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Chronic histiocytic intervillositis – Clinical, biochemical and radiological findings: An observational study (Koby et. al)

This ‘retrospective observational’ study (which means a study where they look at people who were diagnosed with CHI and looked back to see if there was anything special about their pregnancies) looked at 33 pregnancies with confirmed ‘CHI’ in Toronto, Canada. They looked at blood results and ultrasound results as well as the overall health and characteristics of the mums and the outcomes of the pregnancies. Almost all the pregnancies (92%) delivered small for gestational age babies and 4/5 pregnancies were delivered before 37 weeks. They also found that more than would be expected number of pregnancies had high levels of alkaline phosphatase (a marker in blood tests) but these weren’t associated with stillbirths. Interestingly, and contradicting other studies, subsequent pregnancies didn’t seem to be affected by CHI although it appears they didn’t consider any pregnancies that ended in a miscarriage.

 

File: Koby et al. – Chronic histiocytic intervillositis – Clinical, biochemical and radiological findings An observational study – 2018 – Plac

Website: Koby, L. et al. (2018) ‘Chronic histiocytic intervillositis – Clinical, biochemical and radiological findings: An observational study’, Placenta. W.B. Saunders, 64, pp. 1–6. doi: 10.1016/J.PLACENTA.2018.02.002.

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Chronic histiocytic intervillositis in three consecutive pregnancies in a single patient: Differing clinical results and pathology according to treatment used. (Ozawa et. al.)

This is a case study series looking at 3 subsequent pregnancies in a woman who has unfortunately had 4 previous early miscarriages and been diagnosed with CHI. They found that pregnancy outcomes changed depending on treatment with the most successful being a combination of low dose aspirin and prednisolone.

File: Ozawa et al. – Chronic histiocytic intervillositis in three consecutive pregnancies in a single patient Differing clinical results and p

Website: Ozawa N, Yamaguchi K, Shibata M, et al. Chronic histiocytic intervillositis in three consecutive pregnancies in a single patient: Differing clinical results and pathology according to treatment used. J. Obstet. Gynaecol. Res. 2017:1-5. doi:10.1111/jog.13404.

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Chronic villitis of unknown etiology and massive chronic intervillositis have similar immune cell composition. (Labarrere et. al 2015)

This study looks in detail at the type of immune cells that are found in placentas with CVUE and MCI. It hypotheseses that these might be differing severities of the same underlying pathology. It also explicitly states two different ideas as to what causes CVUE/MCI – either due to the fetus responding to an infectious agent within the placenta, or the maternal immune response to the fetus.

File: Labarrere et al. – Chronic villitis of unknown etiology and massive chronic intervillositis have similar immune cell composition – 2015

Website: Labarrere CA, Hardin JW, Haas DM, Kassab GS. Chronic villitis of unknown etiology and massive chronic intervillositis have similar immune cell composition. Placenta 2015;36(6). doi:10.1016/j.placenta.2015.03.008.

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An Immunological Basis for Chronic Histiocytic Intervillositis in Recurrent Fetal Loss. (Reus et. al)

Reus et al. – An Immunological Basis for Chronic Histiocytic Intervillositis in Recurrent Fetal Loss – 2013 – American Journal of Reproductive Immunology

This paper ‘scores’ or grades placentas as to how many/much lesions associated with CHI and finds that a higher score (more lesions) is associated with worse outcomes and is considered to be more severe CHI. They specifically found that anti-CD68 antibodies were associated with CHI suggesting that there is an immunological association as CD68 is found on macrophages – one of the immune response cells. They make the link with the woman mounting an immune response to the paternal cells. Unfortunately, of the 30 pregnancies that were involved in the study, only 10 of them resulted in a healthy baby. This study links to others suggesting that there is mixed evidence as to the efficacy of using prednisolone and aspirin in pregnancy to improve outcomes.

