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Chronic histiocytic intervillositis (CHI) is a recurrent placental lesion where maternal macrophages infiltrate the intervillous space. Its cause is unknown, though due to similarities to rejected allografts one hypothesis is that CHI represents maternal-fetal rejection. Here, virtual crossmatching was applied to healthy pregnancies and those with a history of CHI. Anti-HLA antibodies, measured by Luminex, were present in slightly more controls than CHI (8/17 (47.1%) vs 5/14 (35.7%)), but there was no significant difference in levels of sensitisation or fetal specific antibodies. Quantification of immunohistochemical staining for HLA-Class II was increased in syncytiotrophoblast of placentas with CHI (Grade 0.44 [IQR 0.1-0.7]) compared to healthy controls (0.06 [IQR 0-0.2]) and subsequent pregnancies (0.13 [IQR 0-0.3]) (P = 0.0004). HLA-Class II expression was positively related both to the severity of CHI (r = 0.67) and C4d deposition (r = 0.48). There was no difference in overall C4d and HLA-Class I immunostaining. Though increased anti-HLA antibodies were not evident in CHI, increased expression of HLA-Class II at the maternal-fetal interface suggests that they may be relevant in its pathogenesis. Further investigation of antibodies immediately after diagnosis is warranted in a larger cohort of CHI cases to better understand the role of HLA in its pathophysiology., (© 2024. The Author(s).)

Chronic Intervillositis of Unknown Etiology (CIUE) is a rare idiopathic inflammatory disorder of the placenta. The evidence suggests an increased risk for poor obstetrical outcomes and a risk of recurrence as high as 100 %. This meta-analysis examined CIUE prevalence, recurrence, association with autoimmune disorders, reproductive outcomes, pregnancy complications, and the benefits of medical treatments. A systematic review, following PRISMA guidelines, involved a thorough search across multiple databases including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Evidence Based Medical Reviews, and Scopus. Out of 590 initially identified studies, 19 studies were included for both qualitative synthesis and meta-analysis after full-text review. Risk of bias was assessed using appropriate tools: The Risk Of Bias In Non-randomized Studies of Interventions tool was applied to twelve studies, while the Joanna Briggs Institute case series critical appraisal tool was used for seven studies. Our findings confirm that CIUE is a rare condition (0.7 %). CIUE is associated with decreased live birth rates (53 %), increased recurrent pregnancy loss (23 %), fetal loss beyond 22 weeks gestation (25 %), a higher prevalence of autoimmune diseases (14 %), and a recurrence rate of 30 % in subsequent pregnancies. Moreover, individuals with CIUE had higher rates of pregnancy complications, including gestational hypertension (19 %), intrauterine growth restriction (45 %), and preterm births (43 %). No significant improvement in live birth rate was observed among treated CIUE patients; however, caution is warranted when interpreting these findings due to the limited sample size. Future research in CIUE is crucial given its rarity and complexity., Competing Interests: Declaration of Competing Interest Dr. Mohamed A. Bedaiwy: Research grants from Canadian Institutes of Health Research (CIHR) and Ferring Pharmaceutical. He is on the advisory board for AbbVie, Pfizer, and Baxter. Other authors do not have any declarations of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Context.—: Case reports and rare case series have demonstrated variable placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In rare small studies demonstrating infection of the placental parenchyma, histologic manifestations have included variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and syncytiotrophoblast necrosis., Objective.—: To characterize the placental pathologic features of SARS-CoV-2-infected placentas, irrespective of fetal-maternal transmission, and to examine the frequency of C4d activation in such cases., Design.—: A retrospective study of 7 placentas from mothers with active SARS-CoV-2 infection and placental infection as demonstrated by RNA in situ hybridization was conducted., Results.—: There were 6 placentas from live-born neonates (5 singletons, 1 nonfused diamniotic-dichorionic twin placenta), and 1 was from a stillbirth. A total of 5 of the 8 neonates (including the stillbirth) tested negative for SARS-CoV-2, and all were negative for neonatal infection. The remaining 3 neonates were well at time of discharge. All placentas were positive for SARS-CoV-2 infection by RNA in situ hybridization and demonstrated variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. Three cases demonstrated features of fetal vascular malperfusion. CD68 highlighted intervillous histiocytes. C4d expression was present along the villous borders in 6 of 7 cases., Conclusions.—: SARS-CoV-2 placentitis is defined by the triad of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. The features may occur in cases without confirmed transplacental transmission. The damage caused by SARS-CoV-2 placentitis is likely mediated by complement activation.

A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB.

Background: Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum -infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria., Methods: We used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea., Results: The machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria., Conclusions: We have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria., Funding: This study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975)., Competing Interests: EA, TD, AO, AA, WH, SD, HU, MO, MN, AS, JS, SK, PH, BW, JS, AC, SR No competing interests declared, (© 2021, Aitken et al.)

