Article

Chronic villitis of unknown etiology and massive chronic intervillositis have similar immune cell composition

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  • California Medical Innovations Institute, San Diego, California, United States
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... Seven groups (39%) stated that only patients with a massive, diffuse, or widespread infiltrate in the intervillous space should be included [1,3,8,18,30,33,34]. Four and three groups used the presence of fibrin deposits and trophoblastic necrosis, respectively, as an inclusion criterion [1,2,9,16,17]. ...
... Eleven groups (61%) specifically excluded patients with an infectious cause of CIUE [1,2,6,8,9,17,18,30,33,34]; four groups excluded patients with malaria or cytomegalovirus infection [2,18,30,35], three groups excluded patients with chorioamnionitis [8,17,33], and four groups excluded patients with other infectious diseases [1,6,9,34]. The largest discrepancy with respect to exclusion criteria was regarding the co-occurrence of chronic villitis with intervillositis; five groups excluded cases with chronic villitis [3,7,9,16,29], whereas one group explicitly stated that they included only cases with focal chronic villitis [2]. ...
... Eleven groups (61%) specifically excluded patients with an infectious cause of CIUE [1,2,6,8,9,17,18,30,33,34]; four groups excluded patients with malaria or cytomegalovirus infection [2,18,30,35], three groups excluded patients with chorioamnionitis [8,17,33], and four groups excluded patients with other infectious diseases [1,6,9,34]. The largest discrepancy with respect to exclusion criteria was regarding the co-occurrence of chronic villitis with intervillositis; five groups excluded cases with chronic villitis [3,7,9,16,29], whereas one group explicitly stated that they included only cases with focal chronic villitis [2]. ...
Article
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Chronic intervillositis of unknown etiology (CIUE) is a poorly understood, relatively rare condition characterized histologically by the intervillous infiltration of mononuclear cells in the placenta. Clinically, CIUE is associated with poor pregnancy outcome (e.g., impaired fetal growth, preterm birth, fetal death) and high risk of recurrence in subsequent pregnancies. Because CIUE is not defined consistently, it is essential to clearly define this condition. We therefore review the published definitions of CIUE. In addition, we provide an overview of the reviewed histopathological and maternal characteristics, obstetric features, and pregnancy outcomes. Medical publication databases were searched for articles published through February 2017. Eighteen studies were included in our systematic review. The sole inclusion criterion used in all studies was the presence of intervillous infiltrates. Overall, CIUE was characterized by adverse pregnancy outcome. Miscarriage occurred in 24% of cases, with approximately half of these miscarriages defined as late. Impaired growth was commonly observed, 32.4% of pregnancies reached term, and the live birth rate was 54.9%. The high recurrence rate (25.1%) of the intervillous infiltrates in subsequent pregnancies underscores the clinical relevance of CIUE, the need for increased awareness among pathologists and clinicians, and the need for further research. Criteria for the diagnosis of CIUE are proposed and a Delphi study could be used to resolve any controversy regarding these criteria. Future studies should be designed to characterize the full clinical spectrum of CIUE.
... Both lymphocytes and macrophages cells participate in VUE (42)(43)(44)(45), the former consisting of mostly maternal CD8+ > CD4+T cells (45,46) and the latter a mix of predominantly maternally derived macrophages in the intervillous space and fetal Hofbauer cells in the villous proper (45,47). Both Class I and Class II MHC antigens are absent from normal syncytiotrophoblast (40), but in VUE lesions, segments of syncytiotrophoblast membrane react to antibodies against Class II antigens (48,49), including HLA-DR, HLA-DP, and HLA-DQ (42), which may be the result of cytokine signaling by activated fetal macrophages (42,50). Abnormally increased intercellular adhesion molecule 1 (ICAM-1) expression has been described on syncytiotrophoblast (50,51), which would facilitate traffic of maternal immune cells into villi, but the reason for such upregulation is unclear. ...
... Both Class I and Class II MHC antigens are absent from normal syncytiotrophoblast (40), but in VUE lesions, segments of syncytiotrophoblast membrane react to antibodies against Class II antigens (48,49), including HLA-DR, HLA-DP, and HLA-DQ (42), which may be the result of cytokine signaling by activated fetal macrophages (42,50). Abnormally increased intercellular adhesion molecule 1 (ICAM-1) expression has been described on syncytiotrophoblast (50,51), which would facilitate traffic of maternal immune cells into villi, but the reason for such upregulation is unclear. Maternal rejection of the fetoplacental unit also is supported observations such as increased rates of VUE when in vitro fertilization pregnancies utilize donor rather than native oocytes (52,53). ...
... The prevalence of CHI is not precisely known, but reports have suggested it is quite rare ranging from approximately 1 to 10 per 1000 gestations depending on gestational age (58,59) or <1% of all pregnancies (50,60,61). It is a pathology that can present at any gestational age but appears to be more common in early gestations (58). ...
Article
Here, we review three important placental pathologies with significant clinical implications and recurrence risks. They are, in order of most to least frequently seen, villitis of unknown etiology, chronic histiocytic intervillositis, and massive perivillous fibrin deposition (also known as maternal floor infarction). These entities occur in both preterm and term gestations and are observed more frequently with maternal and obstetric disorders including prior pregnancy loss, hypertension/preeclampsia, and autoimmune disease. They are associated with, and probably the cause of, significant perinatal morbidity and mortality including intrauterine growth restriction, fetal and neonatal demise, and fetal/neonatal neurocompromise (seizures and cerebral palsy). All three entities have high recurrence risks, with recurrence rates ranging from 34 to 100%. The histologic features of villitis of unknown etiology, chronic histiocytic intervillositis, and massive perivillous fibrin deposition are described herein. We discuss the clinical associations and suggest the subsequent clinical and pathological evaluation. Hypotheses as to the biology of these lesions are reviewed.
... ICAM1 is expressed in the CTBs [95], STB [95,96], and in vascular endothelial cells throughout the decidua. It enhances the adhesion of leukocytes to the vascular endothelium. ...
... ICAM1 is upregulated in the placentae of preeclamptic women [46,86]. Also, it is upregulated in the STB during massive chronic intervillositis and chronic villitis of unknown etiology [96]. This increased expression may be an important pathological feature of the immuno-inflammatory disorders characterized by an excessive accumulation of leukocytes in the intervillous space. ...
Article
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Placentation is a major determinant of the success of pregnancy. It is regulated by several factors such as cell adhesion molecules, tight junctions, and gap junctions. The cell adhesion molecules are integrins, cadherins, immunoglobulins, nectins, and selectins. The tight junctions are composed of claudins, occludin, and junction adhesion molecule proteins while the gap junctions are composed of connexins of varying molecular weights. During placentation, some of these molecules regulate trophoblast proliferation, trophoblast fusion, trophoblast migration, trophoblast invasion, trophoblastendothelium adhesion, glandular remodeling, and spiral artery remodeling. There is a dysregulated placental expression of some of these molecules during obstetric complications. We have, hereby, indicated the expression patterns of the subunits of each of these molecules in the various trophoblast subtypes and in the decidua, and have highlighted their involvement in physiological and pathological placentation. The available evidence points to the relevance of these molecules as distinguishing markers of the various trophoblast lineages and as potential therapeutic targets in the management of malplacentation-mediated diseases.
... ICAM1 is expressed in the CTBs [95], STB [95,96], and in vascular endothelial cells throughout the decidua. It enhances the adhesion of leukocytes to the vascular endothelium. ...
... ICAM1 is upregulated in the placentae of preeclamptic women [46,86]. Also, it is upregulated in the STB during massive chronic intervillositis and chronic villitis of unknown etiology [96]. This increased expression may be an important pathological feature of the immuno-inflammatory disorders characterized by an excessive accumulation of leukocytes in the intervillous space. ...
Article
Full-text available
Placentation is a major determinant of the success of pregnancy. It is regulated by several factors such as cell adhesion molecules, tight junctions, and gap junctions. The cell adhesion molecules are integrins, cadherins, immunoglobulins, nectins, and selectins. The tight junctions are composed of claudins, occludin, and junction adhesion molecule proteins while the gap junctions are composed of connexins of varying molecular weights. During placentation, some of these molecules regulate trophoblast proliferation, trophoblast fusion, trophoblast migration, trophoblast invasion, trophoblast-endothelium adhesion, glandular remodeling, and spiral artery remodeling. There is a dysregulated placental expression of some of these molecules during obstetric complications. We have, hereby, indicated the expression patterns of the subunits of each of these molecules in the various trophoblast subtypes and in the decidua, and have highlighted their involvement in physiological and pathological placentation. The available evidence points to the relevance of these molecules as distinguishing markers of the various trophoblast lineages and as potential therapeutic targets in the management of malplacentation-mediated diseases.
... ICAM1 is expressed in the CTBs [95], STB [95,96], and in vascular endothelial cells throughout the decidua. It enhances the adhesion of leukocytes to the vascular endothelium. ...
... ICAM1 is upregulated in the placentae of preeclamptic women [46,86]. Also, it is upregulated in the STB during massive chronic intervillositis and chronic villitis of unknown etiology [96]. This increased expression may be an important pathological feature of the immuno-inflammatory disorders characterized by an excessive accumulation of leukocytes in the intervillous space. ...
Article
Placentation is a major determinant of the success of pregnancy. It is regulated by several factors such as cell adhesion molecules, tight junctions, and gap junctions. The cell adhesion molecules are integrins, cadherins, immunoglobulins, nectins, and selectins. The tight junctions are composed of claudins, occludin, and junction adhesion molecule proteins while the gap junctions are composed of connexins of varying molecular weights. During placentation, some of these molecules regulate trophoblast proliferation, trophoblast fusion, trophoblast migration, trophoblast invasion, trophoblast-endothelium adhesion, glandular remodeling, and spiral artery remodeling. There is a dysregulated placental expression of some of these molecules during obstetric complications. We have, hereby, indicated the expression patterns of the subunits of each of these molecules in the various trophoblast subtypes and in the decidua, and have highlighted their involvement in physiological and pathological placentation. The available evidence points to the relevance of these molecules as distinguishing markers of the various trophoblast lineages and as potential therapeutic targets in the management of malplacentation-mediated diseases. Keywords Trophoblast. Integrin. Cadherin. Immunoglobulin. Nectin. Selectin. Claudin. Occludin. Connexin. Preeclampsia Abbreviations PECAM1 platelet-endothelial cell adhesion molecule-1 VCAM1 vascular cell adhesion molecule-1 EMILIN1 elastin microfibril interface-located protein-1 ECM extracellular matrix Dsg2 desmoglein-2 Dsg3 desmoglein-3 PECAM1 platelet-endothelial cell adhesion molecule-1 NCAM neural cell adhesion molecule Mel-CAM melanoma cell adhesion molecule ICAM1 intercellular adhesion molecule-1 VCAM1 vascular cell adhesion molecule-1 ZO zonnula occludens CTB cytotrophoblast STB syncytiotrophoblast EVTs extravillous trophoblasts PCT proximal column trophoblast DCT distal column trophoblast iEVT intestitial extravillous trophoblast egEVT endoglandular extravillous trophoblast evEVT endovascular extravillous trophoblast GC giant cell dSC decidual stromal cell dNK decidual natural killer cell
... The mechanism by which T-cells pass the maternal-fetal barrier is unknown. Lymphocytes and histiocytes in VUE express inflammatory cell adhesion molecule ICAM1, supporting a model similar to typical leukocyte extravasation (108). Alternatively, maternal inflammatory cells may pass through disruption of the trophoblastic barrier. ...
