Exploration of Allograft Humoral Rejection in Chronic Histiocytic Intervillositis (RH-PL)

Chronic histiocytic intervillositis (CHI) is a rare condition with an incidence of 5 in 10,000 pregnancies. This rare condition is associated with placental inflammatory lesions leading to severe and recurrent obstetrical complications: intrauterine growth retardation (IUGR), fetal death in utero and miscarriage. The pathophysiological mechanisms of CHI are poorly understood, while the empirical treatments prescribed to prevent recurrence are cumbersome and of poor efficacy.

Recent findings suggest that an alloimmune response may play a role. In a recent work, the investigators have demonstrated the role of maternal alloantibodies directed against fetal HLA antigens in two patients followed for recurrent IUGR associated with CHI. Their work suggests that a humoral alloimmune response directed against fetal HLA antigens mimics an allograft rejection process.

The investigators propose to extend the preliminary results obtained in these patients to provide new insights into the pathophysiological mechanisms of CHI, and eventually to predict the risks of fetal loss.

Study Overview

• Status: Not yet recruiting
• Conditions: Miscarriage; Intrauterine Growth Retardation; Chronic Histiocytic Intervillositis; Fetal Death in Utero
• Intervention / Treatment: Procedure: Biological collection

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexandra LETOURNEAU, Doctor; Phone Number: 331 45 37 44 76; Email: letourneau.alexandra@aphp.fr
• Study Contact Backup: Name: Alexandra BENACHI, Professor; Phone Number: 331 45 37 44 76; Email: alexandra.benachi@aphp.fr

Study Locations

• France
  • Clamart, France
    • Antoine Beclère Hospital
    • Contact: Alexandra BENACHI, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Family Inclusion Criteria:

• Mother and father ≥ 18 years old

• For mothers in the CHI group :

  • History of a normal pregnancy (full term, alive child) or IUGR/MFIU or miscarriage(s) or abortion followed by at least 1 obstetrical complication such as IUGR, MFIU, miscarriage
  • Diagnosis of chronic histiocytic intervillitis made by placental anatomopathological examination with CD68+ marking

• For the mothers of the antiphospholipid syndrom group

  • History of miscarriage(s)
  • Having an anti-phospholipid syndrome

• For mothers in the normal pregnancy group:

  • Third consecutive pregnancy of normal course, at term (≥ 36 weeks of amenorrhea) with eutrophic child

For the mother and father:

o Consent to participate in the study and for the participation in the study of at least one child and/or the use of existing samples (placenta / fetal DNA) from at least one previous pregnancy with CHI for the CHI group or at least one previous miscarriage for the APS group

For the father:

o Father of the last pregnancy and of the child(ren) participating in the study

Exlusion criteria :

• For mothers in the normal pregnancy group:

  o Suspected or confirmed intra-amniotic infection

• For all the mothers:

  • History of blood transfusion
  • History of allogeneic organ transplantation

• For the mother and the father:

  • Person under legal protection (guardianship, curatorship)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patient with chronic histiocytic intervillositis; Patient with CHI, as well as her children and their father. Blood collection from the parents, saliva collection (or blood collection) from the children, placenta collection	Procedure: Biological collection; up to 25 mL of blood collection for the adults and saliva collection for the minor at inclusion, and placenta collection at childbirth
Active Comparator: patients with anti-phospholipid syndromes (APS); Patient with antiphospholipid syndrome, as well as her children and their father. Blood collection from the parents, saliva collection (or blood collection) from the children, placenta collection	Procedure: Biological collection; up to 25 mL of blood collection for the adults and saliva collection for the minor at inclusion, and placenta collection at childbirth
Placebo Comparator: women with a third full-term pregnancy without growth retardation.; Patient with normal pregnancies, as well as her children and their father. Blood collection from the parents, saliva collection (or blood collection) from the children, placenta collection	Procedure: Biological collection; up to 25 mL of blood collection for the adults and saliva collection for the minor at inclusion, and placenta collection at childbirth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients diagnosed with CHI, defined by the concomitant presence of the 3 criteria required to evoke humoral alloimmune rejection for this pathology	Proportion of patients diagnosed with CHI, defined by the concomitant presence of the 3 criteria required to evoke humoral alloimmune rejection for this pathology, namely CD68+ infiltrate, AND C4d deposits on the trophoblastic villi AND the presence of at least one FSA (fetus-specific antibody, directed against fetal HLA antigens in the maternal blood) with an elevated level, defined by a Mean Fluorescence Intensity (MFI) > 10,000). This proportion of patients observed in CHI carriers will be compared to the proportion of patients with the concomitant presence of the same 3 criteria observed in the other two control groups.	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To measure the FSA levels by Mean Fluorescence Intensity for the different obstetrical complications: intrauterine growth retardation (IUGR), fetal death in utero and abortion for IUGR.		up to 6 months
to measure the correlation between fetus-specific antibody level by Mean Fluorescence Intensity and the severity and/or precocity of obstetrical complications		up to 6 months
measure of semi-quantitative graduation of C4d in placenta compared to percentage of villositis		up to 6 months
measure of semi-quantitative graduation of CD68+ infiltrate in placenta compared to surface and number of involved villositis		up to 6 months
To measure the expression of HLA class I and II molecules by placental villi by ß2-microglobulin and HLA-DR labelling		up to 6 months
Epitope analysis with algorithm developped by laboratoire HLA de St Louis (Pr JL Taupin)	Epitope analysis with algorithm developped by laboratoire HLA de St Louis (Pr JL Taupin) to determine whether an antibody response against a limited number of epitopes present during a first pregnancy that resulted in a healthy child can explain immunization against both paternal alleles	up to 6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Alexandra LETOURNEAU, Doctor, APHP, Antoine Béclère Hospital, CLAMART, France

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2023
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: June 12, 2023
• First Submitted That Met QC Criteria: June 30, 2023
• First Posted (Actual): July 7, 2023

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: June 30, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Fetal Diseases; Pregnancy Complications; Death; Growth Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Fetal Growth Retardation; Abortion, Spontaneous; Fetal Death
• Other Study ID Numbers: APHP221169

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No