Introduction: Pregnant women have an increased risk of P. falciparum infection, which is associated with low birth weight and preterm delivery. VAR2CSA, a variant surface antigen expressed on the parasitized erythrocyte surface, enables sequestration in the placenta. Few studies have prospectively examined relationships between antibody responses during pregnancy and subsequent adverse birth outcomes, and there are limited data outside Africa., Methods: Levels of IgG against VAR2CSA domains (DBL3; DBL5) and a VAR2CSA-expressing placental-binding P. falciparum isolate (PfCS2-IE) were measured in 301 women enrolled at their first visit to antenatal care which occurred mid-pregnancy (median = 26 weeks, lower and upper quartiles = 22, 28). Associations between antibody levels at enrolment and placental infection, birthweight and estimated gestational age at delivery were assessed by linear and logistic regression with adjustment for confounders. For all outcomes, effect modification by gravidity and peripheral blood P. falciparum infection at enrolment was assessed., Results: Among women who had acquired P. falciparum infection at enrolment, those with higher levels of VAR2CSA antibodies (75 th percentile) had infants with higher mean birthweight (estimates varied from +35g to +149g depending on antibody response) and reduced adjusted odds of placental infection (aOR estimates varied from 0.17 to 0.80), relative to women with lower levels (25 th percentile) of VAR2CSA antibodies. However, among women who had not acquired an infection at enrolment, higher VAR2CSA antibodies were associated with increased odds of placental infection (aOR estimates varied from 1.10 to 2.24)., Conclusions: When infected by mid-pregnancy, a better immune response to VAR2CSA-expressing parasites may contribute to protecting against adverse pregnancy outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 McLean, Opi, Stanisic, Cutts, Feng, Ura, Mueller, Rogerson, Beeson and Fowkes.)

Problem: Ascending placentitis is the leading cause of abortion in the horse. Interleukin (IL)-6 is considered predictive of placental infection in other species, but little is understood regarding its role in the pathophysiology of ascending placentitis., Method of Study: Sub-acute ascending placentitis was induced via trans-cervical inoculation of S zooepidemicus, and various fluids/serum/tissues collected 8 days later. Concentrations of IL-6 were detected within fetal fluids and serum in inoculated (n = 6) and control (n = 6) mares. RNASeq was performed on the placenta (endometrium and chorioallantois) to assess transcripts relating to IL-6 pathways. IHC was performed for immunolocalization of IL-6 receptor (IL-6R) in the placenta., Results: IL-6 concentrations increased in allantoic fluid following inoculation, with a trend toward an increase in amniotic fluid. Maternal serum IL-6 was increased in inoculated animals, while no changes were noted in fetal serum. mRNA expression of IL-6-related transcripts within the chorioallantois indicates that IL-6 is activating the classical JAK/STAT pathway, thereby acting as anti-inflammatory, anti-apoptotic, and pro-survival. The IL-6R was expressed within the chorioallantois, indicating a paracrine signaling pathway of maternal IL-6 to fetal IL-6R., Conclusion: IL-6 plays a crucial role in the placental response to induction of sub-acute equine ascending placentitis, and this could be noted in amniotic fluid, allantoic fluid, and maternal serum. Additionally, IL-6 is acting as anti-inflammatory in this disease, potentially altering disease progression, impeding abortion signals, and assisting with the production of a viable neonate., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2020 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Objectives: Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity., Methods: A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study., Results: Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005)., Conclusions: Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

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., (Copyright © 2020 Goldstein, Gallagher, Beck, Kumar and Gernand.)

Introduction: the objective of this study was to evaluate the incidence of Chronic Intervillositis of Unknown Etiology (CIUE) at our institution and to report on the pregnancy outcomes based on severity of lesions., Methods: retrospective cohort study including 29 889 perinatal specimens from 27 968 patients. The pathology database at our institution was queried for the keywords "intervillositis" and "CIUE" between February 2006 and April 2019. Histology was re-examined using a standardized diagnostic criterion to confirm diagnosis. Cases in which diagnosis was confirmed were categorized as low grade (5-49% intervillous space involvement) or high grade (≥50% involvement). Interventions and pregnancy outcomes were recorded., Results: The overall prevalence of CIUE is 0.17% (47 of 27 968 patients), with significantly higher prevalence in 1st trimester products of conception compared with 2nd and 3rd trimester specimens (0.38% vs 0.09%; p < 0.0001). A total of 97 specimens were initially diagnosed with chronic intervillositis. 56 out of 97 (57.7%) specimens met our diagnostic criteria for CIUE on review. Pregnancies with confirmed CIUE had significantly higher rates of pregnancy loss compared with pregnancies with chronic intervillositis not meeting our study criteria for CIUE (94% vs 71%; p = 0.003). Pregnancy loss between low grade (42.9%; 24 out of 56 cases of CIUE) and high grade (57.1%; 32 out of 56 cases) CIUE were not significantly different., Discussion: CIUE prevalence is low at 0.17%, but it is associated with pregnancy loss, particularly in the first trimester. High grade disease may be associated with worse pregnancy outcomes than low grade disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Preeclampsia is a multifactorial hypertensive disorder of pregnancy, with variable presentation in both maternal and fetal factors, such that no treatment or marker is currently universal to all cases. Here, we demonstrate that the prothrombinase and immunomodulatory secreted factor FGL-2 (fibrinogen-like protein 2) is differentially expressed across previously characterized gene expression clusters containing clinically relevant disease subtypes. FGL2 is low in a cluster consistent with the traditional paradigm of the pathology of preeclampsia (canonical preeclampsia) and high in a cluster exhibiting evidence of immune activation (immunological preeclampsia). We show that it is part of an immunoregulatory gene module integral to the transcriptional profile and placental pathology specific to immunological preeclampsia. We determine that FGL2 associates positively with chronic inflammation lesions of the placenta while associating negatively with maternal vascular malperfusion lesions. The transcriptional profiles of maternal vascular malperfusion lesions show downregulation of FGL2 and upregulation of previously investigated preeclampsia biomarkers, such as FLT1 (Fms Related Receptor Tyrosine Kinase 1) and ENG (endoglin). Conversely, the profiles of chronic inflammation lesions show an interesting downregulation of these genes, but an upregulation of FGL2 and of FGL2 -correlated immunoregulatory genes, suggesting it is upregulated downstream of major inflammatory mediators such as TNF (tumor necrosis factor)-α and IFN (interferon)-γ, hallmarks of the immunological preeclampsia subtype. This work, overall, demonstrates that FGL-2 expression levels in the term placenta reflect the unique pathophysiology that leads to immunological preeclampsia, leading to its potential as a subtype-specific biomarker.