... Alternatively, maternal inflammatory cells may pass through disruption of the trophoblastic barrier. Lymphocytes and histiocytes also show expression of nuclear factor kappa B (NFkB) (108). Histiocytes express HLA-DR and histiocytes and syncytiotrophoblast show phosphorylated Signal Transducer and Activator of Transcription 1 (STAT1), indicating activation of the JAK-STAT pathway. ...
Article
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Events in fetal life impact long-term health outcomes. The placenta is the first organ to form and is the site of juxtaposition between the maternal and fetal circulations. Most diseases of pregnancy are caused by, impact, or are reflected in the placenta. The purpose of this review is to describe the main inflammatory processes in the placenta, discuss their immunology, and relate their short- and long-term disease associations. Acute placental inflammation (API), including maternal and fetal inflammatory responses corresponds to the clinical diagnosis of chorioamnionitis and is associated with respiratory and neurodevelopmental diseases. The chronic placental inflammatory pathologies (CPI), include chronic villitis of unknown etiology, chronic deciduitis, chronic chorionitis, eosinophilic T-cell vasculitis, and chronic histiocytic intervillositis. These diseases are less-well studied, but have complex immunology and show mechanistic impacts on the fetal immune system. Overall, much work remains to be done in describing the long-term impacts of placental inflammation on offspring health.
... Furthermore, the analysis of the four cases with recurrent lesions of villitis in the form of intervillositis or combined lesions suggests, contrary to the current data, two different stages of the same disease, even if it is not possible to draw a conclusion for this point. The recent works of Labarrere and al [23] which conclude that immune cells of the two infiltrates have very similar phenotypic characteristics, also suggest the same conclusion. In view of the results presented, we think that combined lesions without major histologic predominance could be considered like CVUE. ...
Article
Introduction: The objective of this work was to evaluate and compare perinatal outcomes of pregnancies complicated by placental chronic intervillositis (CIUE) or villitis (CVUE) of unknown etiology and combined lesions. Methods: Retrospective study of all cases of significant CVUE and CIUE occurring during a 12-year period in a university tertiary hospital center. Multiple pregnancies, infectious and medical termination of pregnancies (TOP) without intra-uterine growth restriction (IUGR) were excluded. Results: 178 placentas were affected (78 cases of CVUE, 24 cases of CIUE and 76 cases of combined lesions involving both villitis and intervillositis) including 12 cases of recurrence. A disorder of fetal growth was found in 73% of cases and we noted 9.5% of cases of abortion. The rate of IUGR appeared to be significantly higher in case of CIUE with a fetal death risk five times higher. These complications seems to be related to more diffuse inflammatory infiltrates (p < 0.05). CVUE was associated with a significant morbidity with 42% of severe IUGR and severe alterations of umbilical artery Doppler in nearly one third of cases. Caesarean section was important (54.8%). Sixty-one percent of newborns were hospitalized and 11.4% in neonatal reanimation. In case of combined lesions, fetal outcomes appeared relatively close to those of CVUE. CVUE could recur in more severe forms or as CIUE with an increased risk for the fetus. Clinicoanatomic correlations were noted. Discussion: Observation of recurrence of CVUE on CIUE or combined lesions and similar phenotypic characteristics of the infiltrates suggest that they could be two different stages of a same disease. CVUE remains a disease to be considered as serious. Association of small lesions of intervillositis does not change the prognosis. The severity of histological lesions and the initial obstetrical accident could be discriminatory to identify patients at risk of serious recurrence. Harmonized classification will be required. Conclusions: This study confirms the higher morbidity of CIUE compared to CVUE but shows the necessity of monitoring pregnancies following an episode of CVUE, which are still at risk of serious and recurrent complications.
... This distinction is important to make because acute and chronic chorioamnionitis represent different pathological entities with acute chorioamnionitis manifested by neutrophilic inflammation and typically associated with acute infection [24,25]. Chronic chorioamnionitis is a lymphocytic infiltrate which includes villitis of unknown etiology and may have some associated inflammatory or alloimmune factors [26]. Animal models to date have been carried out with LPS injection resulting in massive and acute increases in IL-1b and IL-6 [17,18]. ...
Article
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Background Chorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known. Methods We enrolled two cohorts to evaluate TH17 and regulatory T cell (Treg) phenotypic markers in chorioamnionitis. From a cohort of 19 live birth infants, we collected cord blood and placenta samples to evaluate for signs of acute and chronic histologic inflammation and cell phenotype characterization. We analyzed a second cohort of stillborn infants with and without chorioamnionitis to classify and enumerate cell infiltrate phenotypes in the spleen, thymus, and lung. We used linear regression analysis determine the association of retinoic acid-related orphan receptor gamma t positive (RORγt⁺) and Treg cell frequency with different types of inflammation seen in the live cohort subjects. Using linear mixed models, we evaluated for any associations between chorioamnionitis and T- and B-cell with a logarithmic scale for level of expression of cellular markers. We then performed Wilcoxon rank sum tests to assess the associations between cell count and chorioamnionitis. Results In the live birth subjects with chronic placental inflammation we observed an increased proportion of RORγt⁺ cells in Foxp3⁺ cells, regardless of the presence of acute inflammation, compared to subjects with neither acute nor chronic inflammation. We also found an increased proportion of RORγt⁺ cells within Foxp3⁺ cells in subjects with acute high stage fetal and maternal inflammation compared to those without acute or chronic inflammation. In the stillborn subjects with chorioamnionitis, we observed a decrease in splenic Foxp3⁺ cells and an increase in lung CD3⁺ cells compared with subjects that did not have chorioamnionitis. Conclusion Exposure to chorioamnionitis in utero may affect immune activation in neonates with an increased frequency of RORγt⁺ cells systemically as well as lymphocytic infiltrate in the lung. Our findings suggest an increase in RORγt⁺ cells during chorioamnionitis and thus may support the known associations between chorioamnionitis with asthma. Electronic supplementary material The online version of this article (10.1186/s13223-018-0297-y) contains supplementary material, which is available to authorized users.
... In our study, villitis of unknown etiology (VUE) occurred in approximately 30% of all cases, distributed equally between both randomized groups. In existing literature, a broad range of incidences of VUE is described, partly because the definition has not been uniform and also due to differences in sampling of placental parenchyma (40)(41)(42)(43). With an equal distribution between our groups, we conclude that prolonged pregnancy in the expectant monitoring group is not associated with an increased prevalence of VUE. ...
Article
Full-text available
Objective: Management of late fetal growth restriction (FGR) is limited to adequate fetal monitoring and optimal timing of delivery. The Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT) trial compared induction of labor with expectant management in pregnancies at (near) term complicated by suspected FGR. Findings of the DIGITAT trial were that expectant monitoring prolonged pregnancy for 10 days and increased birth weight with only 130 grams. This resulted in more infants born below the 2.3rd percentile compared to induction of labor, respectively, 12.5% in induction of labor and 30.6% in expectant monitoring group. The main placental lesions associated with FGR are maternal vascular malperfusion, fetal vascular malperfusion, and villitis of unknown etiology. We investigated whether placentas of pregnancies complicated with FGR in the expectant monitoring group reveal more and more severe pathology due to pregnancy prolongation. Material and methods: The DIGITAT trial was a multicenter, randomized controlled trial with suspected FGR beyond 36 + 0 weeks. We now analyzed all available cases (n = 191) for placental pathology. The macroscopic details were collected and histological slides were recorded and classified by a single perinatal pathologist, blinded for pregnancy details and outcome. The different placental lesions were scored based on the latest international criteria for placental lesions as defined in the Amsterdam Placental Workshop Group Consensus Statement. Results: The presence of maternal vascular malperfusion and chorioamnionitis were higher in the expectant management group (p < 0.05 and p < 0.01, respectively). No differences in placental weight and maturation of the placenta between the induction of labor and the expectant management group were seen. Fetal vascular malperfusion, villitis of unknown etiology and nucleated red blood cell count did not differ between the groups. Conclusion: Expectant management of late FGR is associated with increased maternal vascular malperfusion and chorioamnionitis. This may have implications for fetal and neonatal outcome, such as programming in the developing child influencing health outcomes later in life.
... Although not significant, villitis of unknown etiology was found twice as often in cases of maternal HPA-1a alloimmunization as compared to non-immunized mothers. This supports the hypothesis that an alloimmune response may play a role in the pathophysiology of unexplained chronic villous/intervillous inflammatory lesions [40,41]. ...
... Nowak et al., who reported outcomes from 76 cases of combined CHI-VUE, suggested that CHI might represent either a precursor lesion or a more aggressive variant of VUE (25). Although Labarrere later described phenotypic similarities in the cellular infiltrates (180), current consensus is that they represent two distinct syndromes, with the chronic inflammation of CHI confined to the intervillous space rather than infiltrating into the villi (13). ...
Article
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Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal Frontiers in Immunology | www.frontiersin.org growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes.
... However, Marchaudon et al 8 found that CHI-affected pregnancies, complicated by spontaneous early miscarriage and FGR, were associated with more intense fibrin deposition within the placenta. In another comparison to healthy pregnancies, pregnancies with CHI demonstrated failure in physiological transformation of spiral arteries and a significantly higher presence of atherosclerotic-like lesions, 18 suggesting that nutrient and gas exchange across the placenta may be affected. Another study speculated that accumulation of cells within the intervillous space increases the oxygen diffusion distance between maternal erythrocytes and foetal villi, 19 a source of reduced placental efficiency and dysfunction. ...
Article
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Chronic histiocytic intervillositis (CHI) is a pregnancy disorder characterized by infiltration of maternal macrophages into the intervillous space of the human placenta, often with accompanying perivillous fibrin deposition. CHI is associated strongly with foetal growth restriction and increased risk of miscarriage and stillbirth. Although rare, affecting 6 in every 10 000 pregnancies beyond 12 weeks’ gestation, the rate of recurrence is high at 25%–100%. To date, diagnosis of CHI can only be made post‐delivery upon examination of the placenta due to a lack of diagnostic biomarkers, and criteria vary across publications. No treatment options have shown proven efficacy, and CHI remains a serious obstetric conundrum. Although its underlying aetiology is unclear, due to the presence of maternal macrophages and the reported increased incidence in women with autoimmune disease, CHI is hypothesized to be an inappropriate immune response to the semi‐allogeneic foetus. Given this lack of understanding, treatment approaches remain experimental with limited rationale. However, there is recent evidence that immunosuppression and antithrombotic therapies may be effective in preventing recurrence of associated adverse pregnancy outcomes. With similarities noted between the pathological features of CHI and acute rejection of solid organ transplants, further investigation of this hypothesis may provide a basis for tackling CHI and other immune‐related placental conditions. This review will explore parallels between CHI and allograft rejection and identify areas requiring further confirmation and exploitation of this comparison.
