from the intervillous space or fetal cells migrating from the vessel. We used fluorescent in situ hybridization (FISH) to differentiate fetal versus maternal cells in ETCV. Placentas with ETCV, previously identified for a published study, were used. Infant sex in each case was identified using the electronic medical record. For male infants, 3-μm sections were cut from archived tissue blocks from placentas involving ETCV and stained with fluorescent X- and Y-chromosome centromeric probes. A consecutive hematoxylin/eosin-stained section was used for correlation. FISH analysis was performed on 400 interphase nuclei at the site of ETCV to determine the proportion of XX, XY, X, and Y cells. Of 31 ETCV cases, 20 were female and 10 were male (1 sex not recorded). Six of 10 cases with male infants had recuts with visible ETCV. In these 6 cases the average percentages (ranges) of XY cells, X-only cells, and Y-only cells in the region of inflammation were 81 (70-90), 11 (6-17), and 8 (2-14), respectively. There was a 2:1 female:male infant ratio in ETCV. Similar to acute chorionic vasculitis, the inflammation in ETCV is of fetal origin. It is still unknown, however, whether the stimulus for ETCV is of fetal or maternal origin.

Placentas are usually submitted for pathologic examination based on obstetrical indications. We hypothesized that the placenta may have diagnostic value to the infant independent of obstetrical events. We specifically tested whether lymphohistiocytic villitis (noninfectious) would predict autoimmune or alloimmune disease based on transfer of activated maternal T-cells to the fetus and whether clinically silent placental separations (retroplacental hematomas, RPH) would predict neurologic injury in the infant. All placentas from consecutive deliveries had a routine pathologic examination of the placenta. The infants with placentas demonstrating inflammation of >1% of villi or RPH >2 cm and matched controls had their hospital charts reviewed and parental interviews by telephone at 5 to 7 years of age. The children of consented patients were also searched for in the office visits of the University of Louisville Pediatric Neurology and Rheumatology divisions. One thousand six hundred eighty-four patients consented to the follow-up study. We found no cases of autoimmune disease among 17 children with villitis >1%. Of 16 infants with RPH, 1 had cerebral palsy but with other placental findings, 1 had lethal hydranenecephaly, and the remainder had no adverse outcome. Of 15 children seen by a pediatric neurologist, none had the same placental lesion. The specific lesions of lymphohistiocytic villitis or asymptomatic RPH do not predict significant pediatric disease by 7 years of age. At least for these 2 lesions, the placenta does not have diagnostic value to the infant.

Eosinophilic/T-cell chorionic vasculitis (ETCV) is characterized by mixed T-cell, eosinophilic, and histiocytic infiltrates within the chorionic vessel wall. We sought to better characterize this lesion with respect to other pathologic correlates and the T-cell populations involved. Epidemiologic data and other pathologic diagnoses, including concurrent chronic villitis (CV), were tabulated for each case of ETCV diagnosed at our institution over a 6-year period. CD3, CD25, FOXP3, and dual FOXP3-CD3 immunostains were used to identify regulatory T-cell populations in ETCV and CV. Cells positive for CD3, FOXP3, and CD25 were quantitated by manual counts of ×40 fields at the sites of ETCV and CV, and FOXP3∶CD3 and CD25∶CD3 ratios were calculated. Digital analysis of ETCV and CV using the dual FOXP3-CD3 immunostain was also performed on select cases. Of 31 ETCV cases, 10 (32%) were accompanied by CV and 13 (42%) by a thrombus in the vessel affected by ETCV. The mean Treg cell marker∶CD3 ratios in ETCV ranged from 0.18 to 0.26 by manual count and digital analysis, but the counts did not statistically differ by method. The mean Treg cell marker∶CD3 ratios in CV ranged from 0.37 to 0.39 by manual count and 0.19 by digital analysis, but these counts also did not statistically differ by method. Chronic villitis was seen in one-third of ETCV cases. FOXP3+ and CD25+ regulatory T cells represent a significant subpopulation of T cells in ETCV and CV, suggesting that they may play a role in these entities.