During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8 + T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis-placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide, affecting 2-8% of all pregnancies. Studies suggest a link between complement activation and preeclampsia. The complement system plays an essential role in the innate immunity, leading to opsonization, inflammation, and elimination of potential pathogens. The complement system also provides a link between innate and adaptive immunity and clearance of immune complexes and apoptotic cells. During pregnancy there is increased activity of the complement system systemically. However, locally at the placenta, complement inhibition is crucial for the maintenance of a normal pregnancy. Inappropriate or excessive activation of the complement system at the placenta is likely involved in placental dysfunction, and is in turn associated with pregnancy complications like preeclampsia. Therefore, modulation of the complement system could be a potential therapeutic target to prevent pregnancy complications such as preeclampsia. This review, based on a systematic literature search, gives an overview of the complement system and its activation locally in the placenta and systemically during healthy pregnancies and during complicated pregnancies, with a focus on preeclampsia. Furthermore, this review describes results of animal and human studies with a focus on the complement system in pregnancy, and the role of the complement system in placental dysfunction. Various clinical and animal studies provide evidence that dysregulation of the complement system is associated with placental dysfunction and therefore with preeclampsia. Several drugs are used for prevention and treatment of preeclampsia in humans and animal models, and some of these drugs work through complement modulation. Therefore, this review further discusses these studies examining pharmaceutical interventions as treatment for preeclampsia. These observations will help direct research to generate new target options for prevention and treatment of preeclampsia, which include direct and indirect modulation of the complement system., (Copyright © 2020 Pierik, Prins, van Goor, Dekker, Daha, Seelen and Scherjon.)

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

Introduction: Chronic histiocytic intervillositis of unknown etiology (CIUE) is a non-infectious, most probably immunologic placenta lesion. CIUE is associated with recurrent miscarriage, intrauterine growth restriction and stillbirth. Among the pathologic-anatomic defined placental lesions this entity displays the highest risk of recurrence in following pregnancies (about 67-100%). The histiocytic cells accumulate in the placental blood space but do not infiltrate into the villi or decidua. Sparsely known is the expression profile of these intervillous cells regarding histiocytic markers., Methods: We analysed 5-22 markers by immunohistochemistry in a total of 41 placenta samples and evaluated decidual, villous and intervillous histiocytic cells., Results: In CIUE, intervillous CD163 +  histiocytes over-express CD11c/CD18 and down-regulate CD206/CD209, while CD163 +  decidual and Hofbauer cells show low CD11c/CD18 and higher CD206/CD209 protein expressions., Discussion: CD163 expression indicates a M2-like polarisation. CD11c and CD18 form the complement receptor 4 which could be related to a complement mediated trigger for aberrant cell accumulation in CIUE., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Placental inflammation increases the risk of adverse pregnancy outcomes and possibly neurodevelopmental disorders in the offspring. Previous research suggests it may be possible to modulate the placental immune response to bacteria to favor an anti-inflammatory phenotype with dietary factors. Sulforaphane (SFN) is a dietary supplement with known anti-inflammatory activities, however, its effects on placental cytokine production are unclear. Therefore, we evaluated the effects of SFN on biomarkers of inflammation and neurodevelopment under basal conditions and a setting of mild infection. Placental explant cultures were established and treated with up to 10 μM SFN in the presence and absence of 10 7 CFU/ml heat-killed E. coli. Concentrations of IL-1β, TNF-α, IL-6, sgp130, HO-1 and BDNF in conditioned medium were quantified by immunoassay. SFN increased antioxidant HO-1 expression in the absence, but not the presence, of infection. SFN inhibited IL-1β and IL-10, but tended to promote, TNF-α production by bacteria-stimulated cultures. IL-6 and BDNF were inhibited by SFN irrespective of co-treatment with E.coli. A negative regulator of IL-6 signaling, sgp130, was increased by SFN under basal conditions, but not in E. coli-stimulated cultures. These results suggest that SFN has mixed effects on the placenta inhibiting both pro-inflammatory (IL-1β) and anti-inflammatory factors (IL-10) but promoting regulators of oxidative stress and inflammation (HO-1 and sgp130) in an infection-dependent manner., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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

Antiphospholipid syndrome is defined by the presence of thrombosis and/or obstetrical adverse events (≥3 recurrent early miscarriage or fetal death or a prematurity<34 weeks of gestation) associated with persistent antiphospholipid antibodies. The pregnancy outcome has been improved by the conventional treatment (aspirin 100mg/day with low molecular weight heparin [LMWH] from 30 to 75% of uncomplicated pregnancies. In PROMISSE study, 19% of pregnancies had at least one obstetrical adverse event despite treatment (maternal, fetal or neonatal complications) in relation with APS. In the European registry of babies born from APS mothers, maternal and foetal adverse events were observed in 13% of cases, with prematurity in 14% despite treatment. The presence of lupus erythematosus, a history of thrombosis, presence of lupus anticoagulant and APL triple positivity are considered as factors associated with unfavorable obstetrical outcome. Hydroxychloroquine (HCQ) has anti-inflammatory and anti-thrombotic properties. Studies in vitro have shown that HCQ is able to restore the placental expression of Annexin V, which has an anticoagulant effect and to prevent the placental injury induced by APL. HCQ used for lupus erythematosus decrease the thrombotic risk and its value for thrombotic APS has been raised in an open labelled French study. In European retrospective study, the addition of HCQ to conventional treatment improved refractory obstetrical APS. Its use during the pregnancy of patients with lupus erythematosus, the evidence of good safety during the pregnancy and follow-up of children born to mothers exposed to HCQ demonstrate an overall good safety profile for mothers and the fetus. This clinical trial is designed to assess the interest of the addition of hydroxychloroquine to conventional treatment in APS during the pregnancy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Villitis of unknown etiology is an inflammatory placental condition associated with adverse pregnancy outcomes, including fetal growth restriction and preterm birth., Case: We describe maternal pyrexia with daily rigors in the third trimester of two consecutive pregnancies in the same woman. In her second pregnancy, we found no evidence of infection despite an extensive antenatal investigation (blood and urine cultures, serologies, chest X-ray, abdominal ultrasonogram, echocardiogram). The fetus was closely monitored for growth and well-being until spontaneous labor ensued at 36 weeks of gestation, followed by the birth of a vigorous female neonate who weighed 2.235 kg and was healthy. Placental pathology was consistent with villitis of unknown etiology and displayed more prominent abscess formation than is usually described. The patient's first pregnancy 4 years previously followed a similar but milder pattern, without preterm delivery but with similar placental pathology., Conclusion: Maternal pyrexia in both pregnancies was ultimately attributed to placental inflammation secondary to a maternal immunologic response to the fetal-placental unit. A placental origin for maternal pyrexia should be considered in cases in which a maternal cause cannot be identified and the pregnancy managed in light of the possible association with adverse fetal outcomes.