... 2 Since the pathogenesis of CVUE also demonstrates an immune origin, both entities can co-exist. 9 CHI are not usually associated with discernable infection, hence cases with clinical or histopathological features of infection should be excluded. Nonetheless, another possible differential diagnosis of chronic intervillositis is malarial infection. ...
Article
Introduction: Chronic histiocytic intervillositis (CHI) is a rare placental lesion strongly associated with recurrent miscarriages and fetal losses. It requires histopathological diagnosis and can only be made after delivery of the products of conception (POC). We describe a case of CHI in a 41-yearold lady with a 16-year history of thirteen recurrent consecutive first trimester miscarriages. Case report: The patient is a 41-year-old lady who suffered first trimester miscarriages in all her thirteen pregnancies. The relevant clinical investigations revealed neither significant nor helpful findings in determining the cause of recurrent miscarriages. Histological findings in each except one of the submitted conceptual tissue showed similar features of histiocytic aggregates primarily within the intervillous spaces, a characteristic description of CHI. One of the samples showed degenerative changes. Discussion: Practicing pathologists are not familiar with the histological features of CHI and this may be a potential pitfall in routine examination of POCs. Recognising this entity allows for accurate diagnosis and hence better management. The aetiology remains unclear, although an immunopathological basis are being explored.
... This rare entity is usually associated with maternal immunologic conditions like systemic lupus erythematosus, lupus anticoagulant and antiphospholipid syndrome [44,46], while this patient's significant comorbidities (chronic hypertension, severe obesity, and gestational diabetes) are not. Despite the different types of inflammatory infiltrate (histiocytic versus lymphocytic) and of etiologies (chronic histiocytic intervillositis is usually not related to viral infections); this pathological entity is frequently associated with chronic villitis (30 to 50% of cases), supporting a potential overlap in terms of involved immunologic pathways [41,50]. Moreover, alveolar histiocytic infiltration is a frequent autoptic hallmark of SARS-CoV-2 infection [15]. ...
Article
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Infection by SARS-CoV-2 has been shown to involve a wide range of organs and tissues, leading to a kaleidoscope of clinical conditions. Within this spectrum, an involvement of the fetal-maternal unit could be expected, but, so far, the histopathological evaluation of placentas delivered by women with SARS-CoV-2 infection did not show distinct hallmarks. A consecutive series of 11 placentas, delivered by 10 women with COVID-19 admitted to our Obstetrics and Gynecology clinic have been investigated and compared to a control cohort of 58 pre-COVID-19 placentas and 28 placentas delivered by women who had a previous cesarean section. Four out of eleven placentas showed changes consistent with chronic villitis/villitis of unknown etiology (VUE), while in one case, chronic histiocytic intervillositis was diagnosed. Thrombo-hemorrhagic alterations were observed in a subset of cases. Compared to the control cohort, chronic villitis/VUE ( p < 0.001), chronic deciduitis ( p = 0.023), microvascular thrombosis ( p = 0.003), presence of infarction areas ( p = 0.047) and of accelerated villous maturation ( p = 0.005) showed higher frequencies in placentas delivered by women with COVID-19. Chronic villitis/VUE ( p = 0.003) and accelerated villous maturation ( p = 0.019) remained statistically significant by restricting the analysis to placentas delivered after a previous cesarean section. The observed differences in terms of pathological findings could be consistent with SARS-CoV-2 pathogenesis, but just a subset of alterations remained statistically significant after adjusting for a previous cesarean section. A careful consideration of potential confounders is warranted in future studies exploring the relationship between COVID-19 and pregnancy.
... Forces of labor themselves [11] and maternal comorbidities (obesity) [12] induce inflammation that may be reflected in the placenta. Chronic placental inflammation (CPI) lesions involve specific cells, such as lymphocytes and histiocytes and have a particular location in the placenta [13]. They may be associated with autoimmune disorders or persistent infection, or may be of unknown etiology. ...
Article
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The placenta is the site of connection between maternal and fetal circulation, and the liaison is established early in pregnancy. A large variety of pregnancy complications such as preterm birth, fetal growth restriction, or pregnancy loss have placental expression and can be accompanied in some cases of acute or chronic identifiable placental inflamatory lesions. Chronic placental inflammatory (CPI) lesions include chronic villitis of unknow etiology (CVUE), chronic intervillositis of unknown etiology, CIUE (also described as chronic histiocytic intervillositis, CHI), and chronic deciduits. Hydroxychloroquine (HCQ) has been prescribed with good results during pregnancy to prevent adverse perinatal outcomes in maternal autoimmune conditions. Its success has paved the way to its use in CPI as CIUE/CHI; however, to date, there are no prospective, informatively designed, controlled studies on its value in these setting. This review aims to explore the potential role of HCQ in CPI of unknown etiology. Ideally, properly designed, probably multicentric studies should be undertaken to fully understand HCQ’s role for prevention of adverse pregnancy outcomes after a chronic placental inflammation.
... In the majority of cases of VUE and CIUE, an underlying clinical infection cannot be detected [7,8]. VUE is characterized by migration of CD4 and CD8 T cells from maternal blood into the stroma of the villi, the functional units of the human placenta and has been well characterized in morphological studies [9][10][11][12][13]. In CIUE maternal macrophages, CD4 and CD8 T cells accumulate in the intervillous space [14]. ...
Article
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Appropriate placental function is essential for successful pregnancy and placental dysfunction is associated with fetal growth restriction (FGR) and stillbirth. Villitis of unknown etiology (VUE) and chronic intervillositis of unknown etiology (CIUE) are immune-mediated conditions characterised by placental infiltrates of macrophages, CD4 and CD8 T cells. VUE and CIUE occur more frequently in the placentas of pregnancies complicated by FGR. The mechanisms by which this inflammation induces placental dysfunction are yet to be defined. We aimed to develop an in vitro model of placental inflammation to investigate functional consequences of immune cells in the placental environment. Fragments of placental tissue were co-cultured with CD4 and CD8 T cells isolated from whole blood. CellTrackerTM fluorescence was used to identify T cells in cultured explants. Tissue histology, endocrine and nutrient transport function was assessed using established methods. This novel preparation will enable future investigations into immune cell interactions with placenta.
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Functional gastrointestinal disorders (FGIDs) in children and adolescents are one of the most common pathologies of the digestive tract. The aim of the study was to study the structure of the colon microbiota in obese adolescents and to establish its relationship with the clinical manifestations of the disease FGIDs. The study included 20 adolescents aged 11-17 years. The main group included 13 adolescents with a clinically confirmed diagnosis of obesity (the standard deviation of the body mass index (SDS BMI) is more than 2,0) in combination with FGIDs. The control group consisted of 7 adolescents with normal body weight and no abdominal complaints (SDS BMI=0,66). Clinical symptoms from the bowel re diagnosed on the basis of the Rome IV. The consistency of feces was evaluated using the Bristol Stool Form Scale. The study of biological material was carried out by standard bacteriological methods. It is shown that in adolescents with obesity and FGIDs, there is a decrease in the concentration of representatives of bifidoflora, an increase in the microbial density of Escherichia coli with altered properties and an excessive growth of potentially pathogenic enterobacteria. It is established that the presence of conditionally pathogenic bacteria is sem. Enterobacteriaceae is associated with abdominal pain during defecation. In obese adolescents in the group with unformed stools, Clostridium spp was recorded as part of the intestinal microbiota.
Preprint
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Infection by SARS-CoV-2 has been shown to involve a wide range of organs and tissues, leading to a kaleidoscope of clinical conditions. Within this spectrum, an increased rate of preterm deliveries has been reported in women with COVID-19. High expression of proteins (ACE2/TMPRSS2) required for SARS- CoV-2 cell entry has been observed in the maternal-fetal tissues, supporting the possibility of placental viral involvement. A consecutive series of 6 placentas, delivered by 5 women with COVID-19 have been investigated. Three out of six placentas showed changes consistent with chronic villitis, while in one case chronic histiocytic intervillositis was diagnosed. Vascular abnormalities consisting of thrombo- hemorrhagic alterations were identified in the three cases with chronic villitis. These pathological findings: i) provide a basis to explain the higher rate of obstetric complications in these patients; 2) suggest the need to investigate heparin use in COVID-19 affected pregnant patients to prevent adverse outcomes.
Article
Objective: This study aimed at determining if first trimester serum biomarkers could predict adverse pregnancy outcomes associated with villitis (VUE) and chronic intervillositis of unknown etiology (CIUE). Study design: Between January 2013 and June 2018, we selected from pathology department files placentas with VUE or CIUE associated with VUE and control placentas with available first trimester Down syndrome screening results. First trimester PAPP-A and βhCG levels were recorded. Placental growth factor (PlGF) levels were measured in patients with an available first trimester serum sample. Histological findings in placentas, course of pregnancies and newborns' characteristics were compared between cases and controls. Results: 78 cases and 75 controls were included. In cases, there were 21,8% intrauterine growth restriction (IUGR), 30,8% small for gestational age (SGA). Compared to controls, placentas from cases were smaller (425 g [IQR 370-480] vs 460 g [IQR 390-523], p = 0,03), showed more maternal vascular malperfusion features (79,5% vs 22,7%, p < 0,0001) and more fetal vascular malperfusion features (33,3% vs 12%, p = 0,002). Cases had lower PlGF (29,74 pg/ml [IQR 19,74-36,17] vs 36,37 pg/ml [IQR 27,36-49,13], p = 0,007) and βhCG levels (0,74 MoM [IQR 0,53-1,12] vs 1,00 MoM [IQR 0,72-1,53], p = 0,002) than controls. These differences resulted from lower PlGF levels in VUE patients compared to CIUE associated with VUE patients and controls (28,35 vs 34,05 and 36,37 pg/ml, p = 0,01) and from lower βhCG levels in CIUE associated with VUE patients compared to VUE patients and controls (0,65 vs 0,86 and 1, p = 0,005). Conclusion: Low first trimester PlGF levels in cases, especially in VUE patients, suggest that reduced angiogenesis is involved in adverse pregnancy outcomes related to VUE.
Chapter
Chronic histiocytic intervillositis (CHIV) is a rare inflammatory condition that is associated with a poor perinatal outcome, including fetal growth restriction and perinatal loss. It may recur in subsequent pregnancies. Recognition of CHIV by pathologists, and explanation of the significance of this finding to clinicians, is important in patient care.
