C4d Staining Is Present in Normal Placentas From Pregnancies Prior to Pregnancy Loss Associated With Chronic Histiocytic Intervillositis and Is Reduced by Immunomodulatory Therapy in Subsequent Pregnancies

Abstract

Introduction: Chronic histiocytic intervillositis (CHI) is associated with adverse pregnancy outcomes and high recurrence risk. Recent studies suggest that CHI may represent a host-vs-graft rejection, and that C4d immunostain can be used as a marker for complement activation and antibody-mediated rejection in CHI. Materials and Methods: This retrospective cohort study focused on 5 fetal autopsy cases associated with CHI (5 index cases) from 5 women. We analyzed placentas from the index cases (fetal autopsy cases associated with CHI) and placentas from the women’s previous and subsequent pregnancies. We assessed the presence and extent of CHI and C4d immunostaining in these placentas. We evaluated each available placenta and graded the severity of CHI as either <50% or ≥50%. Additionally, we conducted C4d immunostaining on one representative section from each placenta and graded the staining levels as follows: 0+ for staining <5%; 1+ for staining between 5% and <25%; 2+ for staining between 25% and <75%; and 3+ for staining ≥75%. Results: Three of the 5 women had pregnancies prior to their index cases (fetal autopsy cases associated with CHI). Despite the absence of CHI in their initial pregnancies, the placentas displayed positive C4d staining with grades of 1+, 3+, and 3+, respectively. These results suggest the presence of complement activation and antibody-mediated rejection in placentas from their prior pregnancies without CHI. Three of the 5 women received immunomodulatory therapy after experiencing pregnancy losses associated with CHI. After treatment, 2 of these women had live births at 35 and 37 gestational weeks, respectively, while the third had a stillbirth at 25 gestational weeks. The severity of CHI and the degree of C4d staining in the placentas decreased in all 3 cases following immunomodulatory therapies. Specifically, the level of C4d staining decreased from 3+ to 2+, 2+ to 0+, and 3+ to 1+ in these 3 cases, respectively. Discussion: In women with a history of recurrent pregnancy loss associated with CHI, C4d immunostaining was present in the placentas from their initial non-CHI pregnancies, suggesting activation of the classical complement pathway and antibody-mediated reaction before the development of CHI in subsequent pregnancies. Immunomodulatory therapy may improve pregnancy outcomes by reducing complement activation, as shown by the reduction of C4d immunopositivity in the placentas after immunomodulatory treatment. Although we believe that the study provides valuable insights, we acknowledge that there are limitations to the findings. Therefore, to further elucidate the pathogenesis of CHI, additional research efforts with a collaborative and multidisciplinary approach are necessary.

Scoping Review of Maternal Monocytes and the Syncytiotrophoblast: Bi-Directional Communication in the Intervillous Space

“…As monocytes have the capacity to bind to the ICAM-1 ligand 39 , an increase in ICAM-1 expression could facilitate increased aggregation at the villi. Similarly, an increase in complement marker C4d was also observed on the microvillous membrane of the STB in MCI cases, implying an allogenic humoral rejection by recruited monocytes to trophoblast antigens 40 .…”

Intravenous Immunoglobulins for Recurrent Chronic Histiocytic Intervillositis: A Series of Case Studies

“…With massive fibrin deposits [3] and C4d immunopositivity on the placentas [3,4]. Despite that immunomodulatory therapies could be of interest in preventing the recurrence of chronic intervillositis, the best regimen is not well determined.…”

SARS-CoV-2 Infection in Late Pregnancy and Childbirth from the Perspective of Perinatal Pathology

“…In SP, viral proteins have been shown to be co-expressed with the complement marker C4d [24,35], suggesting a role of the complement fixation along the villous borders in the tissue destruction. However, this process is not specific and has been demonstrated in the CHI of noninfectious etiologies [61]. Another finding that may shed light on the pathogenesis of SP is the decreased expression of anti-apoptotic marker BCL-2, implicating apoptosis as a mechanism at least partially responsible for extensive trophoblast damage in SP [24].…”