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., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2016 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of decidual-trophoblast interaction, regulation of trophoblast invasion, immune cells at the maternal-fetal interface, and placental inflammation., (Copyright © 2017 IFPA, Elsevier Ltd. Published by Elsevier Ltd.. All rights reserved.)

Bidirectional transplacental exchange characterizes human pregnancy. Cells exchanged between mother and fetus can durably persist as microchimerism and may have both short- and long-term consequences for the recipient. The amount, type, and persistence of microchimerism are influenced by obstetric characteristics, pregnancy complications, exposures to infection, and other factors. A reproductive-aged woman enters pregnancy harboring previously acquired microchimeric "grafts," which may influence her preconception health and her subsequent pregnancy outcomes. Many questions remain to be answered about microchimerism with broad-ranging implications. This review will summarize key aspects of this field of research and propose important questions to be addressed moving forward., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In human pregnancy the maternal immune system plays a critical role in the regulation of many aspects of human reproduction including implantation, placentation and defence against infection. Interest has been focussed on the role of uterine natural killer cells (uNK) in the maternal decidua whereas effector CD4+ and CD8+ T cells have received much less attention despite the observation that they represent a major proportion of decidual leucocytes in the latter phase of pregnancy. A range of recent studies have demonstrated that human decidual T cells are highly differentiated, express a range of cytokines and cytotoxic markers, and demonstrate a unique transcriptional profile characterized by high level expression of genes involved in interferon-signalling. Moreover, subpopulations of effector T cells demonstrate specificity for fetal tissue and are regulated through expression of inhibitory checkpoint proteins and T regulatory cells. Nevertheless, many questions remain to be answered, such as the potential role of maternal effector T cells in either supporting successful pregnancy or potentially clearing fetal cells that have entered the maternal circulation. In addition, there is an increasing interest in the role of maternal effector T cells in the pathogenesis of disorders such as chronic villitis miscarriage, stillbirth, fetal growth restriction and pre-eclampsia. Current debates in relation to these questions will be discussed within this review., (Copyright © 2017. Published by Elsevier Ltd.)

Introduction: Placental histologic examination can assist in revealing the mechanism leading to preterm birth. Accumulating evidence suggests an association between intrauterine pathological processes, morbidity and mortality of premature infants, and their long term outcome. Neonatal brain activity is increasingly monitored in neonatal intensive care units by amplitude integrated EEG (aEEG) and indices of background activity and sleep cycling patterns were correlated with long term outcome. We hypothesized an association between types of placental lesions and abnormal neonatal aEEG patterns., Objective: To determine the association between the placental lesions observed in extreme preterm deliveries, and their neonatal aEEG patterns and survival., Patients and Methods: This prospective cohort study included extreme premature infants, who were born ≤ 28 weeks of gestation, their placentas were available for histologic examination, and had a continues aEEG, soon after birth)n = 34). Infants and maternal clinical data were collected. aEEG data was assessed for percentage of depressed daily activity in the first 3 days of life and for sleep cycling. Associations of placental histology with clinical findings and aEEG activity were explored using parametric and non-parametric statistics., Results: Twenty two out of the 34 newborns survived to discharge. Preterm prelabor rupture of membranes (PPROM) or chorioamnionitis were associated with placental lesions consistent with fetal amniotic fluid infection (AFI) or maternal under perfusion (MUP) (P < 0.05). Lesions consistent with fetal response to AFI were associated with absence of SWC pattern during the 1st day of life. Fetal-vascular-thrombo-occlusive lesions of inflammatory type were negatively associated with depressed cerebral activity during the 1st day of life, and with aEEG cycling during the 2nd day of life (P<0.05). Placental lesions associated with MUP were associated with depressed neonatal cerebral activity during the first 3 days of life (P = 0.007)., Conclusions: Depressed neonatal aEEG patterns are associated with placental lesions consistent with maternal under perfusion, and amniotic fluid infection of fetal type, but not with fetal thrombo-oclusive vascular disease of inflammatory type. Our findings highlight the association between the intrauterine mechanisms leading to preterm parturition and subsequent depressed neonatal cerebral function early after birth, which eventually may put premature infants at risk for abnormal neurodevelopmental outcome.