Link: http://onlinelibrary.wiley.com/doi/10.1111/aji.12125/abstract

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Successful pregnancy following treatment of recurrent chronic histiocytic intervillositis (Vardi et. al) – 2017

This New Zealand case report looks at a woman who had recurrent pregnancy loss and was diagnosed with CHI.

A subsequent pregnancy was successful with a combination of therapy including: prednisone, enoxaparin, calcium and aspirin, close monitoring with regular growth scans, and an elective c-section at 34 weeks when it was seen the baby’s growth was plateauing.

 

Vardi, Paterson, Hung – Successful pregnancy following treatment of recurrent chronic histiocytic intervillositis – 2017 – BMJ Case Repo

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Recurrent Chronic Histiocytic Intervillositis with Intrauterine Growth Restriction, Osteopenia, and Fractures (Crawford et. al) – 2016

This Australian paper looks at a single woman who unfortunately had 4 pregnancies affected by CHI. Her fetuses also appeared to have a bone condition (osteogenesis imperfecta – OI) although the histology (looking down a microscope) of the bones didn’t match typical OI and she didn’t have any genetic markers for it either.

 

Crawford et al. – Recurrent chronic histiocytic intervillositis with intrauterine growth restriction, osteopenia, and fractures. – 2016

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Expression of Toll-Like Receptors in Chronic Histiocytic Intervillositis of the Placenta. (Hussein K, Stucki-Koch A, Kreipe H, et al.)

This paper notes the previously known histological (looking down the microscope) similarity between placental malaria and CHI and suggests that they may both result/be due to cells ‘expressing’ receptors on their surface. They looked at cells from CHI placentas as well as cells from normal placentas and those from CVUE placentas and found that there were indeed an increase in some specific ‘Toll-like receptors (TLR). They noted that there was a difference in which receptors were seen but suggest that this could still suggest that CHI could be an immune system related phenomenon. They suggest that this could be due to the mother having a blood-borne bacterial infection that her body could be fighting off (even if she isn’t outwardly unwell).

They are aware that multiple pregnancies could be affected by CHI and thus this infection would have to either recur or be continuing to happen over multiple pregnancies. They say that CHI over more than one pregnancy has not been officially found, I’m not sure if this is still/actually the case.

Hussein et al. – Expression of Toll-Like Receptors in Chronic Histiocytic Intervillositis of the Placenta. – 2015 – Fetal and pediatric

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Chronic histiocytic intervillositis: Outcome, associated diseases and treatment in a multicenter prospective study.

Chronic histiocytic intervillositis: Outcome, associated diseases and treatment in a multicenter prospective study.

Citation: Mekinian A, Costedoat-Chalumeau N, Masseau A, et al. Chronic histiocytic intervillositis: Outcome, associated diseases and treatment in a multicenter prospective study. Autoimmunity 2014;6934:1–6. doi:10.3109/08916934.2014.939267

Introduction: In this prospective multicenter study, we aimed to describe (1) the outcome of pregnancy in the case of previous chronic histiocytic intervillositis (CHI), (2) the immunological findings and associated diseases, (3) the treatments, and (4) the factors associated with pregnancy loss.

Methods: We prospectively included all patients with a prior CHI with ongoing pregnancy between 2011 and 2013.

Results: Twenty-four women (age 34 ± 5 years) were included in this study. An autoimmune disease was present in seven (29%) cases. Twenty-one prospective pregnancies were treated. The number of live births was more frequent comparatively to the previous obstetrical issues (16/24 versus 24/76; p = 0.003). Most of the pregnancies were treated (88%), whereas only 13% of previous pregnancies were treated (p < 0.05). No difference was found with respect to the pregnancy outcome in the different treatment regimens. In univariate analyses, a prior history of intrauterine death and intrauterine growth restriction and the presence of CHI in prospective placentas were associated with failure to have a live birth.

Discussion: In this multicenter study, we show the frequency of the associated autoimmune diseases in CHI, as well as the presence of autoantibodies without characterized autoimmune disease. The number of live births increased from 32% to 67% in the treated pregnancies. Despite the treatment intervention, the risk of preterm delivery remained at 30%. Last, we show that the recurrence rate of an adverse pregnancy outcome persisted at 30% despite treatment intervention.