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Introduction Maternal alloimmunization against human platelet antigen (HPA)-1a has been implied to mediate both reduced birth weight and chronic placental inflammation. Fetal growth restriction is associated with different types of chronic inflammation in the placenta, mainly chronic histiocytic intervillositis and chronic villitis. The aim of this prospective study was to do a systematic examination of placentas from HPA-1a alloimmunized pregnancies, with focus on the histopathological and immunohistochemical diagnosis of variants of chronic inflammation. Material and methods In a Polish-Norwegian study, 48 placentas were examined. The histopathology of placentas from 27 HPA-1a immunized women was compared with 21 placentas from non-immunized HPA-1a negative women (controls). In the group of alloimmunized women, ten received antenatal intravenous immunoglobulin G (IVIg). Tissue sections from formalin fixed paraffin embedded placental tissue were stained with hematoxylin and eosin and microscopically examined with focus on various types of chronic placental inflammations. Results Chronic histiocytic intervillositis was observed in 40.7 % of placentas from HPA-1a alloimmunized pregnancies, compared to none in the control group (p=0.001). Chronic villitis of unknown etiology was more frequently found in the alloimmunized group, however this difference was not statistically significant. Maternal administration of IVIg did not seem to protect against chronic inflammatory lesions. Discussion Placentas with detectable maternal anti-HPA-1a antibodies are associated with highly increased risk of low-grade chronic histiocytic intervillositis.
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To identify new criteria for predicting the outcome of pregnancy in women with threatened preterm labor based on the establishment of the characteristics of differentiation and functional activity of memory T-cells in the population of CD8 + T-lymphocytes. The study involved 56 women with threatened preterm labor at 22-34 weeks of pregnancy. Depending on the outcome of pregnancy, patients were divided into 3 groups: Group I included 22 women by premature labor; group II - 34 women whose pregnancy ended by deliver at term. By tricolor flow cytofluorometry method the content of peripheral Tn, Tcm, Tem and Temra cells in CD8+ population was studied. Statistical analysis was carried out using programs «Statistica for Windows 13.0», «Microsoft Excel 2019» and «MedCalc 19.3». Patients with the threat of preterm birth were characterized by a significant increase in the relative content of CD8+ T-lymphocytes in the peripheral blood compared to the control group (p=0.001). When comparing this indicator in the subgroups of women with the threat of preterm birth, it was found that preterm birth was associated with significantly higher relative CD8 + lymphocyte counts (p=0.03) compared to the indicators of the subgroup of women who gave birth on time. When evaluating the results obtained, it was found that the percentage of CD8+Temra GranzymeB-producing cells in the group of patients with threatened preterm birth, whose pregnancy ended in preterm birth, was significantly lower than in the group of women who gave birth on time (p=0.003). The content of Tcm, Tem memory cells producing GranzymeB in the subgroups of women with pregnancy outcomes of timely and preterm birth did not have significant differences compared to the control group. Thus, the prediction of preterm birth is possible with a value of GranzymeB-producing CD8 + Tem equal to 8.2% or less (sensitivity-87.9%, specificity-85%, accuracy-87.9%). Thus, the identification of a new criterion will make it possible to predict preterm birth in a timely manner and promote the choice of optimal pregnancy management tactics, reasonable prevention of fetal respiratory distress syndrome and transfer of a woman to an obstetric hospital designed to provide high-tech care to premature newborns.
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A successful pregnancy largely relies on proper immune regulation in the gravid uterus. This review describes immune mechanisms that permit the fetal allograft to continue to grow to term. Chronic inflammatory lesions may be manifestations of altered immune status in the placenta and are often present in preterm placentas. These lesions are compared with the more common acute inflammatory lesions of pregnancy, and described with respect to their pathology and clinical significance. © 2016 by the American Academy of Pediatrics. All rights reserved.
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Identification of risk is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure due to CAV (GFDCAV) in heart transplant patients, which account for 30% of all deaths. Early CAV detection involves invasive, risky, and expensive monitoring approaches. We determined whether prediction of CAV and GFDCAV improves by adding inflammatory markers to a previously validated atherothrombotic (AT) model. AT and inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) were measured in heart biopsies and sera of 172 patients followed prospectively for 8.9±5.0 years. Models were estimated for 5- and 10-year risk using (1) the first post-transplant biopsy only, or (2) all biopsies obtained within 3 months. Multivariate models were adjusted for other covariates and cross-validated by bootstrapping. After adding IL-6 and CRP to the AT models, we evaluated the significance of odds ratios (ORs) associated with the additional inflammatory variables and the degree of improvement in the area under the receiver operating characteristic curve (AUROC). When inflammatory markers were tested alone in prediction models, CRP (not IL-6) was a significant predictor of CAV and GFDCAV at 5 (CAV: p<0.0001; GFDCAV: p = 0.005) and 10 years (CAV: p<0.0001; GFDCAV: p = 0.003). Adding CRP (not IL-6) to the best AT models improved discriminatory power to identify patients destined to develop CAV (using 1st biopsy: p<0.001 and p = 0.001; using all 3-month biopsies: p<0.04 and p = 0.008 at 5- and 10-years, respectively) and GFDCAV (using 1st biopsy: 0.92 vs. 0.95 and 0.86 vs. 0.89; using all 3-month biopsies: 0.94 vs. 0.96 and 0.88 vs. 0.89 at 5- and 10-years, respectively), as indicated by an increase in AUROC. Early inflammatory status, measured by a patient's CRP level (a non-invasive, safe and inexpensive test), independently predicts CAV and GFDCAV. Adding CRP to a previously established AT model improves its predictive power.
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Introduction: Pandemic influenza A/H1N1 infection during pregnancy has a negative impact on several aspects of pregnancy outcome. As yet, no elucidating mechanism has been revealed for these effects. We investigated whether placentas of pregnancies complicated by 2009 influenza A/H1N1 infection demonstrated an increased rate of chronic villitis and whether this villitis was caused by influenza virus. Methods: We performed a cohort study on 145 pregnant outpatients during the 2009-2010 influenza A H1N1 pandemic. The placentas of patients with influenza infection were examined for histologic signs of chronic villitis. In case of villitis, polymerase chain reaction (PCR) on influenza virus was performed on placental tissue. Results: 29 patients had influenza infection. Placentas of 15 of these patients were collected and examined. In 7 cases (47%) chronic villitis was detected. Placental weight and birth weight of the neonates did not differ between cases with and without chronic villitis. In all cases PCR was negative for influenza. Conclusion: In our series, chronic villitis was present in a high proportion of placentas of pregnancies complicated by 2009 influenza A/H1N1 infection. We could not demonstrate the presence of influenza virus in placental tissue.
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Studies on gestational malaria and placental malaria have been scarce in malaria-endemic areas of the Western Hemisphere. To describe the histopathology of placental malaria in Colombia, a longitudinal descriptive study was conducted. In this study, 179 placentas were studied by histologic analysis (112 with gestational malaria and 67 negative for malaria). Placental malaria was confirmed in 22.35%, 50.0% had previous infections, and 47.5% had acute infections. Typical malaria-associated changes were observed in 37%. The most common changes were villitis, intervillitis, deciduitis, increased fibrin deposition, increased syncytial knots, mononuclear (monocytes/macrophages and lymphocytes), polymorphonuclear cell infiltration, and trophozoites in fetal erythrocytes. No association was found between type of placental changes observed and histopathologic classification of placental malaria. The findings are consistent with those reported for placental malaria in other regions. Plasmodium vivax was the main parasite responsible for placental and gestational malaria, but its role in the pathogenesis of placental malaria was not conclusive.
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Cardiac allograft vasculopathy (CAV) is the principal cause of long-term graft failure following heart transplantation. Early identification of patients at risk of CAV is essential to target invasive follow-up procedures more effectively and to establish appropriate therapies. We evaluated the prognostic value of the first heart biopsy (median: 9 days post-transplant) versus all biopsies obtained within the first three months for the prediction of CAV and graft failure due to CAV. In a prospective cohort study, we developed multivariate regression models evaluating markers of atherothrombosis (fibrin, antithrombin and tissue plasminogen activator [tPA]) and endothelial activation (intercellular adhesion molecule-1) in serial biopsies obtained during the first three months post-transplantation from 172 patients (median follow-up = 6.3 years; min = 0.37 years, max = 16.3 years). Presence of fibrin was the dominant predictor in first-biopsy models (Odds Ratio [OR] for one- and 10-year graft failure due to CAV = 38.70, p = 0.002, 95% CI = 4.00-374.77; and 3.99, p = 0.005, 95% CI = 1.53-10.40) and loss of tPA was predominant in three-month models (OR for one- and 10-year graft failure due to CAV = 1.81, p = 0.025, 95% CI = 1.08-3.03; and 1.31, p = 0.001, 95% CI = 1.12-1.55). First-biopsy and three-month models had similar predictive and discriminative accuracy and were comparable in their capacities to correctly classify patient outcomes, with the exception of 10-year graft failure due to CAV in which the three-month model was more predictive. Both models had particularly high negative predictive values (e.g., First-biopsy vs. three-month models: 99% vs. 100% at 1-year and 96% vs. 95% at 10-years). Patients with absence of fibrin in the first biopsy and persistence of normal tPA in subsequent biopsies rarely develop CAV or graft failure during the next 10 years and potentially could be monitored less invasively. Presence of early risk markers in the transplanted heart may be secondary to ischemia/reperfusion injury, a potentially modifiable factor.
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Infections with Mycobacterium tuberculosis (MTb) are globally prevalent in many countries, yet descriptions of placental pathology in tuberculous patients are scanty. The usual necrotizing granulomatous response associated with tuberculous infections requires an activation of the adaptive immune system. However, before this system is turned on, the 1st encounter with the tubercle bacillus is mediated by the innate immune system. This pathway utilizes innate surface receptors in neutrophils and histiocytes predominantly and does not produce a granulomatous pattern of inflammation. In this report we describe 2 cases of placental involvement with MTb in which an acute abscess-like inflammatory response with Myeloperoxidase and CD68-positive neutrophils and histiocytes causing acute villitis and intervillitis, with abundant acid-fast mycobacteria, were identified. Other cellular markers consistent with adaptive immunity were negative. These nongranulomatous lesions are seen in primary tuberculous infections occurring in a naïve woman and, obviously, a naïve fetus. These cases with early response inflammation in the placenta are frequently missed precisely because the mother is not known to be infected or has been recently diagnosed and because the symptoms in the newborn may not develop for several weeks, by which time the placenta may have been discarded. This report also shows that the differential diagnosis of acute villitis and intervillitis in the placenta should include tuberculosis aside from the more common bacterial infections such as listeriosis.
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Late stages of Plasmodium falciparum-infected erythrocytes (IRBCs) frequently sequester in the placentas of pregnant women, a phenomenon associated with low birth weight of the offspring. To investigate the physiological mechanism of this sequestration, we developed an in vitro assay for studying the cytoadherence of IRBCs to cultured term human trophoblasts. The capacity for binding to the syncytiotrophoblast varied greatly among P. falciparum isolates and was mediated by intercellular adhesion molecule 1 (ICAM-1), as binding was totally inhibited by 84H10, a monoclonal antibody specific for ICAM-1. Binding of the P. falciparum line RP5 to the syncytiotrophoblast involves chondroitin-4-sulfate (CSA), as this binding was dramatically impaired by addition of free CSA to the binding medium or by preincubation of the syncytiotrophoblast with chondroitinase ABC. ICAM-1 and CSA were visualized on the syncytiotrophoblast by immunofluorescence, while CD36, E-selectin, and vascular cell adhesion molecule 1 were not expressed even on tumor necrosis factor alpha (TNF-alpha)-stimulated syncytiotrophoblast tissue, and monoclonal antibodies against these cell adhesion molecules did not inhibit cytoadherence. ICAM-1 expression and cytoadherence of wild isolates was upregulated by TNF-alpha, a cytokine that can be secreted by the numerous mononuclear phagocytes present in malaria-infected placentas. These results suggest that cytoadherence may be involved in the placental sequestration and broaden the understanding of the physiopathology of the malaria-infected placenta.