Background: In malaria-endemic areas, the first exposure to malaria antigens often occurs in utero when the fetal immune system is poised towards the development of tolerance. Children exposed to placental malaria have an increased risk of clinical malaria in the first few years of life compared to unexposed children. Recent work has suggested the potential of pregnancy-associated malaria to induce immune tolerance in children living in malaria-endemic areas. A study was completed to evaluate the effect of malaria exposure during pregnancy on fetal immune tolerance and effector responses., Methods: Using cord blood samples from a cohort of mother-infant pairs followed from early in pregnancy until delivery, flow cytometry analysis was completed to assess the relationship between pregnancy-associated malaria and fetal cord blood CD4 and dendritic cell phenotypes., Results: Cord blood FoxP3 + T reg counts were higher in infants born to mothers with Plasmodium parasitaemia early in pregnancy (12-20 weeks of gestation; p = 0.048), but there was no association between T reg counts and the presence of parasites in the placenta at the time of delivery (by loop-mediated isothermal amplification (LAMP); p = 0.810). In contrast, higher frequencies of activated CD4 T cells (CD25 + FoxP3 - CD127 + ) were observed in the cord blood of neonates with active placental Plasmodium infection at the time of delivery (p = 0.035). This population exhibited evidence of effector memory differentiation, suggesting priming of effector T cells in utero. Lastly, myeloid dendritic cells were higher in the cord blood of infants with histopathologic evidence of placental malaria (p < 0.0001)., Conclusion: Together, these data indicate that in utero exposure to malaria drives expansion of both regulatory and effector T cells in the fetus, and that the timing of this exposure has a pivotal role in determining the polarization of the fetal immune response.

Background: Placental malaria is caused by Plasmodium falciparum-infected erythrocytes (IEs) that surface-express VAR2CSA and bind chondroitin sulfate A. The inflammatory response to placenta-sequestered parasites is associated with poor pregnancy outcomes, and protection may be mediated in part by VAR2CSA antibodies that block placental IE adhesion., Methods: In this study, we used a new approach to assess VAR2CSA domains for functional epitopes recognized by naturally acquired antibodies. Antigen-specific immunoglobulin (Ig) G targeting Duffy binding-like (DBL) domains from different alleles were sequentially purified from plasma pooled from multigravid women and then characterized using enzyme-linked immunosorbent assay, flow cytometry, and antiadhesion assays., Results: Different DBL domain-specific IgGs could react to homologous as well as heterologous antigens and parasites, suggesting that conserved epitopes are shared between allelic variants. Homologous blocking of IE binding was observed with ID1-DBL2-ID2a-, DBL4-, and DBL5-specific IgG (range, 42%-75%), whereas partial cross-inhibition activity was observed with purified IgG specific to ID1-DBL2-ID2a and DBL4 antigens. Plasma retained broadly neutralizing activity after complete depletion of these VAR2CSA specificities., Conclusions: Broadly neutralizing antibodies of multigravidae are not depleted on VAR2CSA recombinant antigens, and hence development of VAR2CSA vaccines based on a single construct and variant might induce antibodies with limited broadly neutralizing activity., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Villitis of unknown etiology (VUE) is an enigmatic inflammatory condition of the placenta associated with fetal growth restriction and stillbirth. Greater understanding of this condition is essential to understand its contribution to adverse outcomes. Our aim was to identify and quantify the cells in VUE in cases of stillbirth and to characterize immune responses specific to this condition. Immunohistochemistry was performed on placentas from stillborn infants whose cause of death was recorded as VUE to identify CD45(+) leukocytes, CD163(+) macrophages, CD4(+) and CD8(+) T cells, neutrophils, and proinflammatory and anti-inflammatory cytokines. Images were quantified with HistoQuest software. CD45(+) leukocytes comprised 25% of cells in VUE lesions: macrophages (12%) and CD4 T cells (11%) being predominant cell types; CD8 T cells were observed in all lesions. Leukocytes and macrophages were increased throughout the placenta in stillbirths; pan-placental CD4(+) and CD8(+) T cells outside VUE lesions were increased in stillbirth with VUE. There was increased IL-2 and IL-12 and reduced IL-4 immunostaining in VUE lesions. Our results suggest VUE in stillbirth has a similar immune cell profile to live birth. Pan-placental macrophages, CD4 and CD8 T cells indicate a wider inflammatory response unrestricted to VUE lesions. The cytokine profile observed suggests a skew towards inappropriate Th1 immune responses. Full characterisation VUE lesion phenotype confirms its immunological origins and provides foundations to develop novel investigations., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to compare immunohistochemical expression of different T type lymphocytes in foci of villitis of placentae with villitis of unknown etiology (VUE) without and with preeclampsia (PE)., Methods: Fifty-four placentae were collected from women who had VUE with (N = 27) and without (N = 27) PE. Immunohistochemistry for types of T lymphocytes was performed on formalin fixed and paraffin-embedded sections by use of the CD3, CD4, FOXP3, CD25, CD8 and CD68 antibodies. All data analyses were done by R Development Core Team., Results: There was higher immunohistochemical CD4 positive T lymphocyte count and CD4 positive/CD8 positive ratio in placentae with VUE complicated with PE compared to control group., Conclusion: The higher immunohistochemical CD4 positive T lymphocyte count and CD4 positive/CD8 positive ratio in placentae with VUE complicated with PE could point to their role in ethiopathogenesis of PE.

