Study of Endometrial Immune and Microbiological Modifications in Cases of Recurrent Implantation Failure and/or Recurrent Pregnancy Loss

Official title

Study of Immune and Microbiological Modifications of the Endometrium in Cases of Recurrent Implantation Failure and/or Recurrent Pregnancy Loss

Overview

The IMERR study aims to improve understanding of certain causes of infertility related to recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL), conditions that affect many women undergoing assisted reproductive technology (ART). Despite medical advances, some patients repeatedly fail to achieve pregnancy, or experience repeated miscarriages. These situations may be linked to subtle immune or microbial disturbances in the uterus. This study seeks to identify immune and microbiological profiles in the endometrium during the implantation window-a crucial period when the embryo attaches to the uterine wall. We will compare women who have experienced RIF and/or RPL with women who have had no such history. Blood and uterine samples will be analyzed to investigate whether certain immune or microbial features are associated with these reproductive failures. The ultimate goal is to uncover predictive factors that may explain why some women experience implantation failure or pregnancy loss, and to lay the foundation for future personalized treatments to improve reproductive outcomes.

Detailed description

The IMERR study is a prospective, monocentric, controlled interventional study aiming to identify immune and microbiological signatures in the eutopic endometrium of women undergoing ART (IVF/ICSI), with and without a history of recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL). RIF is defined as the absence of clinical pregnancy after at least three embryo transfers of good-quality blastocysts, and RPL as two or more consecutive pregnancy losses before 24 weeks of gestation.

Participants will be divided into two groups: a study group (with RIF and/or RPL) and a control group (without RIF or RPL). Endometrial biopsies will be collected during the implantation window, alongside peripheral blood and vaginal samples. These samples will undergo immunological and microbiological analyses, including histology, immunophenotyping, and microbiota profiling.

The study aims to (i) Characterize immune cell populations in the endometrium and blood, (ii) Investigate the endometrial microbiome and its potential dysbiosis, (iii) Explore associations between these biological profiles and clinical features such as endometriosis, adenomyosis, chronic endometritis, or uterine contractility disorders.

The study includes 100 participants and spans a total duration of 60 months (36 months for inclusion and 24 months of follow-up). A subgroup analysis will assess the association between immuno-microbiological profiles and clinical outcomes after embryo transfer within the 24-month post-inclusion period.

By identifying predictive markers of RIF and RPL, this study may help establish new diagnostic tools and personalized treatment strategies in reproductive medicine.

Interventions

• Diagnostic test Endometrial Biopsy
  Endometrial biopsy with Cornier Pipelle (part of the treatment in the RIF/RPL group and some patients of the control group / added for the research for the other patients of the control group)
• Diagnostic test Vaginal Swab
  Vaginal sample collection using a cotton swab. Part of the treatment
• Diagnostic test Blood sample
  Peripheral blood draw. Part of the treatment + 10 mL additional for research
• Diagnostic test Pelvic ultrasound (±pelvic MRI)
  Pelvic ultrasound (±pelvic MRI). Part of the treatment

Primary outcome measures

• Profiling of endometrial immune cell populations [Time frame: Baseline]

Secondary outcome measures (4)

• Microbiological profiling of endometrial tissue [Time frame: Baseline]
• Characterization of peripheral blood immune cell populations [Time frame: Baseline]
• Exploratory analysis of associations between immune and microbiological profiles and clinical, radiological, and histological characteristics [Time frame: Baseline]
• Exploratory analysis of associations between immune and microbiological profiles and clinical, radiological, and histological characteristics [Time frame: Through 24 months of follow-up]

Eligibility criteria

Inclusion criteria

• Female aged ≥18 and <36 years
• Undergoing assisted reproductive technology (ART) in a fertility center
• Covered by the French national health insurance system
• Belonging to one of two groups:

• Study group: history of recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL)
• Control group: no history of RIF or RPL

Exclusion criteria

• Pregnant at inclusion
• Refusal to provide written informed consent
• Antibiotic use within one month prior to endometrial biopsy Positive serology for hepatitis B, hepatitis C or HIV
• Uterine anatomical abnormalities (e.g., polyps, cavity-distorting fibroids, untreated hydrosalpinx)
• Known chromosomal abnormality in either partner
• Known autoimmune disease, thrombophilia, or antiphospholipid antibody syndrome
• Persons under legal protection (e.g., guardianship, curatorship)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 1 center

• Service de Gynécologie Obstétrique II et Médecine de la Reproduction - Cochin Hospital — Paris

Publications

• Benner M, Ferwerda G, Joosten I, van der Molen RG. How uterine microbiota might be responsible for a receptive, fertile endometrium. Hum Reprod Update. 2018 Jul 1;24(4):393-415. doi: 10.1093/humupd/dmy012. PMID 29668899
• Bourdon M, Santulli P, Jeljeli M, Vannuccini S, Marcellin L, Doridot L, Petraglia F, Batteux F, Chapron C. Immunological changes associated with adenomyosis: a systematic review. Hum Reprod Update. 2021 Jan 4;27(1):108-129. doi: 10.1093/humupd/dmaa038. PMID 33099635
• Campo S, Campo V, Benagiano G. Infertility and adenomyosis. Obstet Gynecol Int. 2012;2012:786132. doi: 10.1155/2012/786132. Epub 2011 Dec 26. PMID 22242025
• Chen P, Chen P, Guo Y, Fang C, Li T. Interaction Between Chronic Endometritis Caused Endometrial Microbiota Disorder and Endometrial Immune Environment Change in Recurrent Implantation Failure. Front Immunol. 2021 Oct 4;12:748447. doi: 10.3389/fimmu.2021.748447. eCollection 2021. PMID 34671363
• Duffy JMN, Adamson GD, Benson E, Bhattacharya S, Bhattacharya S, Bofill M, Brian K, Collura B, Curtis C, Evers JLH, Farquharson RG, Fincham A, Franik S, Giudice LC, Glanville E, Hickey M, Horne AW, Hull ML, Johnson NP, Jordan V, Khalaf Y, Knijnenburg JML, Legro RS, Lensen S, MacKenzie J, Mavrelos D, Mol BW, Morbeck DE, Nagels H, Ng EHY, Niederberger C, Otter AS, Puscasiu L, Rautakallio-Hokkanen S, PMID 33272617
• ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Mcheik S, Peramo B, Quenby S, Nielsen HS, van der Hoorn ML, Vermeulen N, Goddijn M. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023 Mar 2;2023(1):hoad002. doi: 10.1093/hropen/hoad002. eCollection 2023. PMID 36873081
• ESHRE Working Group on Recurrent Implantation Failure; Cimadomo D, de Los Santos MJ, Griesinger G, Lainas G, Le Clef N, McLernon DJ, Montjean D, Toth B, Vermeulen N, Macklon N. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023 Jun 15;2023(3):hoad023. doi: 10.1093/hropen/hoad023. eCollection 2023. PMID 37332387
• Giuliani E, Parkin KL, Lessey BA, Young SL, Fazleabas AT. Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis. Am J Reprod Immunol. 2014 Sep;72(3):262-9. doi: 10.1111/aji.12259. Epub 2014 May 8. PMID 24807109

Identifiers

NCT: NCT07265505 · APHP241344 · 2024-A02100-47

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