Chapter
Prenatal infections are important aspects of placental pathology. They are common and varied. Their pathogenesis and related circumstances must be understood if the pathological lesions are to be interpreted correctly. Many types of infection cause placental changes, but in some types, the infection may be difficult to prove from placental examination. Ultrastructural studies are especially lacking in this area and might be helpful, particularly when virus infection is suspected. Infections may ascend from the endocervical canal, or they may reach the placenta hematogenously through the maternal blood. Rarely are they acquired by amniocentesis, chorionic villus sampling, amnioscopy (Horky and Amon 1967), percutaneous umbilical blood sampling (“PUBS”; Wilkins et al. 1989), or intrauterine fetal transfusion (Goodlin 1965; Scott and Henderson 1972). Many infections cause gross and microscopic changes of the placenta, but others, e.g., the Coxsackie virus infection, leave few characteristic or specifically recognizable traces. This is also the case with parvovirus B19 infection, which often leads to fetal hydrops but has no specific placental alteration other than perhaps intranuclear inclusions in nucleated red blood cell precursors and endothelium, as a report by Hartwick et al. (1989) showed. Samra et al. (1989) described villous necrosis and calcification in the placenta from a 20 weeks’ gestation with hydrops due to this infection (see Chap. 16).
Article
Pregnant women, especially primigravidas, are highly susceptible to malaria infection, resulting in maternal anemia and low birth weight infants, Because circulating parasitemia is rare in the newborn, the cause of poor fetal outcomes has been unclear, We measured cytokine concentrations in placentas collected from women delivering in urban hospitals in malaria-holoendemic or nonendemic areas of Kenya. Normal placentas displayed a bias toward type 2 cytokines; type 1 cytokines IFN-gamma and IL-2 were absent in placentas not exposed to malaria but present in a large proportion of placentas from a holoendemic area. TNF-alpha and TGF-beta concentrations were significantly higher, and IL-10 concentrations significantly lower, in placentas from the holoendemic area, Among primigravidas, placental TNF-alpha concentrations were significantly higher in the presence of severe maternal anemia, and both IFN-gamma and TNF-alpha were significantly elevated when a low birth weight, rather than normal weight, infant was delivered, We conclude that maternal malaria decreases IL-10 concentrations and elicits IFN-gamma, IL-2, and TNF-alpha in the placenta, shifting the balance toward type 1 cytokines. This is the first demonstration that these placental cytokine changes are associated with poor pregnancy outcomes in humans.
Article
The chronic inflammatory lesions of the placenta often run in the shadows of the better-known acute inflammatory processes of the placenta, such as acute chorioamnionitis and acute funisitis. A heterogeneous population of T-cell lymphocytes, plasma cells, and macrophages is the primary player in chronic villitis, chronic chorioamnionitis, chronic deciduitis, and chronic intervillositis, and eosinophils are an added component of eosinophilic/T-cell chorionic vasculitis. The histologic appearance, sites of occurrence in the placenta, and pathogeneses of these entities are reviewed.
Article
Introduction: ICAM-1 expression on the villous syncytiotrophoblast (ST) is believed to participate in migration of maternal cells into the inflamed villi regardless of villitis etiology. However, its expression on immune cells in chronic villitis (CV) has yet to be analyzed. ICAM-1 induces cell-cell adhesion allowing intercellular communication, T cell-mediated defense mechanism, and inflammatory response. Material and methods: 21 cases of CV (all without an identifiable etiologic agent) and 3 control placentas were analyzed using ICAM-1, and for immune cells CD45, CD3 and CD68. These cells were subdivided according to their location in inflamed villi: a) within the inflamed villi and b) outside forming perivillous aggregates. Results: Large amounts of CD45, CD3 and CD68 were found within the inflamed villi and forming perivillous aggregates attached to areas of trophoblastic loss. Inflamed villi usually showed ICAM-1+ ST. The majority of immune cells surrounding areas of trophoblastic rupture presented marked expression of ICAM-1. In contrast, a small number of immune cells within the inflamed villi exhibited ICAM-1 expression. Only some (<5%) inflamed villi without trophoblastic rupture and with ICAM-1+ ST presented adherence of immune cells. Discussion: In inflamed villi of chronic villitis, the level of ICAM-1 expression on immune cells depends on their location: high in number of cells in the perivillous region and low within the villi. The strongest expression of ICAM-1 on immune cells attached to areas of trophoblastic rupture suggests that the loss of trophoblast can lead to an amplification of the inflammatory response.
Article
Introduction Massive chronic intervillositis (MCI), also known as chronic intervillositis of unknown etiology, is a placental lesion associated with massive infiltration of mononuclear cells in the intervillous space, poor perinatal outcome, and high rate of recurrence. Our previous demonstration of increased syncytiotrophoblast (st) intercellular adhesion molecule-1 (ICAM-1) expression in villitis lesions and the finding of extensive monocyte/macrophagic cells in the maternal intervillous space in MCI, led us to further investigate stlCAM-1 in MCI. Materials and Methods A cross-sectional study of placentas from the third trimester of pregnancy (34-41 weeks gestation) was conducted to determine stICAM-1 in MCI (n=7). MCI stICAM-1 expression was compared to stICAM-1 in villitis (n=7) and in normal villi from placentas with (n=7) and without (n=7) villitis. Maternal cells within villi in MCI were identified in placentas mismatched for maternal/fetal human leukocyte antigen (HLA)-DRw52. Villitis was diagnosed with hematoxylin and eosin staining and antibody to CD3 in serial sections, and ICAM-1 in syncytiotrophoblasts was confirmed with antibodies to ICAM-1 and cytokeratin. Results Placentas with MCI had higher stICAM-1 (79.8%) than placentas with villitis (27.1%), normal villi from placentas with villitis (11.5%), and normal villi from placentas without villitis (0.3%). Maternal cells were identified within villi of placentas (n=5) mismatched (mothers positive, fetuses negative) for HLA-DRw52. Conclusions Placentas with MCI have more stICAM-1 than placentas with or without villitis lacking MCI. The finding that MCI and villitis have prominent stICAM-1 and maternal cells in the villi suggests that MCI and villitis could have a similar pathophysiologic mechanism.
Article
Villitis of unknown etiology (VUE) is a common lesion affecting from 6.6% to 33.8% of third-trimester placentas. VUE needs to be distinguished from villitis of infectious etiology, most commonly cytomegalovirus and syphilis. Clinically, this lesion is associated with intrauterine growth retardation, intrauterine fetal demise, fetal neural impairment, maternal alloimmune and autoimmune disease, and maternal hypertension. It has a tendency to recur in subsequent pregnancies. Massive chronic intervillositis (MCI), also known as chronic histiocytic intervillositis, is a rare lesion that has an unclear relationship with VUE. MCI is associated with recurrent abortions.
Article
Acute atherosis is a maternal vascular lesion observed regularly in cases of pre-eclampsia and idiopathic intrauterine growth retardation. This vasculopathy is characterized by fibrinoid necrosis of the vessel wall, an accumulation of lipid-laden macrophages, and a mononuclear perivascular infiltrate. Similar vascular lesions are seen in the decidual vessels of patients with autoimmune diseases, and in renal, cardiac and hepatic homograft rejection. Immunohisto-chemical studies often reveal extensive vascular deposition of IgM and complement in acute atherosis-like lesions. Granular deposition of immunoglobulins and complement within the vessel walls and mononuclear perivascular infiltrate may be a histopathological hallmark of a maternal immunological aggression against fetal tissues.
Article
Chronic histiocytic intervillositis of the placenta (CHI) is a rare and potentially recurrent disease. Characteristically it shows accumulation of CD68+ cells in the intervillous space but no destructive tissue infiltration. An immunopathological background is likely but it is unknown what attracts circulating monocytes to the placenta. We analysed the expression profile of 102 inflammation- and angiogenesis-associated genes with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in 16 placentas: CHI (n = 5) and, as controls, villitis of unknown aetiology (VUE, n = 4) and normal placenta (n = 7). Compared to controls, CHI had significantly higher levels of matrix metallopeptidase 9 (MMP9) and transforming growth factor, beta receptor 1 (TGFBR1). MMP14 was lower in VUE than CHI (p < 0.05) and controls (not significant). Chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL12, chemokine (C-C motif) ligand 5 (CCL5) and TIMP metallopeptidase inhibitor 1 (TIMP1) were significantly higher in VUE versus controls but not deregulated in CHI. The expression profile could not clearly discriminate CHI from VUE or controls but a tendency for grouping of massive CHI was found. Angiogenesis-associated factors were not deregulated in CHI. The discrepancy of massive histiocytic accumulation and the lack of striking up-regulation of cytokines might be the basis of the non-destructive behaviour of the histiocytes in CHI.
Article
Massive chronic intervillositis (MCI) is an unusual placental lesion associated with poor fetal growth and adverse pregnancy outcome; it has not previously been associated with spontaneous abortion or recurrent pregnancy loss. This article reports a patient who had 10 spontaneous abortions with repetitious massive chronic intervillositis documented in four of five gestations spanning all three trimesters. Characteristic placental histology included massive infiltration of the maternal intervillous space by chronic inflammatory cells and fibrin, without associated chronic villitis; the cellular infiltrate was composed predominantly of LCA and CD68 immunoreactive cells with scattered CD45RO positivity, consistent with a monocyte/macrophage population with occasional T lymphocytes. Elevated maternal serum alphafetoprotein was documented in two pregnancies. These findings support the concept that this unusual placental lesion may have an immunologic basis, and suggest that MCI may be a histopathologically recognizable cause of recurrent spontaneous abortion.
Article
Chronic histiocytic intervillositis (CHI) is an infrequent inflammatory placental disorder associated with unfavorable pregnancy outcomes and a high rate of recurrence. This disorder is thought to reflect a maternal delayed hypersensitivity response to fetal antigen(s) in placental tissue. We report a case of a 20-week-gestation hydropic fetus in which the placenta showed chronic histiocytic intervillositis with cytomegalovirus placentitis. Immunophenotyping studies supported a delayed hypersensitivity response. This is the first report of these two diseases co-occurring, raising the possibility of a relationship between chronic histiocytic intervillositis and infection. Chronic histiocytic intervillositis may represent an idiosyncratic immune response, in this case to cytomegalovirus.
Article
Acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV) are important limitations for the long-term survival of heart transplant recipients. Although much progress has been made in reducing ACR with modern immunosuppressive treatments and continuous biopsy surveillance, there is still a long way to go to better understand and treat AMR, to enable early detection of patients at risk of CAV, and to reduce the development and sustained progression of this irreversible disease that permanently compromises graft function. This review considers the advances made in ACR detection and treatment allowing a more prolonged survival and the risk factors leading to endothelial injury, dysfunction, inflammation, and subsequent CAV, as well as new treatment modalities for CAV. The review also evaluates the controversies around the definition, pathogenesis, and treatment of AMR. To date, much progress is still needed to significantly reduce post-transplant complications and increase graft and patient survival.