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

The efficacy of mother-to-child placental transfer of antibodies specific to malaria blood stage antigens was investigated in the context of placental malaria infection, taking into account IgG specificity and maternal hypergammaglobulinemia. The impact of the resulting maternal antibody transfer on infections in infants up to the age of 6 months was also explored. This study showed that i) placental malaria was associated with a reduced placental transfer of total and specific IgG, ii) antibody placental transfer varied according to IgG specificity and iii) cord blood malaria IgG levels were similar in infants born to mothers with or without placental malaria. The number of malaria infections was negatively associated with maternal age, whereas it was not associated with the transfer of any malaria-specific IgG from the mother to the fetus. These results suggest that i) malaria-specific IgG may serve as a marker of maternal exposure but not as a useful marker of infant protection from malaria and ii) increasing maternal age contributes to diminishing febrile infections diagnosed in infants, perhaps by means of the transmission of an effective antibody response.

Placental malaria (PM) due to Plasmodium falciparum is a major cause of maternal, fetal and infant mortality, but the mechanisms of pathogenesis and protective immunity are relatively well-understood for this condition, providing a path for vaccine development. P. falciparum parasites bind to chondroitin sulfate A (CSA) to sequester in the placenta, and women become resistant over 1-2 pregnancies as they acquire antibodies that block adhesion to CSA. The protein VAR2CSA, a member of the PfEMP1 variant surface antigen family, mediates parasite adhesion to CSA, and is the leading target for a vaccine to prevent PM. Obstacles to PM vaccine development include the large size (∼ 350 kD), high cysteine content, and sequence variation of VAR2CSA. A number of approaches have been taken to identify the combination of VAR2CSA domains and alleles that can induce broadly active antibodies that block adhesion of heterologous parasite isolates to CSA. This review summarizes these approaches, which have examined VAR2CSA fragments for binding activity, antigenicity with naturally acquired antibodies, and immunogenicity in animals for inducing anti-adhesion or surface-reactive antibodies. Two products are expected to enter human clinical studies in the near future based on N-terminal VAR2CSA fragments that have high binding affinity for CSA, and additional proteins preferentially expressed by placental parasites are also being examined for their potential contribution to a PM vaccine., (Copyright © 2015. Published by Elsevier Ltd.)

Background: Antibodies (Ab) to VAR2CSA prevent Plasmodium falciparum-infected erythrocytes from sequestrating in the placenta, i.e., prevent placental malaria (PM). The specificity of Ab to VAR2CSA associated with absence of PM is unknown. Accordingly, differences in the specificity of Ab to VAR2CSA were compared between multigravidae with and without PM who had Ab to VAR2CSA., Methods: In a retrospective case-control study, plasma collected from Cameroonian multigravidae with (n = 96) and without (n = 324) PM were screened in 21 assays that measured antibody levels to full length VAR2CSA (FV2), individual VAR2CSA DBL domains, VAR2CSA domains from different genetic backgrounds (variants), as well as proportion of high avidity Ab to FV2., Results: Multigravidae with and without PM had similar levels of Ab to FV2, the six VAR2CSA DBL domains and different variants, while the proportion of high avidity Ab to FV2 was significantly higher in women without PM at delivery (p = 0.0030) compared to women with PM. In a logistic regression model adjusted for gravidity and age, the percentage of high avidity Ab to FV2 was associated with reduced likelihood of PM in multigravidae. A 5 % increase in proportion of high avidity Ab to FV2 was associated with a nearly 15 % lower likelihood of PM., Conclusion: Ab avidity to FV2 may be an important indicator of immunity to PM.

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

Objectives: Chronic intervillositis of unknown etiology (CIUE) is characterized by an intervillous infiltrate of mononuclear cells and a high recurrence rate of adverse obstetrical outcomes. The aim was to describe obstetrical history in patients with at least one event characterized by CIUE, and the possible impact of systematic investigation of an underlying autoimmune disease on the obstetrical outcome of subsequent pregnancies., Methods: We retrospectively reviewed all pregnancies in patients having experienced at least one adverse obstetric outcome associated with chronic intervillositis of unknown etiology diagnosed by placental histological analysis between 2004 and 2011 in our university hospital. For each patient, data pertaining to obstetrical history, treatments during pregnancies, the results of systematic investigation of an underlying autoimmune disease, and treatments as well as obstetrical outcome in subsequent pregnancies, were collected., Results: Twelve patients with 38 pregnancies were included [median age 30 (22; 40 years)]. Autoimmune disease or autoimmune antibodies (AID group) were found in 7/12 patients: primary antiphospholipid syndrome (APS) (n = 4), Sjögren's syndrome (n = 1), pernicious anemia (n = 1) and celiac disease (n = 1). When comparing pregnancies of patients with and without AID, there was no difference with regard to the type of obstetrical events or live-born babies, in spite of appropriate treatment. Corticosteroids (prednisone 10 mg/day) were used in only 2 cases with AID (Sjögren's syndrome and APS; n = 1 each), and these 2 pregnancies resulted in live-born babies., Conclusion: This study shows that the immunological assessment in patients with CIUE raises the possibility of a specific severity when AID or obstetrical APS is associated with CIUE, since conventional treatment did not improve obstetrical outcome in these patients as compared to those without autoimmune diseases. The benefit of immunosuppressant agents in this subset of patients needs further evaluation.