ABSTRACT Chronic villitis of unknown etiology (VUE) occurs in 5% of placentas submitted to pathology and is characterized by lymphohistiocytic infiltration of chorionic villi. VUE is associated with fetal growth restriction, preterm birth, and recurrent pregnancy loss. Accumulating evidence indicates that VUE may represent a host-versus-graft reaction analogous to transplant rejection. Pathologists routinely screen for antibody-mediated rejection in transplant biopsies by immunostaining for C4d, which highlights the recognition of donor cells by the host immune system. Since the hemochorial placenta is bathed in maternal blood, we hypothesized that cases of VUE may show C4d deposition onto villous syncytiotrophoblasts (STB). Chronic villitis was diagnosed in 82 of 1986 (4%) singleton placentas submitted to our department from 2007 through 2011. Forty randomly selected cases were gestational age-matched with 40 negative controls. Patient charts were reviewed and representative placental sections were immunostained for C4d. A positive C4d result was defined as circumferential immunostaining of the STB around at least one villous, or strong staining of fetal endothelial cells in the chorionic plate or stem villi. Our data indicate that VUE usually occurs in the 3rd trimester (37 ± 0.5 weeks) and is associated with significantly reduced placental weight (P  =  0.006). Positive C4d staining of STB was more common in VUE (35/40, 88%) compared with negative controls (2/40, 5%) (P < 0.0001). It was also more common in multiparous (35/66, 53%) than primiparous (2/14, 14%) women (P < 0.01). Although the precise mechanism remains to be determined, our data support the hypothesis that VUE may represent host-versus-graft rejection by the mother.

Maternal T cells and fetal macrophages constitute the primary infiltrate of chronic villitis of unknown etiology (CVUE), but the role of CD25(+)/FOXP3(+) regulatory T (Treg) cells in CVUE has not been examined. Moreover, little is known about the expression of immune markers, such as the major histocompatibility complex (MHC) class II antigen, human leukocyte antigen-DR (HLA-DR), in trophoblasts in this disease. We, therefore, examined CVUE placentas for the presence of Treg cells and aberrant activation of HLA-DR in trophoblasts. Sequential formalin-fixed, paraffin-embedded tissue sections from 8 CVUE placentas and 10 control placentas were stained by immunohistochemistry with antibodies for CD3, CD4, CD8, CD20, CD25, FOXP3, CD56, CD68, HLA-DR, STAT-1, and phosphorylated STAT-1 [P-(Y701)-STAT-1]. T cells and histiocytes were confirmed as the inflammatory infiltrate in CVUE. In areas of CVUE, histiocytes strongly expressed HLA-DR and nuclear P-(Y701)-STAT-1, and the relative numbers of CD25(+)/FOXP3(+) Treg cells were increased, compared with control placentas. In 5 of 8 CVUE cases, there was patchy nuclear expression of P-(Y701)-STAT-1 in syncytiotrophoblast most extensively involved by villitis, but no other marker examined was detected in the trophoblast cell layer. We confirmed the influx of T cells and histiocytes in CVUE. Our results are the 1st, to our knowledge, to identify increased numbers of Treg cells in CVUE vs noninflamed placentas. However, we were unable to verify HLA-DR expression in trophoblasts of placentas with CVUE, suggesting that this does not contribute to the influx of T cells. Our observation that P-(Y701)-STAT-1 expression in a syncytiotrophoblast is restricted to regions of inflammation suggests that the JAK-STAT-1 pathway is aberrantly activated in these cells.

Chronic villitis is a histologic diagnosis that may be either associated with infection, or termed villitis of undetermined etiology (VUE). The lymphocytic infiltrate in VUE has been reported to consist of maternal lymphocytes, but the origin of the lymphocytic infiltrate in infectious villitis has not been identified. The purpose of our study was to compare the maternal vs. fetal origin of the infiltrating lymphocytes in VUE and syphilitic villitis, and to expand the immunophenotypic data provided by previous studies. Paraffin-embedded placentas from four males with VUE and two males with syphilitic villitis were subjected to fluorescence in situ hybridization (FISH) for the X and Y chromosomes. Serial sections were stained with antibodies to CD3, CD4, CD8, CD68, HLA-DR, and CD20. Quantitation of the relative number of cells marking with each antibody was done for four villi in each slide. CD3 lymphocytes predominated in both VUE and syphilitic villitis, with slightly more CD8 cells compared to CD4 cells. CD68 and HLA-DR positive cells were as frequent as CD3 cells, and B-lymphocytes were rare. Maternal cells were the predominant intravillous population in both VUE and syphilitic villitis, and neutrophils in syphilitic villitis were also maternal. These data indicate that the immune response in both syphilitic villitis and VUE is similar, raising the possibility of a similar immunopathogenetic pathway.