Article
Pregnant women, especially primigravidas, are highly susceptible to malaria infection, resulting in maternal anemia and low birth weight infants. Because circulating parasitemia is rare in the newborn, the cause of poor fetal outcomes has been unclear. We measured cytokine concentrations in placentas collected from women delivering in urban hospitals in malaria-holoendemic or nonendemic areas of Kenya. Normal placentas displayed a bias toward type 2 cytokines; type 1 cytokines IFN-gamma and IL-2 were absent in placentas not exposed to malaria but present in a large proportion of placentas from a holoendemic area. TNF-alpha and TGF-beta concentrations were significantly higher, and IL-10 concentrations significantly lower, in placentas from the holoendemic area. Among primigravidas, placental TNF-alpha concentrations were significantly higher in the presence of severe maternal anemia, and both IFN-gamma and TNF-alpha were significantly elevated when a low birth weight, rather than normal weight, infant was delivered. We conclude that maternal malaria decreases IL-10 concentrations and elicits IFN-gamma, IL-2, and TNF-alpha in the placenta, shifting the balance toward type 1 cytokines. This is the first demonstration that these placental cytokine changes are associated with poor pregnancy outcomes in humans.
Article
Placental malaria is associated with local accumulation of parasitized erythrocytes, deposition of the parasite hemoglobin metabolite, hemozoin, and accumulation of mononuclear cells in the intervillous space. Fetal syncytiotrophoblast cells in contact with maternal blood are known to respond immunologically to cytoadherent Plasmodium falciparum-infected erythrocytes, but their responsiveness to hemozoin, a potent pro-inflammatory stimulator of monocytes, macrophages and dendritic cells, is not known. The biochemical and immunological changes induced in primary syncytiotrophoblast by natural hemozoin was assessed. Changes in syncytiotrophoblast mitogen-activated protein kinase activation was assessed by immunoblotting and secreted cytokine and chemokine proteins were assayed by ELISA. Chemotaxis of peripheral blood mononuclear cells was assessed using a two-chamber assay system and flow cytometry was used to assess the activation of primary monocytes by hemozoin-stimulated syncytiotrophoblast conditioned medium. Hemozoin stimulation induced ERK1/2 phosphorylation. Treated cells secreted CXCL8, CCL3, CCL4, and tumor necrosis factor and released soluble intercellular adhesion molecule-1. Furthermore, the dependence of the hemozoin responses on ERK1/2 stimulation was confirmed by inhibition of chemokine release in syncytiotrophoblast treated with an ERK pathway inhibitor. Hemozoin-stimulated cells elicited the specific migration of PBMCs, and conditioned medium from the cells induced the upregulation of intercellular adhesion molecule-1 on primary monocytes. These findings confirm an immunostimulatory role for hemozoin and expand the cell types known to be responsive to hemozoin to include fetal syncytiotrophoblast. The results provide further evidence that syncytiotrophoblast cells can influence the local maternal immune response to placental malaria.
Article
Chronic intervillositis of the placenta is known to be associated with poor reproductive outcome and a high risk of recurrence. The aims of the present study were to quantify the risk of recurrence of chronic intervillositis in subsequent pregnancies, to explore if there are possible interventions and to assess the success of interventions. Systematic review of published literature using published guidelines. No randomised controlled trials were identified. Sixty-one papers, published between 1977 and 2009 were identified after abstract screening but only 6 studies could be included in the systematic review. From the 6 selected studies, 69 pregnancies at gestational age of 14 weeks or over, with a histopathologic diagnosis of chronic intervillositis were available for analysis. The rate of intrauterine growth restriction in the study population was 66.7%, the overall rate of livebirth was 53.6%. In 16/20 (80.0%) cases recurrence of CI was confirmed at histopathology. The livebirth rate reported with treatment was 30.8% against 58.9% without treatment (RR=0.47, 95% CI=0.2-1.1). This difference was not statistically significant. Chronic intervillositis has a high (80.0%) recurrence risk. In pregnancies reaching 14 weeks, the chance of a livebirth is 53.6%. The livebirth rate reported with treatment was 30.8% against 58.9% without treatment (RR=0.47, 95% CI=0.2-1.1). This difference was not statistically significant. Intervention with drug therapy is of no demonstrable benefit, and may even be harmful.
Article
There are previous indications that transplacental transmission of cytomegalovirus (CMV), parvovirus B19 (PB19) and herpes simplex virus types 1 and 2 (HSV-1/2) cause fetal infections, which may lead to fetal death. In a prospective case-control study we examined the incidence of these viruses in intrauterine fetal death and their association with fetal and placenta pathological findings. Molecular assays were performed on placenta tissue extracts of 62 fetal deaths and 35 controls for the detection of CMV, PB19 and HSV-1/2 genomes. Formalin-fixed, paraffin-embedded liver, spleen and placenta tissues of fetal death cases were evaluated histologically. Thirty-four percent of placental specimens taken from intrauterine fetal deaths were positive for any of the three viruses (16%, 13%, and 5% positive for CMV, PB19, and HSV-1/2, respectively), whereas only 6% of those taken from full term newborns were positive (P = 0.0017). No dual infection was observed. This difference was also observed when fetal deaths with a gestational age <20 weeks or a gestational age >20 weeks were compared with the controls (P = 0.025 and P = 0.0012, respectively). Intrauterine death and the control groups differed in the detection rate of CMV DNA (16% and 3%, respectively; P = 0.047), which was more pronounced in a gestational age >20 weeks (P = 0.03). Examination of the pathological findings among the PCR-positive and PCR-negative fetal deaths revealed that hydrops fetalis and chronic villitis were more common among the former group (P = 0.0003 and P = 0.0005, respectively). In conclusion, an association was detected between viral infection and fetal death, which was more pronounced in the advanced gestational age. Fetal hydrops and chronic villitis were evidently associated with viral DNA detection in cases of intrauterine death.
Article
The histopathologic features of cytomegalovirus placentitis, an established cause of chronic villitis, are well documented. However, the immunologic features of the fetal inflammatory response to placental cytomegalovirus infection are largely unknown. The characterization of the fetal-derived inflammatory cell reaction may be important in our understanding of both the intrauterine as well as the antenatal immunological response of the neonate to this important viral infection. We examined formalin-fixed placentas from four cases of confirmed congenital cytomegalovirus infection using an in situ DNA probe to cytomegalovirus, and a variety of antibodies to leukocyte antigens, including anti-CD68, CD45RO, CDw75, CD74, IgG, IgM, and IgA. All four placentas showed marked hyperplasia of fetal-derived placental macrophages, termed Hofbauer cells. A lymphocytic villitis was present in all placentas, which was characterized by positive staining in all cases with T-cell antibodies. There was no evidence of positive staining of lymphocytes using B-cell antibodies in any of the cases. Two placentas showed plasmacellular villitis, which stained positively for both IgG- and IgM-secreting cells, that was present as early as the second trimester of gestation. No IgA positivity of plasma cells was observed. These data are presented in light of current theories of fetal viral immunity.
Article
Villous stromal cells (VSC) play an important role in fetomaternal placental immune function. We studied the phenotype of VSC in infection by cytomegalovirus (CMV) and syphilis as well as nonspecific villitis and compared the findings with gestational age-matched controls. Monoclonal antibodies directed against total leukocytes, T cells, B cells, macrophages, dendritic cells, granulocytes and HLA-DR as well as polyclonal antibodies against S-100, alpha-1 antichymotrypsin, and lysozyme were used. In controls, the immunocytochemical response for each marker was either negative or weakly positive. In contrast, the VSC in CMV-infected and nonspecific villitis showed intense reactivity to various macrophage markers. In syphilis, reactivity with macrophage markers such as lysozyme and MAC387 were weaker, and reactivity to HLA-DR and S-100 was much stronger. Endothelial cells strongly expressed the monocyte/granulocyte marker CD15 in the diseased states, especially in syphilis, relative to controls. We conclude that the phenotype of VSC is altered in disease states and that the changes are dependent to some degree on the specific subset of chronic villitis.
Article
Villitis is characterized by an inflammatory infiltrate within the substance of the chorionic villi. Quantitative and qualitative analyses of the mononuclear infiltrate in areas of villitis were performed in placentas with villitis of unknown etiology (VUE). We used a panel of monoclonal antibodies and immunoperoxidase technique in paraffin sections from 17 placentas with VUE and 8 without VUE. Macrophages followed by T lymphocytes were the predominant inflammatory cells in areas of villitis in virtually all cases. B lymphocytes were not observed and monocytes were present usually in small number in 58 per cent of the cases. Mononuclear cells which expressed HLA-DR antigens were found in 75 per cent of the cases. In areas of villitis with trophoblastic necrosis, we found monocytes and some T lymphocytes adhered to them. These cells apparently had migrated from the maternal circulation. We suggest that in areas of villitis with destruction of the trophoblast and its basal membrane the inflammatory infiltrate might have a mixture of fetal and maternal cells. The maternal monocytes and T lymphocytes might be attracted to these sites of trophoblastic necrosis and activated due to exposure to fetal MHC antigens of the villous stroma.
Article
The purpose of this study was to identify the possible effect of enteroviruses on placental tissue. Seventy-eight pregnant women were studied throughout their pregnancy: enteroviral infection was detected by faecal viral isolation and seric neutralization of previously identified virus in cell culture. In 19 cases of confirmed maternal infection, placentae were examined grossly, by optical microscopy, immunohistochemical and electron microscopic methods. Ten term placentae from women included in the study, with no clinical, serological or virological evidence of enteroviral infection, were used as control, and examined by gross and optical microscopy. In 17 specimens (echovirus-coxsackievirus) an haematogenous placentitis was suspected on the basis of gross observation. Microscopic lesions were similar to those found in other viral infections, with specific features. The nature of the inflammatory reaction pointed to the presence of an acute type of haematogenous placentitis, not present in placentae of the control group. The authors (AA) comment on the results and present the hypotheses about the available data: (1) maternal enteroviremia and faecal virus shedding without placental invasion, placentary damage being an unspecific consequence of infection; (2) direct virus-induced injury is not the only possible cause for the lesions: (3) placental enteroviral infection occurred with placental pathology but the virus did not cross the organ as the newborn had no signs of infection.
Article
Villitis of unestablished origin is a lesion in placentas from normal and high-risk pregnancies. We have studied villitis areas in 25 normal term placentas for immune cells, coagulation components, and endothelial markers. Villitis areas were filled with activated (HLA-DR, HLA-DP, and HLA-DQ reactive) macrophages. B lymphocytes were not identified, and T lymphocytes were of the helper (CD4) phenotype. Antibodies to coagulation components revealed perivascular and trophoblastic basement membrane deposits of factor IX, increased numbers of platelets, and fetal stem vessels that did not react with endothelial markers. These findings suggest helper T lymphocytes activate macrophages that mediate coagulation activation and alter endothelium. This combination of immunologic events results in tissue changes that are histologically diagnosed as villitis. It is not known what triggers these immunologic events, but the finding of villitis in normal placentas suggests the causative factor(s) is present in all pregnancies.