Introduction: Chronic villitis of unknown etiology (CVUE) and massive chronic intervillositis (MCI) are placental lesions associated with infiltration of mononuclear cells in the chorionic villi and the intervillous spaces, respectively. It is not well known whether immune cells in CVUE and MCI have similar phenotypic characteristics., Methods: A cross-sectional study of third trimester placentas was conducted to identify immune cell subpopulations in CVUE and MCI (n = 17/group). CVUE was diagnosed with H&E staining and antibody to CD3 in serial sections; and MCI, by the presence of massive infiltration of mononuclear cells in the intervillous spaces. Immune cells, ICAM-1 expression and nuclear factor κB (NF-κB) activation were determined immunohistochemically., Results: CVUE and MCI showed similar infiltrates, mainly CD68+ and CD3+ cells. Most cells (>80%) were CD45RB+, and one third were CD45RO+ in both lesions. There were slightly more CD8+ than CD4+ cells in both CVUE and MCI. More than 90% of cells in CVUE and MCI were ICAM-1+ with NFκB nuclear localization. Syncytiotrophoblast ICAM-1 expression was significantly (p < 0.001) higher in MCI (mean of 81.0; range of 71.6-86.0) than in CVUE (52.4; 36.4-59.4) or normal placentas (0.2; 0.0-0.6). Both, failure of physiologic transformation of spiral arteries and placental atherosclerosis-like lesions of atherosis were significantly more frequent in MCI than in CVUE or normal placentas (p = 0.044 and p = 0.007, respectively)., Discussion: These finding suggest that MCI and CVUE have very similar infiltration of immune cells although MCI has more severe placental lesions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Extracellular membrane vesicles (EVs) also termed microvesicles (MVs) are secreted from different cells, are present in the blood circulation under normal physiological conditions, and their levels increase in a wide range of disease states. EVs contain proteins, growth and apoptotic factors, DNA fragments, microRNAs as well as messenger RNAs (mRNAs); therefore, they may function as regulators in cell-cell communication and mediators of cell signaling during multiple biological processes. The current review focuses on the role of EVs in healthy pregnancy and gestational vascular complications and discusses the involvement of EVs in gene regulation, placental hemostasis and cell function that overall reflect the placental-maternal crosstalk., (© 2015 Elsevier Ltd. All rights reserved.)

Chronic histiocytic intervillositis of the placenta (CHI) shows monocytic/histiocytic infiltration of the intervillous space. Placental malaria has a CHI-like histopathology and induces an aberrant expression of Toll-like receptors (TLR) 3, 7-9. We hypothesized that, similar to placental malaria, CHI could be associated with increased TLR expression. TLR1-10 and other inflammation-associated factors were analyzed by real-time PCR and immunohistochemistry. A total of 31 formalin-fixed and paraffin-embedded placenta samples were evaluated: CHI (n = 9), and for control purposes, villitis of unknown etiology (VUE, n = 8) and placentas without inflammation (n = 14). CHI shows increased expression of monocytic TLR1, a receptor which is involved in bacterial lipopolysaccharide (LPS)-induced inflammation. This could indicate a TLR1-mediated immune mechanism in the placenta (e.g. triggered by transient, clinically inapparent maternal bacteraemia) which leads to massive monocytic/histiocytic accumulation in the intervillous space. The increased expression of TLR1 with no increased expression of TLR3 and TLR7-9 is different from that in malaria.

Viral infections in pregnancy are known to cause fetal malformation, growth restriction, and even fetal death. Macroscopic placental examination usually shows slight and unspecific changes. Histology may show secondary, non-specific tissue reaction, i.e. villitis with lymphocytic invasion. Primary specific morphology characteristics are known for some virus, like cytomegalovirus, parvovirus, and herpes simplex, however many viral infections show non-specific changes. Placenta relevant cells as human first trimester trophoblasts HTR8/SVneo, primary human umbilical vein endothelial cells (HUVEC), and primary human embryonic fibroblasts were examined following infection with commonly occurring virus like adenovirus and enterovirus. Morphology in routine stained sections and virus-specific immunostains were studied 4, 8, 24, 48, 72 h after infection. Nuclear enlargement was seen in the infected cells. A specific diagnosis of adenovirus or enterovirus infection, however, was not possible without specific immunostains., (© 2014 APMIS. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Problem: Currently, placentitis, an important cause of late pregnancy loss in mares, is diagnosed by clinical signs and ultrasonography. Acute phase proteins (APP) are mainly produced and secreted by the liver in response to acute inflammatory stimuli. We hypothesized that APP are increased in mares with placentitis., Method of Study: Concentrations of serum amyloid A (SAA), haptoglobin (Hp), fibrinogen (Fb), and white blood cell counts (WBC) were determined in plasma of mares with experimentally induced placentitis and gestationally age-matched control mares. Placentitis was induced via intracervical inoculation of Streptococcus equi subspecies zooepidemicus, a common isolate from clinical cases of bacterial placentitis. Concentrations of SAA and Hp were also determined in the 10 days pre-partum in normal mares., Results and Conclusion: Mares with placentitis aborted within 5-25 days after inoculation. Concentrations of SAA and Hp rapidly increased subsequent to experimental induction of placentitis and remained increased until abortion. Neither Fb nor WBC appeared to be useful markers for placentitis. Parturition did not trigger increase in either SAA or Hp in normal foaling mares., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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

After oral administration of ewes during mid gestation with 2000 freshly prepared sporulated oocysts of T. gondii isolate M4, abortions occurred between days 7 and 11 in 91.6% of pregnant and infected ewes. Afterwards, a further infection was carried out at late gestation in another group of sheep with 500 sporulated oocysts. Abortions happened again between days 9 and 11 post infection (pi) in 58.3% of the infected ewes. Classically, abortions in natural and experimental ovine toxoplasmosis usually occur one month after infection. Few experimental studies have reported the so-called acute phase abortions as early as 7 to 14 days after oral inoculation of oocysts, and pyrexia was proposed to be responsible for abortion, although the underline mechanism was not elucidated. In the present study, all placentas analysed from ewes suffering acute phase abortions showed infarcts and thrombosis in the caruncullar villi of the placentomes and ischemic lesions (periventricular leukomalacia) in the brain of some foetuses. The parasite was identified by PCR in samples from some placentomes of only one sheep, and no antigen was detected by immunohistochemical labelling. These findings suggest that the vascular lesions found in the placenta, and the consequent hypoxic damage to the foetus, could be associated to the occurrence of acute phase abortions. Although the pathogenesis of these lesions remains to be determined, the infectious dose or virulence of the isolate may play a role in their development.