Conclusion: CHI is associated with high recurrence rate and the combined regimen seems to be necessary, in particular, in the presence of previous intrauterine death.

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Expression analysis of leukocytes attracting cytokines in chronic histiocytic intervillositis of the placenta: Freitag, von Kaisenberg, Kreipe, Hussein

Abstract: Chronic histiocytic intervillositis of the placenta (CHI) is a rare and potentially recurrent disease. Characteristically it shows accumulation of CD68+ cells in the intervillous space but no destructive tissue infiltration. An immunopathological background is likely but it is unknown what attracts circulating monocytes to the placenta.

Methods: We analysed the expression profile of 102 inflammation- and angiogenesis-associated genes with real-time revers transcriptase-polymerase chain reaction (RT-PCR) in 16 placentas: CHI (n = 5) and, as controls, villitis of unknown aetiology (VUE, n = 4) and normal placenta (n = 7). Results: Compared to controls, CHI had significantly higher levels of matrix metallopeptidase 9 (MMP9) and transforming growth factor, beta receptor 1 (TGFBR1). MMP14 was lower in VUE than CHI (p < 0.05) and controls (not significant). Chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL12, chemokine (C-C motif) ligand 5 (CCL5) and TIMP metallopeptidase inhibitor 1 (TIMP1) were significantly higher in VUE versus controls but not deregulated in CHI. The expression profile could not clearly discriminate CHI from VUE or controls but a tendency for grouping of massive CHI was found. Angiogenesis-associated factors were not deregulated in CHI.

Conclusion: The discrepancy of massive histiocytic accumulation and the lack of striking up-regulation of cytokines might be the basis of the non-destructive behaviour of the histiocytes in CHI.

Keywords: Cytokine, chemokine, histiocyte, monocyte, placenta pathology, chronic histiocytic intervillositis, massive perivillous histiocytosis

Expression analysis of leukocytes attracting cytokines in chronic histiocytic intervillositis of the placenta: Freitag, von Kaisenberg, Kreipe, Hussein

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Fetal death in primary Sjögren’s syndrome (SS) associated with chronic intervillositis. Arsene Mekinian

Letter to the Editor (case report)

SIR, Chronic intervillositis is a rare and poorly understood disease characterized by intervillous infiltrates of maternal origin. The intervillositis infiltrates from mononuclear cells (monocytes, histiocytes) correlate with placental insufficiency, and result in intrauterine growth restriction, intrauterine fetal death and spontaneous miscarriage [1]. Chronic intervillositis aetiology is not well established. Recent physiopathological studies have argued in favour of an immune response resulting from an abnormal maternal reaction to the placental tissue, which could preferentially implicate T-lymphocytes. Thus chronic intervillositis could be associated with auto- immune diseases, such as antiphospholipid syndrome (APS), but its association with other autoimmune disorders has not yet been determined [2]. We describe the case of a pregnant woman with underlying primary Sjögren’s syndrome (SS) who presented intrauterine fetal death in relation with chronic intervillositis of the placenta.

Fetal death in primary Sjögren’s syndrome (SS) associated with chronic intervillositis. Arsene Mekinian

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Fetal Demise Associated With Influenza A Infection. Richard Lieberman, MD

DIAGNOSES: Intrauterine fetal demise (second trimester). Diffuse villous fibrosis, perivillous and intravillous fibrin deposition associated with chronic villitis and intervillositis (placentitis), histiocytic type. Influenza A virus infection (type not specified) with
ultrastructural, immunohistochemical, and PCR confirmation.