Article
Absence of class II MHC antigens from human syncytiotrophoblast is a common finding in normal-term placentae. Since chronic villitis of unestablished etiology is a placental lesion frequently found in normal and abnormal term placentae, and fetal stem vessels are MHC class II-positive in these lesions, we asked if syncytiotrophoblast in villitis is reactive for MHC class II antigens. We found segments of syncytiotrophoblast that were reactive for the MHC class II HLA-DR, DP, and DQ antigens in villitis areas of normal-term placentae and in placentae from women with a history of recurrent spontaneous abortions. This reactivity was not due to trophoblast replacement by activated macrophages, though the possibility of crossreactive antigens and binding of soluble MHC class II antigens by receptors developed in areas of villitis could not be excluded. MHC class II antigen expression on syncytiotrophoblast could be due to cytokine release from activated macrophages and helper T lymphocytes which we have previously described in areas of villitis of unestablished etiology.
Article
Reports have supported an association between elevated midtrimester maternal serum alpha-fetoprotein concentrations (unexplained by fetal anomalies) and intrauterine growth retardation. Our observations show an association between such elevations of maternal serum alpha-fetoprotein levels and two types of placental pathology at delivery, chronic villitis and placental vascular lesions of infarction or intervillous thrombosis. If chronic villitis was present, the frequency of intrauterine growth retardation was significantly increased, whereas no increase in intrauterine growth retardation was found in the absence of placental pathology.
Article
Chronic villitis is a placental lesion of unestablished etiology. It is characterized by destruction of chorionic villi with a mononuclear infiltrate and focal areas of fibrinoid necrosis. The lesion frequently is seen in normal placentae, yet more lesions have been reported in placentae from abnormal pregnancies. We measured the extent of villitis in 25 normal term placentae by using both light microscopy and immunocytology for class II (HLA-DR) antigens of the major histocompatibility complex. HLA-DR antigens were found to be characteristic of villitis areas. Normal placentae showed striking variations in the incidence of villitis, but these variations did not correlate with clinical outcome.
A placental lesion, characterized by fibrinoid and trophoblastic necrosis with massive infiltration of the intervillous space by mononuclear cells (massive chronic intervillositis, MCI), was observed in six cases, five with intrauterine growth retardation (IUGR) and one with sudden intrauterine fetal death. Four out of six had chronic villitis of unknown etiology (CVUE) associated with this lesion, and five had lesions of anchoring villitis. In three cases, acute atherosislike lesions in spiral arteries of parietal and/or basal decidua were observed. Massive deposits of IgM, a smaller amount of C3 and Clq, and slight deposits of IgG and IgA were found in these vessels. Neither mothers nor infants had any clinical or serological evidence of infection. Cases with MCI were compared with those having CVUE without intervillositis. Patients with MCI showed lower values of infant weight, infant length, and ponderal index than controls. However, cases with MCI group showed a higher incidence of IUGR. Placentas from the MCI group had a greater number of acute atherosislike lesions than controls. Massive chronic intervillositis may represent an extreme variant of villitis of unknown etiology. A maternal immunological aggression toward fetal tissues is proposed as pathophysiological mechanism, although a nondetermined placental infection cannot be excluded.
Article
Two groups of placentae from 18 cases of maternal rubella were examined morphologically and virologically. Placentae in Group I (four cases) had a mean gestational age of 21 +/- 1.9 weeks, whilst those in Group 2 (14 cases) had a mean gestational age of 38 +/- 2.8 weeks. A tendency to hypoplasia was observed. The microscopic lesions were similar to those found in other viral infections but in each group some specific features were noted. Only placentae of Group I showed nodules of villi agglutinated by fibrin. This lesion suggested recent maternal infection. Attention is drawn to the presence of abnormal areas of lobular rarefaction due to dysmaturity of villous stem and terminal villi. This aspect was more diffuse and accentuated in Group 2 placentae. Villitis of reactive, necrotic, proliferative and reparative types was seen only in placentae of Group 2. Devastating villitis was not observed. Inclusions in placental cells suggested rubella infection. The lesions were non-specific and hence stress the need for virological examination of the placenta, immunofluorescence studies and electron microscopy to confirm the diagnosis.
Article
In a retrospective survey, recurrent villitis was identified in ten of 59 patients in whom placental villitis had been diagnosed. The ten patients had a total of 41 pregnancies, with a reproductive loss of 60 per cent. In addition to enhanced fetal losses in all trimesters of gestation and postnatally, the incidences of fetal growth retardation and premature delivery were increased. There was no evidence of recent TORCH (toxoplasma, rubella, cytomegalovirus, herpes) infection, but all patients tested had rubella immunity. In six patients genital cultures were positive for gonorrhea and assorted microorganisms. Uterine abnormalities, including two septate uteri, one incompetent cervix, one submucosal leiomyoma, and one retroflexion, were common, and vaginal bleeding had occurred in five patients. Other factors included obesity (five patients) and clinical and laboratory evidence of autoimmunity (four of the five patients tested). In a control group of 20 patients with nonrecurrent villitis, the perinatal loss rate (37 per cent) was lower, and the incidences of positive cultures, uterine structural anomalies, obesity, and autoimmunity were also lower. Placental histologic findings included decidual plasma cell and intervillous fibrin and histiocytic infiltration, in addition to villous inflammation. These lesions, although consistent for a given patient, defined two clinically relevant groups of patients. The results of this study suggest that recurrent villitis is more frequent than previously reported, that it is associated with high perinatal mortality, and that immunologic and structural abnormalities in the host may play a role in its pathogenesis.
Article
Between 1978 and 1983 1240 singleton placentas were examined macroscopically and histologically. In 82 cases (6.6%) a "chronic placentitis" was diagnosed. The pathognomonic inflammatory foci were localized within the placental villi. The vast majority showed mixtures of both fibrohistiocytes and lymphoid cells, which were occasionally interspersed with plasma-cells. The clinical data relating to 67 placentas were correlated retrospectively with the degree of inflammation. 46 showed mild and 21 moderate to severe chronic placentitis. In both of these groups the proportion of preterm deliveries and cases with preeclampsia was equally high. With increasing severity of chronic placentitis, however, there was a significant reduction in weight and size of both, placenta and infant, and the incidence of perinatal asphyxia was significantly raised.
Article
In a mother's two successive pregnancies, the products of conception, a liveborn premature infant and a 6-month abortion, infection with toxoplasma organisms was shown. Where severe maceration of the fetus makes identification of toxoplasma organisms difficult, two tissues in particular should be examined histologically: (1) chorion of placenta and umbilical cord, where toxoplasma trophozoites and pseudocysts tend to be abundant; (2) fetal adrenals, where characteristic necrotic and calcified foci, as well as toxoplasma organisms, may persist.
Article
A histological study of 1000 randomly selected placentae from women delivered in Manchester, UK, revealed 136 cases of villitis; this is a higher incidence than that recorded in Australia and North America but lower than that noted in South America. There were no obvious clinical differences between mothers whose placentae showed a villitis and those in a control group whose placentae were free of villitis. As in other studies, there was an association between the presence of a villitis, particularly severe villitis, and fetal intrauterine growth retardation. The nature of this association cannot, however, be clarified until the aetiology of villitis is determined.
Article
Placentae from 63 term pregnancies were studied. Of these, 19 were from normal pregnancies in which the neonates were within the normal weight range for their gestational age. The remaining 44 placentae were from pregnancies in which the infants were small for their gestational age (SGA). A chronic villitis was found in 68 per cent of all placentae. In the control group this lesion was present in 26 per cent but a mean of only 1.2 per cent of villi in these cases was inflamed. In the SGA group 86 per cent of placentae showed a chronic villitis and in these an average of 10 per cent of the villi were inflamed. Lymphocytic infiltrates in basal plate anchoring villi were observed in 48 of the 63 placentae and there were no differences among the various groups. Vascular lesions were found, similar to those described in placental bed arteries in preeclampsia and more recently in biopsies of the placental bed of SGA infants and in the decidua of mothers with systemic lupus erythematosus: this type of vasculopathy has also been described in rejection of renal transplants. It is suggested that the cellular infiltrate around and inside anchoring villi and free villi in cases of chronic villitis may represent the histological hallmark of an immunological reaction between mother and fetus rather than a response to infection.
Article
A case is reported of recurrent reproductive failure due to a severe placental villitis of unknow etiology. Five successive pregnancies ended in four unexpected third-trimester deaths in utero and one live birth at 37 weeks' gestation. This infant of the fourth pregnancy showed severe intrauterine growth retardation but no other stigmata of chronic infection. The placentas of the last three pregnancies showed marked focal chronic parenchymal inflammation with widespread necrosis, villous vasculitis and a lymphocytic deciduitis of the maternal floor. Microbiologic, serologic and electron microscopic techniques variously employed on maternal, fetal and placental specimens failed to demonstrate a possible causative agent although the placental inflammatory pattern was strongly suggestive of recurrent infection.
Article
All placentae delivered in a large obstetrics hospital in a two-year period were examined macroscopically and histologically. Of 7505 consecutive singleton placentae, chronic focal placental villitis of unknown aetiology (VUE) was found in 575 (7.6 per cent). The clinical correlates of these cases have been published previously (Russell, 1979). The present report details histological spectra of severity and distribution of the lesions, cell types within the inflammatory foci and secondary changes consequent upon local reduction in both maternal and fetal blood flow through the placenta. Histological findings tend to support direct extension of the infection from uterine sources rather than haematogenous inoculation of the placenta. The clinical sequelae for the infant appear to correlate positively with the severity of the villitis process.
Article
We asked if activated macrophages and CD4 positive T lymphocytes in placental chorionic villi with villitis were of maternal or fetal origin. We employed a double antibody immunocytochemical technique on placental sections from three normal and four abnormal pregnancies with small-for-gestational-age infants. All studied placentae were mismatched for the maternal-fetal HLA-DRw 52 antigen. Areas of immunopathology were identified by using a monoclonal antibody to a monomorphic determination on HLA-DR, and the origin of immunological cells in areas of immunopathology was identified by using a monoclonal antibody to a polymorphic determinant on HLA-DRw 52. We used a double antibody technique that employed monoclonal antibodies to HLA-DR and HLA-DRw 52 antigens and placentae that were mismatched for the maternal-fetal HLA-DRw 52 antigen. We found that the vast majority of immunological cells within villi with inflammation were of maternal origin. Quantitative studies showed that between 75 and 100% of the cells in normal as well as in abnormal pregnancies were of maternal origin, and that abnormal pregnancies had a significantly higher percentage of villi with maternal cellular infiltrates. Our data show unequivocally that cells in areas of placental immunopathology are predominantly of maternal origin, and that abnormal pregnancies are associated with significantly more villi containing immunological cells of maternal origin.
