Understanding the"paradox" of pregnancy remains a challenging field of investigation especially when immunological dysregulation is suspected in pathological pregnancies. Chronic histiocytic intervillositis (CHI) is an example of a rare placental inflammatory disease that can occur during any trimester of pregnancy. The pathogenesis of CHI involves an abnormal immune response characterized by an inflammatory infiltrate of maternal CD68+ mononuclear immune cells in the intervillous space. CHI may be associated with villous and intervillous fibrinoid deposits. The precise immunological mechanism is not yet fully understood; it probably relies on an allo-immune of graft rejection rather than an auto-immune mechanism, although it has been described in several autoimmune diseases. CHI has also been described in COVID19 infected pregnant women. The recurrence rate is high and complications are severe: CHI is strongly associated with fetal growth restriction, miscarriage and stillbirth. The management of these patients remains an issue lacking of -standardized guidelines. The aim of this narrative review is to focus on the knowledge, pathogenesis, diagnosis and treatment of CHI over the last 5 years.

Chronic histiocytic intervillositis of unknown origin (CHI) is a rare placental disorder associated with adverse pregnancy outcomes, frequent recurrence, and a lack of effective preventive strategies. Recent insights indicate a potential link between CHI-associated inflammatory lesions and the inflammasome pathway, suggesting innovative therapeutic avenues. Here we show a potential role of the inflammasome pathway in CHI through comprehensive transcriptomic analysis of grade 2 or 3 histopathologic CHI samples, paired with placental controls. Additionally, we present case studies of three individuals with recurrent CHI, who have undergone treatment with anakinra and colchicine throughout pregnancy, resulting in improved perinatal outcomes. Notably, all cases are characterized by the birth of healthy, full-term infants, with reduced or absent intervillositis recurrence. Placental assessment unveils heightened activation of the NLRP3-PYCARD inflammasome pathway and IL-1β processing in CHI samples, with downregulation observed in treated pregnancy samples, devoid of intervillositis. Collectively, these findings suggest a potential therapeutic role for targeting the inflammasome pathway in preventing recurrent CHI in pregnant individuals.

It is well-known that hydroxychloroquine (HCQ) treats malaria, systemic lupus erythematosus, and rheumatoid arthritis in women for its immunomodulatory and anti-inflammatory action. Additionally, HCQ was used in cases with refractory antiphospholipid syndrome. HCQ safety was reinforced in pregnant women owing to insignificant reports of adverse pregnancy outcomes and major congenital malformation. Recently, HCQ was tested in cases with chronic placental inflammation with a promising result of increased life birth; however, its benefit needs further validation. We aimed to highlight the recent updates for HCQ use in various conditions in pregnancy.

Villitis of unknown etiology (VUE) is an inflammatory disease characterized by the infiltration of maternal CD8 +T cells into the placental villi. Although the pathogenesis of VUE is still debated, dysregulation of the immune system appears to be an important factor in the development of the disease. Interaction of maternal T cells with the fetal antigens seems to be the trigger for the VUE onset. In this context, graft vs host disease (GVHD) and allographic rejection seem to share similarities in the VUE immunopathological mechanism, especially those related to immunoregulation. In this review, we compared the immunological characteristics of VUE with allograft rejection, and GVHD favoring a better knowledge of VUE pathogenesis that may contribute to VUE therapeutics strategies in the future.

Potential risks of treatment with hydroxychloroquine (HCQ) include QT interval prolongation, hypoglycemia, a wide range of neuropsychiatric manifestations, hematotoxicity, and potential genetic defects. HCQ is extremely toxic when used in overdose and can lead to tachycardia, hypotension, known central nervous system, transmission defects, hypokalemia and other manifestations in individuals. The mechanism of excessive HCQ leading to these manifestations is still unclear. In this paper, overdose HCQ at different concentrations was used to treat zebrafish embryos, and the phenomena like human beings were obtained, such as increased heart rate and nervous system inhibition. With the increase of concentration to 100 μM, embryo mortality and malformation rate increased and hatching rate decreased, in situ hybridization showed abnormal differentiation of embryo germ layers and formation of vital organs. We selected embryos treated with 50 μM HCQ, in which concentration the mortality rate, hatching rate and malformation rate of the embryos were like those of the control group, for transcriptome analysis. Although the above indexes did not change significantly, the molecular changes related to the development of the heart, eye, nerve and other important organs were significant. This study provides useful information for further research on the toxicity mechanism of HCQ overdose, and provides some insight that can guide future studies in humans.

Chronic histiocytic intervillositis (CHI) is a rare placental lesion with a high recurrence rate and poor perinatal outcomes. There are currently limited guidelines regarding the diagnosis of this condition in the index pregnancy and treatment where recurrence is suspected.

The primary objective of this systematic review and meta-analysis was to determine the perinatal outcomes of pregnancies affected by chronic histiocytic intervillositis and to what extent they can be improved with treatment. The secondary objective was to assess the relationship between CHI lesion severity and pregnancy loss.

A systematic search of Ovid Embase, Web of Science, Science Direct, PubMed, Ovid Medline, Google Scholar and CINAHL was carried out. Case reports, cohort, case-control and randomised controlled trials (RCT) detailing the perinatal outcomes of CHI pregnancies, both treated and untreated, were included.

No RCTs were identified. However, in a review population of 659 pregnancies, with additional 7 in case reports, CHI treatments included aspirin, prednisone, prednisolone, low molecular weight heparin (LMWH), hydroxychloroquine and adalimumab. A descriptive synthesis of data found mixed results for treatments in relation to live birth, miscarriage and fetal growth restriction outcomes. Furthermore, quantitative synthesis of 38 pregnancies revealed a non-significant improvement in live birth rate with CHI targeted treatment (OR 1.79 [95% CI 0.33-9.61] (p=0.50), while meta-analysis of CHI severity in line with pregnancy loss, in a sample of 231 pregnancies, revealed lower odds of pregnancy loss with less severe lesions (OR: 0.17 [0.03-0.80], p=0.03).

This systematic review and meta-analysis reinforce notions surrounding the insufficient evidence for CHI treatment. It also strengthens previous hypotheses detailing the positive association between CHI lesion severity and odds of pregnancy loss. Aspirin, LMWH, prednisolone, hydroxychloroquine and adalimumab are candidates with varying levels of weak to moderate evidence supporting their use. Further prospective research is required to obtain robust evidence pertaining to treatment safety and efficacy and optimal drug regimes.

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