CASE 2: Fetal Demise Associated With Influenza A Infection. Richard Lieberman, MD

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CD68 Immunostaining in the Evaluation of Chronic Histiocytic Intervillositis. Debra S. Heller, MD

Context.—Chronic histiocytic intervillositis is an uncommon and poorly recognized lesion associated with poor perinatal outcomes, including intrauterine growth retardation and stillbirth. It has a high recurrence rate.
Objective.—To evaluate utility of CD68 immunostaining in the evaluation of chronic histiocytic intervillositis.
Design.—Institutional review board–approved retrospective review was performed. Cases were selected from the departmental archives of University Hospital, Newark, New Jersey, between 2002 and 2009. Controls were from second-trimester pregnancies with chromosomal abnormalities or multiple severe anomalies.
Results.—There were 9 cases and 11 controls. The mean CD68 count per high-power field for the cases was 88 23 (range, 51–180) and for the controls, 8 5 (range, 0–24), P .001.
Conclusions.—This study establishes a range for histiocyte counts in chronic histiocytic intervillositis and pregnancies without chronic histiocytic intervillositis, and suggests that CD68 staining may have utility in the diagnosis, particularly for nonperinatal pathologists, who may be less familiar with this lesion.
(Arch Pathol Lab Med. 2012;136:657–659; doi: 10.5858/
arpa.2011-0328-OA

CD68 Immunostaining in the Evaluation of Chronic Histiocytic Intervillositis Debra S Heller MD

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Co-occurrence of Massive Perivillous Fibrin Deposition and Chronic Intervillositis: Case Report

ABSTRACT
Chronic intervillositis (CI) and massive perivillous fibrin deposition (MFD), together with its related entity, maternal floor infarction (MFI), are rare and poorly understood placental lesions. Both MFD/MFI and CI are associated with poor fetal outcome and high risk of recurrence. We report a patient who was found to have both MFD and CI in the same placenta, resulting in severe intrauterine fetal growth restriction and intrauterine fetal death at 37 weeks of gestation. Characteristic histological findings included both very extensive perivillous deposition of fibrinoid material and a heavy infiltrate of CD68-positive macrophages/monocytes in the maternal intervillous space. To our knowledge, this is the first time the co-occurrence of MFD and CI is reported in the literature.
Key words: chronic intervillositis, intrauterine fetal death, intrauterine growth restriction, massive perivillous fibrin deposition, maternal floor infarction

Co-occurrence of Massive Perivillous Fibrin Deposition and Chronic Intervillositis: Case Report MARTIN A. WEBER,1,2 PETER G.J. NIKKELS,3 KAREN HAMOEN,1 JOHANNES J.
DUVEKOT,4 AND RONALD R. DE KRIJGER
1*

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Combining corticosteroid and aspirin for the prevention of recurrent villitis or intervillositis of unknown etiology

Summary (translation from the original paper in French):

We report the cases of two patients who had a favourable outcome with aspirin and corticosteroid therapy during pregnancy for chronic villitis of unknown etiology complicated by labor asphyxia and further intrauterine fetal demise in one gravida 3 patient and for chronic intervillositis of unknown etiology diagnosed after three perinatal deaths in another patient (gravida 4). Chronic villitis of unknown etiology (CVUE) is detected in 7 to 33% of placentas, mainly after intrauterine growth retardation (IUGR), unexplained prematurity, preeclampsia, perinatal asphyxia and intrauterine fetal death (IUFD). The less frequent chronic intervillositis of unknown etiology (CIUE) (0.6 to 0.9/1.000) has been implicated in recurrent severe pregnancy complications, such as spontaneous abortions, IUGR and IUFD. Histopathology and immunohistology are in favour of an immune response against the foreign fetal allograft. The favourable results obtained with corticosteroids and aspirin remain to be confirmed by larger series.