Article
Reciprocal expression of CD45RA and CD45RO in human CD4+ T cells defines populations understood to be naive cells (CD45RA+CD45RO-) and memory cells (CD45RA-CD45RO+). We investigate two subsets of CD45RA-CD45RO+ CD4+ human T cells which differ by fourfold in their expression of the CD45RB isoform; one is CD45RBbright and the other is CD45RBintermediate. In contrast, CD45RA+ naive cells are all CD45RBbright. Both subsets of CD45RA- cells proliferate in response to recall antigens so we designate them MEM 1 (CD45RO+RBbright) and MEM 2 (CD45RO+RBintermediate). CD45RA and CD45RB expression are regulated independently during in vitro activation of naive cells. When MEM 1 cells are activated they tend to down-regulate CD45RB expression, whereas activated MEM 2 cells tend to up-regulate CD45RB expression. Thus, in contrast to the stability of the CD45RA-CD45RO+ phenotype, the MEM 1 and MEM 2 phenotypes are labile and may interconvert. MEM 1 and MEM 2 cells produced comparable amounts of interleukin(IL)-2, IL-4, and IL-5 though MEM 1 cells produced slightly more interferon(IFN)-gamma (mean 1.7-fold more). MEM 1 cells consistently proliferated more (mean 2.3-fold more) than MEM 2 cells early during in vitro activation. Thus, differential expression of CD45RB within CD45RA- cells defines two subsets that have similar properties except for somewhat greater IFN-gamma production and proliferative responses by MEM 1 cells. Variability in CD45RB expression may represent a mechanism for fine-tuning the responsiveness of memory cells in vivo.
Article
We report six cases of chronic intervillositis, an infrequently recognized placental lesion that is characterized by a prominent mononuclear inflammatory cell infiltrate in the intervillous space and that is associated with poor fetal outcome. In all six placentas, the inflammatory infiltrate was essentially limited to the intervillous space: chronic villitis was present focally only in one and absent in the other five. Additional placental histopathologic findings included increased villous fibrinoid material in all six, infarcts in two, atherosis in decidual vessels in two, and acute chorioamnionitis in two. Results of immunohistochemical staining confirmed the predominantly histiocytic nature of the intervillous infiltrate. Two mothers had a history of severe preeclampsia, one had elevated blood pressure at the time of delivery, two had a history of substance abuse, two had a history of systemic lupus erythematosus treated with prednisone, and one of these last two also had diabetes. Five of the six pregnancies resulted in perinatal death. One fetus was nonviable, one was anencephalic, one died in utero, and two died of complications of prematurity shortly after birth; one of the premature infants was small for gestational age. The mononuclear nature of the inflammatory cell infiltrate and its association with increased villous fibrinoid material and atherosis suggests an immunological origin, although the possibility that this lesion may have an infectious cause cannot be excluded.
Article
Villitis of unknown etiology (VUE) is a common placental lesion and an important cause of intrauterine growth retardation and recurrent reproductive failure. Two theories have been proposed to explain VUE. One proposes that VUE is an exclusively fetal immune response to microbial antigen, whereas the other suggests that maternal cells cross the maternal-fetal interface and mount an immune response to fetal antigens. To differentiate between these alternatives, we performed in situ hybridization using X and Y chromosome-specific probes and immunostaining for CD3 and CD45 on VUE placentas from male infants. A total of eight foci and 40 villi were studied from four male VUE placentas. Controls included nonaffected villi from each male VUE placenta, a female VUE placenta, and male and female tonsils. Affected villi showed a major proportion of XX (maternal) cells (range 30 to 54%). An appropriate percentage of the remaining (fetal) cells contained Y chromosomes. The fraction of cells within the eight foci staining for CD3 (T lymphocytes) ranged from 34 to 57%, whereas the fraction staining for CD45/LCA (total leukocytes) ranged from 45 to 74%. The proportion of maternal cells within each focus was significantly correlated with the number of CD3-positive T lymphocytes but not with the number of CD3-negative leukocytes. We conclude that maternal cells, probably CD3-positive T cells, cross the maternofetal barrier and participate in VUE.
Article
Massive chronic intervillositis (MCI) is an infrequently recognized placental lesion thought to be of immunologic origin that has been associated with poor fetal outcome. It is characterized by a prominent inflammatory infiltrate in the intervillous space, composed mainly of monocytes and macrophages that can simulate a maternal malignant disorder involving the placenta. The villi are characteristically spared. We report 74 cases of placental malarial infection with morphologic features of MCI. In all cases, the massive inflammatory infiltrate was limited to the intervillous space, which appeared largely obliterated. Increased fibrin deposition and prominent syncytial knots were frequent associated findings. Inflammatory cells were CD45 and CD68 positive, consistent with a monocyte-macrophage population. Some polymorphonuclear leukocytes and scattered T and B lymphocytes were also present. Villi were not inflamed. Malarial pigment was present in all cases, and parasitized maternal erythrocytes were evident in 73 of 74 patients. The histologic pattern of MCI was observed in 17.6% of placentas with malarial parasites. Malarial MCI affected predominantly primigravida women (77%) and was associated with a reduced birth weight, which in 39 (53%) of the infants was less than 2500 g, and a low gestational age. None of the infants with placentas with MCI died in the early neonatal period. Morphologic changes of MCI are seen in a significant percentage of placentas with malarial infection, especially in primigravida women, and are associated with a low birth weight. Malarial infection should therefore be considered in the differential diagnosis of massive intervillous infiltrates.
Article
The management of patients with first-trimester spontaneous abortions is handicapped by two problems: difficulty in recognizing conceptions that abort because of abnormal karyotypes and an incomplete understanding of what causes abortions with normal karyotypes. Our goals in this study were to define features useful in distinguishing normal from abnormal karyotype and to identify pathological processes contributing to abortions with a normal karyotype. The study population consisted of 668 well-characterized first-trimester spontaneous abortions derived from a larger study of 1,054 consecutively karyotyped spontaneous abortions. Clinical factors increased in specimens with normal karyotype were maternal age younger than 20 years (P=.0003) and autoimmune markers (P=.0474). Developmental features associated with abnormal karyotype were developmental stage less than 6 weeks (P=.0017), hydropic villi greater than 1 mm (P=.0004), and villi with two or more dysmorphic features (P=.0001). Developmental stage greater than 11.5 weeks was increased with normal karyotype (P=.0001). Histological features increased in specimens with a normal karyotype were chronic intervillositis (P=.0003), increased perivillous fibrin deposition with intermediate trophoblast (P=.0006), decidual plasma cells (P=.0040), deciduitis without plasma cells (P=.0660), and chronic villitis (P=.1581). Overall, 19% of samples with a normal karyotype versus 8% with abnormal karyotype had one or more of these findings (P < .0001). Autoimmune markers, chronic intervillositis, and increased perivillous fibrin with intermediate trophoblast all had positive predictive values greater than 85% for normal karyotype, whereas dysmorphic villi had a positive predictive value of 90% for abnormal karyotype. Patients with recurrent spontaneous abortion and normal karyotype were more likely to have one or more of the histological features listed above (31%) than patients with normal karyotype and no prior abortions (13%) and patients with recurrent abortion and abnormal karyotype (11%).
Article
Chronic villitis is a common condition in human placentae. In some cases an infectious cause can be demonstrated, such as infection with cytomegalovirus and rubella virus. Most often it is of unknown aetiology, the so-called VUE (villitis of unknown aetiology). We describe two cases with identification of specific infectious agents, each demonstrating previously unreported findings, i.e. persistent varicella antigen in the villi in case 1, and presence of toxoplasma cysts in Wharton's jelly in case 2. The identification of the pathogens, varicella virus and toxoplasma, would easily have been overlooked in routine study of the placenta and were possible because of clinical suspicion.
Article
Chagas' disease, a systemic illness endemic to some regions of South America, is caused by the protozoan Trypanosoma cruzi. Transplacental infection may occur during any phase and cause fetal death. This study is the first to characterize the inflammatory cells in chagasic villitis by immunohistochemistry. Paraffin sections of 8 placentas with villitis by T. cruzi (4 live births and 4 stillbirths), as well as 8 control placentas without inflammation, were stained with hematoxylin and eosin, monoclonal antibodies for CD45RO, CD20, CD45RO/OPD4, CD8, HNKI, CD15, MAC387, and CD68 proteins, and a polyclonal antibody for S-100 protein. Quantification of positive cells was performed in 3 different high-power fields. In all cases of chagasic villitis, the inflammatory infiltrate was composed mainly of CD68+ macrophages, T lymphocytes, and a few natural killer cells. Among T cells, CD8+ cells outnumbered CD4+ cells in all placentas (CD4+:CD8+ ratios ranged from 0.04 to 0.38). B cells were absent or rare. In stillbirths, villitis was diffuse and severe with numerous T. cruzi, while in live births it was focal with few parasites. Other features that characterized villitis in stillbirths were 1) frequent trophoblastic necrosis, 2) presence of MAC387+ macrophages and CD15+ granulocytes attached to the sites of trophoblastic necrosis, 3) low CD4+: CD8+ ratios in most cases, 4) increased numbers of S-100 positive cells in the villous stroma. In conclusion, CD68+ macrophages and CD8+ T lymphocytes were the major cell population in villitis caused by T. cruzi. However, the pattern of inflammatory reaction differed between stillbirths and live births and was probably related to the number of parasites in the placental villi.
Article
Chronic (histiocytic) intervillositis (CHIV), defined for the purposes of this study as diffuse histiocytic infiltration of the intervillous space without villitis, is an idiopathic lesion seen in the chorionic sacs of some spontaneous abortion specimens and placentas. In this retrospective study, we evaluated all patients diagnosed with CHIV from 2 hospitals between 1993 and 2000, plus 1 additional patient from 1977. Histopathology, phenotype of the leukocytic infiltrate, perinatal outcome, and other associated clinical features were assessed by review of clinical records and all available pathology specimens plus immunohistochemical staining. CHIV was found in 31 of 45 specimens examined from 21 patients (23 of 31 first trimester, 3 of 5 second trimester, and 5 of 9 third trimester). Recurrence rate was 67% for patients with more than one specimen reviewed. Overall perinatal mortality rate was 77%, and only 18% of pregnancies reached 37 weeks. Eight of 19 patients with 3 or more pregnancies had recurrent spontaneous abortion (RSA); 5 with primary RSA (> or = 3 consecutive spontaneous abortions (SAB) with no living children) and 3 with secondary RSA (> or = 3 consecutive SAB with 1 or more living children). Severe intrauterine growth restriction was seen in 5 of 8 second- and third-trimester placentas with CHIV. Patients were generally not of advanced maternal age (mean, 29.8 +/- 6.2 years), and there was no obvious racial predisposition. Autoimmune or allergic phenomena were identified in 11 patients. Immunohistochemical staining of the intervillous infiltrate showed a near uniform population of monocyte-macrophages at varying stages of maturity and activation: more than 90% CD45Rb and CD68 positive, 30% to 40% MAC387 positive, less than 5% CD3 positive, and CD1a, CD20, CD30, and CD56 negative. We conclude that CHIV is an uncommon but important cause of recurrent spontaneous abortion and, in some cases, loss at later gestational ages. HUM PATHOL 31:1389-1396.