Immunomodulatory Therapy Reduces the Severity of Placental Lesions in Chronic Histiocytic Intervillositis

Abstract

Chronic histiocytic intervillositis (CHI) is a rare, but highly recurrent inflammatory placental lesion wherein maternal macrophages infiltrate the intervillous space. Pregnancies with CHI are at high risk of fetal growth restriction, miscarriage or stillbirth. Presently, the diagnosis can only be made after histopathological examination of the placenta. Given its proposed immunological etiology, current treatments include aspirin, heparin, and immunomodulatory agents. However, the rationale for these medications is largely based upon small case series and reports as there is a lack of larger studies investigating treatment efficacy. Therefore, this study sought to determine whether inclusion of immunomodulatory medications was effective at reducing the severity of lesions and improving pregnancy outcomes in subsequent pregnancies. Thirty-three women with a history of CHI in at least one pregnancy (index case) were identified retrospectively through medical records. Twenty-eight participants presented with a first subsequent pregnancy and a further 11 with a second subsequent pregnancy at a specialist clinic for pregnancy after loss. Data on maternal demographics, medical history, medication, pregnancy outcome, and placental pathology was collected and compared between pregnancies. Twenty-seven (69%) subsequent pregnancies were treated with at least one or both of prednisolone and hydroxychloroquine. Inclusion of at least one immunomodulatory agent in treatment regimen resulted in an almost 25% increase in overall livebirth rate (61.5 vs. 86.2%). In women treated with immunomodulatory medication a greater proportion of placentas had reduced severity of lesions compared to those treated without (86.7 vs. 33.3%, respectively). A reduction in CHI severity was associated with a 62.3% improvement in livebirth rate compared to those where severity remained unchanged in relation to the index case. These data provide preliminary evidence that the use of immunomodulatory medication in the management of CHI improves histopathological lesions and the chance of livebirth in subsequent pregnancies. Due to CHI's rarity and ethical and feasibility issues, randomized controlled trials in affected women are challenging to conduct. As a result, collaboration between centers is required in future to increase study sample sizes and elucidate the mechanisms of hydroxychloroquine and prednisolone in reducing pathology.

Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome

“…This combination significantly reduced histological severity of CHI: in the index pregnancy, 11/28 (39%) cases were mild, 11/28 (39%) were moderate and 6/28 (21%) were severe; whereas in subsequent pregnancies treated with prednisolone and/or hydroxychloroquine, CHI was absent in 18/30 (60%) and only severe in 2/30 (7%). It also translated into a non-significant trend towards higher rates of live birth in the prednisolone and/or hydroxychloroquine group, compared with those who received non-immunomodulatory treatment: 25/29 (86%) vs. 8/13 (62%), p=0.11 (179).…”

“…A large Canadian series analysed almost 30,000 placentas and reported a prevalence of 0.17% (10). However, CHI and VUE frequently coexist (179): in the first account of CHI published by Labarrere & Mullen in 1987, it was described as an "extreme variant" of VUE (17). Nowak et al, who reported outcomes from 76 cases of combined CHI-VUE, suggested that CHI might represent either a precursor lesion or a more aggressive variant of VUE (25).…”

“…The global stillbirth rate is estimated to have fallen by 35% since 2000 (218). Alongside this, increased obstetric surveillance and various forms of treatment for women with VUE, CHI and MPFD have become the norm in several countries and it is difficult to ascertain which of these, if any, lead to improved outcome (179).…”

“…Availability of specialist perinatal pathology services is subject to financial constraints and regional disparities, exacerbated by the recent COVID-19 pandemic. Many obstetric units use their own local eligibility criteria, with variable adherence (179,219,220). This makes accurate quantification of recurrence risk and patient counselling extremely challenging.…”

The Missing Role of Prenatal Diagnosis of Chronic Histiocytic Intervillositis in the Management of Growth Restricted Fetuses

“…Although evidence regarding therapeutic interventions for CHI are few and far between, a small number of studies have suggested that thromboprophylactic drugs, such as aspirin and heparin, as well agents targeting the immune system, including hydroxychloroquine and glucocorticoids, may be of therapeutic benefit which is consistent with immunologic origin of the disease and the potential role of anti-human platelet antigen antigen-1a in induction of low-grade CHI (8,9). For instance, hydroxychloroquine and prednisolone were associated with 62% improvement in live birth rate compared to untreated pregnancies (8). Furthermore, heterogenous combinations of all of the aforementioned agents in a multicenter study by Melkinian et al led to the increased number of live births from 32 to 67%.…”