Identification of a unique intervillous cellular signature in chronic histiocytic intervillositis.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta characterized by an infiltrate of CD68+ cells in the intervillous space. CHI is associated with adverse pregnancy outcomes such as miscarriage, fetal growth restriction, and (late) intrauterine fetal death. The adverse pregnancy outcomes and a variable recurrence rate of 25-100% underline its clinical relevance. The pathophysiologic mechanism of CHI is unclear, but it appears to be immunologically driven. The aim of this study was to obtain a better understanding of the phenotype of the cellular infiltrate in CHI. METHOD: We used imaging mass cytometry to achieve in-depth visualization of the intervillous maternal immune cells and investigated their spatial orientation in situ in relation to the fetal syncytiotrophoblast. RESULTS: We found three phenotypically distinct CD68+HLA-DR+CD38+ cell clusters that were unique for CHI. Additionally, syncytiotrophoblast cells in the vicinity of these CD68+HLA-DR+CD38+ cells showed decreased expression of the immunosuppressive enzyme CD39. DISCUSSION: The current results provide novel insight into the phenotype of CD68+ cells in CHI. The identification of unique CD68+ cell clusters will allow more detailed analysis of their function and could result in novel therapeutic targets for CHI.

The effect of antenatal corticosteroid use on offspring cardiovascular function: A systematic review.

BACKGROUND: Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short-term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. OBJECTIVES: To systematically review the human clinical literature to determine the effects of ACS on offspring cardiovascular function. SEARCH STRATEGY: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE, EMBASE and Cochrane databases. SELECTION CRITERIA: Offspring who had been exposed to ACS during fetal life, in comparison with those not receiving steroids, those receiving a placebo or population data, were included. Studies not performed in humans or that did not assess cardiovascular function were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently screened the studies, extracted the data and assessed the quality of the studies. Results were combined descriptively and analysed using a standardised Excel form. MAIN RESULTS: Twenty-six studies including 1921 patients were included, most of which were cohort studies of mixed quality. The type of ACS exposure, gestational age at exposure, dose and number of administrations varied widely. Offspring cardiovascular outcomes were assessed from 1 day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (eight studies), heart rate (five studies), electrocardiogram (ECG, three studies) and cardiac magnetic resonance imaging (MRI, one study). There were no clinically significant effects of ACS exposure on offspring blood pressure. However, there were insufficient studies assessing cardiac structure and function using echocardiography or cardiac MRI to be able to determine an effect. CONCLUSIONS: The administration of ACS is not associated with long-term effects on blood pressure in exposed human offspring. The effects on cardiac structure and other measures of cardiac function were unclear because of the small number, heterogeneity and mixed quality of the studies. Given the preclinical and human evidence of potential harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS.

Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome.

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 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.

One-Sided Chronic Intervillositis of Unknown Etiology in Dizygotic Twins: A Description of 3 Cases.

Chronic intervillositis of unknown etiology (CIUE) is a rare, poorly understood, histopathological diagnosis of the placenta that is frequently accompanied by adverse pregnancy outcomes including miscarriage, fetal growth restriction, and intrauterine fetal death. CIUE is thought to have an immunologically driven pathophysiology and may be related to human leukocyte antigen mismatches between the mother and the fetus. Dizygotic twins with one-sided CIUE provide an interesting context to study the influence of immunogenetic differences in such cases. The main immune-cell subsets were investigated using immunohistochemistry. We identified three dizygotic twin pregnancies in which CIUE was present in only one of the two placentas. Two of the pregnancies ended in term delivery and one ended in preterm delivery. Presence of CIUE was correlated with lower placental weight and lower birthweight. Relative number of CD68, CD56, CD20, and CD3 positive cells were comparable between co-twins. The presence of one-sided CIUE in dizygotic twin pregnancy was associated with selective growth restriction in the affected twin. This suggests a unique fetal immunogenetic contribution to the pathogenesis of CIUE. Further study of dizygotic and monozygotic placentas affected by CIUE could identify new insights into its pathophysiology and into the field of reproductive immunology.

Monochorionic twins discordant for trisomy 13: A case report, systematic literature search and synthesis of available evidence.

This article presents the tenth reported case of monochorionic twins discordant for trisomy 13. Discordant aneuploidies in monochorionic twins are rare. Aetiologies include mitotic error in early cell division and "rescue" chromosome loss in an initially trisomic zygote. Clinicians should offer early amniocentesis of both sacs and consider selective termination.

Innate Immune Responses to Acute Viral Infection During Pregnancy.

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.

Improving access to contraception through integration of family planning services into a multidrug-resistant tuberculosis treatment programme.

OBJECTIVES: Multidrug-resistant tuberculosis (MDR-TB) is a global public health priority. The advent of the World Health Organisation's Short Course regimen for MDR-TB, which halves treatment duration, has transformed outcomes and treatment acceptability for affected patients. Bedaquiline, a cornerstone of the Short Course regimen, has unknown teratogenicity and the WHO therefore recommends reliable contraception for all female MDR-TB patients in order to secure eligibility for bedaquiline. We were concerned that low contraceptive uptake among female patients in our rural South African MDR-TB treatment programme could jeopardise their access to bedaquiline. We therefore conducted a service delivery improvement project that aimed to audit contraceptive use in female MDR-TB patients, integrate family planning services into MDR-TB care, and increase the proportion of female patients eligible for bedaquiline therapy. METHODS: Contraceptive use and pregnancy rates were audited in all female patients aged 13-50 years initiated on our MDR-TB treatment programme in 2016. We then implemented an intervention consisting of procurement of depot-medroxyprogesterone acetate (DMPA) for the MDR-TB unit and training of specialist MDR-TB nurses in administration of DMPA. The audit cycle was repeated for all female patients aged 13-50 years initiated on the programme in January-October 2017 (post-intervention). RESULTS: The proportion of women on injectable contraceptives by the time of MDR-TB treatment initiation increased significantly in the post-intervention cohort (77.4% vs 23.9%, p<0.0001). CONCLUSION: By integrating contraceptive services into our MDR-TB programme we significantly increased contraceptive uptake, protecting women from the obstetric risks associated with pregnancy during MDR-TB treatment and maximising their eligibility for bedaquiline therapy.