Combining corticosteroid and aspirin for the prevention of recurrent villitis or intervillositis of unknown etiology: G. Boog, C. Le Vaillant, F. Alnoukari, F. Jossic, J. Barrier, J.-Y. Muller

NB: Cet article est en anglais. Pour lire l’article original en français: Association des corticoïdes à l’aspirine pour la prévention des récidives de villite ou d’intervillite chroniques d’étiologie indéterminée: G. Boog, C. Le Vaillant, F. Alnoukari, F. Jossic, J. Barrier, J.-Y. Muller

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Association des corticoïdes à l’aspirine pour la prévention des récidives de villite ou d’intervillite chroniques d’étiologie indéterminée

RÉSUMÉ- Article en Français

Les auteurs rapportent les résultats favorables obtenus en cours de grossesse par l’association aspirine et corticoïdes, d’une part, chez une patiente troisième geste ayant présenté des lésions placentaires de villite chronique d’étiologie indé- terminée, compliquée d’une asphyxie fœtale pendant le travail, puis d’une mort in utero, d’autre part, chez une quatrième geste atteinte d’intervillite chronique d’étiologie indéterminée découverte après trois morts périnatales. Dans la littérature, la villite chronique d’étiologie indéterminée (CVUE) est retrouvée dans 7 à 33 % des placentas, notamment lors de retards de croissance intra-utérins (RCIU) « idiopathiques », de prématurités inexpliquées, de pré-éclampsies, d’asphyxies fœtales et de morts in utero. L’intervillite chronique d’étiologie indéterminée (CIUE), beaucoup plus rare (0,6 à 0,9/1000), a été incriminée dans les accidents gravidiques à répétition, fausses couches, RCIU et morts in utero. L’aspect histologique de ces lésions inflammatoires chroniques du placenta et l’étude immuno-histochimique évoquent un conflit immunologique sous la forme d’un rejet de l’allogreffe de la grossesse. L’effet favorable de la corticothérapie (prednisone) associée à l’aspirine doit être confirmé par des séries plus importantes.

Mots-clés : Villite chronique d’étiologie indéterminée Intervillite chronique d’étiologie indéterminée Accidents périnatals

à répétition • Aspirine • Corticoïdes.

Association des corticoïdes à l’aspirine pour la prévention des récidives de villite ou d’intervillite chroniques d’étiologie indéterminée: G. Boog, C. Le Vaillant, F. Alnoukari, F. Jossic, J. Barrier, J.-Y. Muller

NB: This article is in French.  If you would like to read the same article in English refer to: Combining corticosteroid and aspirin for the prevention of recurrent villitis or intervillositis of unknown etiology: G. Boog, C. Le Vaillant, F. Alnoukari, F. Jossic, J. Barrier, J.-Y. Muller

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Chronic histiocytic intervillositis of unknown etiology: Clinical features in a consecutive series of 69 cases: Marchaudon et. al

(Summary to come!)

Chronic histiocytic intervillositis of unknown etiology: Clinical features in a consecutive series of 69 cases: Marchaudon et. al

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Chronic intervillositis of unknown etiology (CIUE) – Relation between placental lesions and perinatal outcome

This study talks about Chronic intervillositis of unknown etiology (CIUE) which appears to be yet another term for CHI/CHIV/MCI. It looks at 20 pregnancies across 14 women affected by CIUE; 10 resulted in live births and the recurrence rate for multiple pregancies was 100% (it should be noted however, that this is a smaller sample than the Redline/Boyd study above). It suggests that how bad the placenta looks in terms of lesions on it directly links to how well (or otherwise) the pregnancy went. It also compares several studies of multiple patients as well as looking at a study that followed one lady who had 4 successful pregnancies before starting to have problems. She had 2 stillbirths and 3 miscarriages and then went on to have one more child successfully with Aspirin and Prednisone. It notes the difference between chronic villitis of unknown etiology (CVUE) and CHI/CIUE.

Chronic intervillositis of unknown etiology (CIUE) – Relation between placental
lesions and perinatal outcome: Olivier Parant, Jerome Capdet, Sylvie Kessler, Jacqueline Aziza, Alain Berrebi

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Chronic villitis of unknown etiology: Georges Boog (2008)

CVUE is thought to be different but a similar and more common disease compared to CHI. It talks about associations with maternal BMI, multiple pregnancies and ethnicity. It also found it showed up in pregnancies affected by autoimmune or alloimmune diseases. It suggests aspirin and corticosteroids as a possible regimen.