Objectives: To describe placental pathological findings in late-onset small-for-gestational age (SGA) births for which Doppler signs of placental insufficiency are lacking., Methods: A series of placentas were evaluated from singleton pregnancies of SGA births (birth weight below the 10th percentile) delivered after 34 weeks with normal umbilical artery Doppler (pulsatility index below the 95th percentile), that were matched by gestational age with adequate-for-gestational age (AGA) controls. Using a hierarchical and standardized system, placental lesions were classified histologically as consequence of maternal underperfusion, fetal underperfusion or inflammation., Results: A total of 284 placentas were evaluated (142 SGA and 142 AGA). In the SGA group, 54.2% (77/142) of the placentas had weights below the 3rd percentile for GA while it was a 9.9% (14/142) in the AGA group (p < 0.001). Only 21.8% (31/142) of SGA placentas were free of histological abnormalities, while it was 74.6% (106/142) in the AGA group (p < 0.001). In the abnormal SGA placentas (111/142) there were a total of 161 lesions, attributable to MUP in 64% (103/161), FUP in 15.5% (25/161), and inflammation in 20.5% (33/161)., Discussion: In most placentas of term SGA neonates with normal UA Doppler histological abnormalities secondary to maternal underperfusion prevail, reflecting latent insufficiency in uteroplacental blood supply. This is consistent with the higher risk of adverse perinatal outcome reported in this population and underscores a need for new markers of placental disease., Conclusions: A significant proportion of late-onset SGA births with normal umbilical artery Doppler may still be explained by placental insufficiency., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Villitis of unknown etiology (VUE) represents a common placental inflammatory lesion, primarily, but not exclusively, identifiable T lymphocytes at term. Despite considerable evidence to contest that this simply represents a benign pathological finding, VUE remains a significantly undervalued diagnosis. Given its association with adverse pregnancy outcomes; including fetal growth restriction, preterm birth, and recurrent pregnancy loss, an increased awareness amongst clinician obstetricians is certainly warranted. The underlying immunopathogenesis of VUE remains uncertain. Despite initial theories that this represents an infectious placental lesion of undiagnosed pathogenic source, a more complex sequence of events involving the "breakdown" of maternal-fetal tolerance is emerging. Characterization of a unique inflammatory phenomenon in which both maternal and fetal T lymphocytes and Höfbauer cells interact has captivated particular research interest and has generated analogies to both the problems of allograft rejection and graft-versus-host disease (GvHD). Within the context of VUE, this review evaluates how disruption of the multidimensional immunological mechanisms underlying feto-maternal tolerance may permit abnormal lymphocyte infiltration into placental villi. We shall review the existing evidence for these events in VUE and outline areas of certain future interest., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS and affects women of childbearing age. Most patients with NMO have circulating Abs, termed NMO-IgG, against the astrocytic water channel protein aquaporin-4. In the CNS, NMO-IgG causes complement-mediated astrocyte damage, inflammatory cell infiltration, and myelin loss. In this study, we show that aquaporin-4 is expressed in the syncytiotrophoblast of human and mouse placenta. Placental aquaporin-4 expression is high during mid-gestation and progressively decreases with advancing pregnancy. Intraperitoneally injected NMO-IgG binds mouse placental aquaporin-4, activates coinjected human complement, and causes inflammatory cell infiltration into the placenta and placental necrosis. There was no damage to maternal organs that express aquaporin-4, including the brain, spinal cord, kidneys, and skeletal muscle. In control experiments, no placentitis was found in mice injected with NMO-IgG without complement, non-NMO-IgG with human complement, or in aquaporin-4 null mice injected with NMO-IgG and human complement. The infiltrating cells were primarily neutrophils with a few scattered eosinophils and macrophages. NMO-IgG and human complement-induced placentitis caused fetal death, but some fetuses were born normal when lower amounts of NMO-IgG and human complement were injected. Sivelestat, a neutrophil elastase inhibitor, and aquaporumab, a nonpathogenic IgG that competes with NMO-IgG for aquaporin-4 binding, significantly reduced NMO-IgG and human complement induced placentitis and fetal death. Our data suggest that NMO-IgG can cause miscarriage, thus challenging the concept that NMO affects only the CNS. These findings have implications for the management of NMO during pregnancy.

Problem: Chronic histiocytic intervillositis (CHIV) is a rare type of placental pathology that is associated with reproductive loss at all gestational ages. The aim of the study was to investigate the relationship between the severity of CHIV and the outcome of pregnancy and to compare the immune response between CHIV patients and controls to explore an immunological origin of CHIV., Method of Study: Microscopic slides were reviewed and scored according to a previously published grading system in 30 pregnancies of 22 CHIV patients. Partner-specific mixed lymphocyte reactions, cytotoxic T-lymphocyte precursor frequencies (CTLpf), and anti-HLA antibodies were determined in four patients and seven controls., Results: Higher CHIV scores are associated with worse pregnancy outcome. CHIV patients demonstrated a higher CTLpf against their partner compared to non-complicated pregnancies (P = 0.03). The CTLpf was extremely high in 75% of the patients. Antipaternal HLA antibodies were only present in 75% of the CHIV patients compared to none of the controls (P = 0.02)., Conclusion: CHIV scores seem to be associated with the severity of adverse pregnancy outcome. High antipaternal cellular (T-cell) and humoral (B-cell) response to partner-specific CTLpf and the presence of anti-HLA antibodies directed to the partner suggest an immunologic origin of CHIV., (© 2013 John Wiley & Sons Ltd.)

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