Chronic villitis of unknown etiology: Georges Boog (2008)

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Villitis of unknown etiology – noninfectious chronic villitis in the placenta: Raymond W. Redline MD

This talks about Villitis of unknown etiology (VUE) which I guess becomes Chronic Villitis of unknown etiology (CVUE) if you have it for life rather than as a result of an acute condition? It describes how this more common condition can affect 5-15% of pregnancies and, as you’d expect from those sort of numbers, isn’t as severe as CHI. It compares VUE to infectious villitis. It talks about anecdotally effective treatment through progesterone, corticosteroids, low-dose heparin, and intravenous immunoglobulin (IVIG).

Villitis of unknown etiology – noninfectious chronic villitis in the placenta: Raymond W. Redline MD

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Massive perivillous fibrin deposition and chronic intervillositis: frequently missed diagnoses with a high recurrence risk: MA Weber, PGJ Nikkels, KE Hamoen, JJ Duvekot, RR de Krijger

This study talks about MFD/MFI and CI as similar conditions both of which are very rare. It looks at one case study and talks about how the diseases may be similar. It mentions heparin-type drugs and immunosuppresants as possible treatment options. Its focus is to encourage better diagnosis of this condition to improve standards of care.

Massive perivillous fibrin deposition and chronic intervillositis: frequently missed diagnoses with a high recurrence risk: MA Weber, PGJ Nikkels, KE Hamoen, JJ Duvekot, RR de Krijger

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Chronic villitis in untreated neonatal alloimmune thrombocytopenia: An etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy.

This study looks at CHIV in the specific case of neonatal alloimmune thrombocytopenia. It suggests that intravenous immunoglobulin given to the mother may help improve the outcome although the results weren’t statistically significant because there weren’t enough case studies.

Chronic villitis in untreated neonatal alloimmune thrombocytopenia: An etiology for severe early intrauterine growth restriction and the effect of intravenous immunoglobulin therapy: Janyne Althaus, MD,a Edward G. Weir, MD,b Fred Askin, MD,b Thomas S. Kickler, MD,b Karin Blakemore, MDa

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Massive Chronic Intervillositis Associated With Recurrent Abortions: Barbara J. Doss

This covers a specific case of MCI/CHIV in a lady who had 10 recurrent miscarriages in her first and second trimesters (although she also had two live births as well!). They look at each pregnancy and try to find similarities and differences between them. Other than that, it draws many similar conclusions as other studies.

Massive Chronic Intervillositis Associated With Recurrent Abortions: Barbara J. Doss

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A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study Clemens B. Tempfer, M.D. et al

This study looks at a treatment in the form of prednisone, aspirin, folate, and progesterone in women who had suffered from more than three miscarriages. It found a statistically significant and positive effect in treating women with this regimen compared to those who weren’t treated. The comment on the study is about how valuable the study may or may not be based on the way they carried it out and how they selected their patients.

A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study Clemens B. Tempfer, M.D. et al

Comment on this study

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The placenta in preterm birth: O M Faye-Petersen (2008)

This is a general paper for pathologists who may need to give a report on a preterm placenta. It talks about lots of different types of issues with placentas and covers of CVUE or VUA as it calls it and also mentions MCI but only very briefly.

The placenta in preterm birth: O M Faye-Petersen (2008)

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Prevalence of Developmental and Inflammatory Lesions in Nonmolar First-Trimester Spontaneous Abortions: Raymond W, Redline, MD, Michael Zaragoza, and Terry Hassold, PhD

This study concentrates only on first trimester miscarriages. It identifies CHIV/MCI as one of the features that shows up when the fetus does not appear to have DNA problems (has normal karotypes) and yet a miscarriage took place.

Prevalence of Developmental and Inflammatory Lesions in Nonmolar First-Trimester Spontaneous Abortions: Raymond W, Redline, MD, Michael Zaragoza, and Terry Hassold, PhD