Implantation Test for Endometrial Receptivity
Condition: Pregnancy Loss; Miscarriage
MeSH terms: Abortion, Spontaneous
Study type: Observational

Summary: 
      Background Miscarriage is the most frequent complication of pregnancy and represents the
      spontaneous loss of the embryo or foetus before it is able to survive independently (24 weeks
      of gestation). It affects up to 50% of pregnancies with the vast majority (80%) occurring at
      pre-clinical stage before the woman recognises the pregnancy. Up to 5% of couples suffer
      recurrent miscarriage defined as 2-3 or more miscarriages leading to physical, emotional and
      financial consequences for couples, doctors and medical systems.

      Different maternal health problems (thyroid disease, sticky blood, autoimmune disease,
      anatomical anomalies of the womb) and embryo defects may be responsible for some of the
      miscarriages; however, more than 50% of the occurrences have no identifiable cause based on
      the current diagnostic tests.

      Aim The aim of the present research proposal is to understand the role of the lining of the
      womb in miscarriage and to explore the development of a potential implantation test that is
      cost-effective and may be implemented in clinical practice.

      Methods Over a period of two years, women who suffered recurrent miscarriage will be
      approached in the advanced miscarriage clinic at Birmingham Women's Hospital during their
      routine appointment. Participants will be invited to participate by undergoing
      chromohysteroscopy and/or a biopsy from the lining of the womb during an outpatient
      appointment.

      Chromohysteroscopy is based on a routine hysteroscopy which involves visualising the inside
      of the womb using a narrow telescope passed through the neck of the womb (cervix). "Chromo"
      comes from the fact that an iodine based dye will be injected to increase the power of the
      test.

      The biopsy will be taken using a narrow plastic tube passed through the cervix. It is a
      standard diagnostic test for women with abnormal bleeding. As part of the present research,
      different cells and molecules will be analysed from the biopsy sample.
    

Detailed description: 
      The Tommy's National Centre for Miscarriage Research in Birmingham is a Research Centre which
      brings together an interdisciplinary translational medicine research grouping jointly at the
      Birmingham Women's and Children's NHS Foundation Trust (BWCNFT) and the University of
      Birmingham (UoB). The overarching Tommy's Centre funding includes sites at the University of
      Warwick and Imperial College London. The Centre is dedicated to research across all aspects
      of miscarriage and early pregnancy complications including basic scientific, medical, social
      and ethical issues.

      This research project will occur alongside an advanced miscarriage clinic at Birmingham
      Women's Hospital. The Study Office belongs to the University of Birmingham and is located
      within the Birmingham Women's Hospital (Academic Department, 3rd floor). Computers are linked
      to the University's Network and all the electronic data will be held within this network.

      The research project is divided into a number of three work packages and the findings from
      these will build on each other. Therefore, we have incorporated each of these distinct work
      packages within this research project protocol, with methodological details and objectives of
      each.

      Work package 1: Target Product Profile (TPP) The TPP will convey information regarding the
      proposed use, context of use, patients' and clinicians' needs for an endometrial test in
      relation to endometrial receptivity, recurrent miscarriage and recurrent implantation
      failure.

      Women who suffer recurrent miscarriage are referred for routine care to the Recurrent
      Miscarriage Clinic within Birmingham Women's Hospital by their GP or by other NHS Early
      Pregnancy Units. Women attending the Recurrent Miscarriage Clinic will be invited to fill in
      a questionnaire during their waiting time prior to the consultation by one of the research
      nurses who work within the Recurrent Miscarriage Clinic. The purpose of the questionnaire is
      to gain insight into women's view and expectations in relation to a new endometrial
      receptivity test.

      Work package 2: Chromohysteroscopy Hysteroscopy is the procedure in which the uterine cavity
      is viewed using a hysteroscope (lighted scope) inserted through the cervix. It is used
      routinely in the NHS for women with varying indications (ie: polyps or fibroids suspected on
      ultrasound, thin endometrium, adhesions etc). In addition to morphologic abnormalities (ie:
      septum, polyps, adhesions), hysteroscopy may identify direct visual appearances relevant to
      endometrial receptivity.

      Chromohysteroscopy involves flushing the endometrial surface with a dye (ie: methylene blue)
      in order to increase the sensitivity of hysteroscopy for the diagnosis of subtle endometrial
      pathologies which have not produced macroscopic changes.

      All previous chromohysteroscopic studies used methylene blue as a dye to enhance the
      visibility of endometrial abnormalities based on the ability of necrotic endometrial cells to
      absorb/retain the dye. The investigators plan to further develop this approach by using
      iodine in relation to the known endometrial properties.

      It is well known that iodine interacts with glycogen to generate a brown-blue colour. The
      glycogen-iodine reaction normally enables the identification of high vaginal and cervical
      lesions during colposcopic examinations that women undergo routinely in the NHS when there is
      a suspicion on their smear tests.

      The investigators hypothesise that aberrations in the secretory phase of the endometrial
      development may be identified using iodine chromohysteroscopy based on the interaction
      between iodine and glycogen which generates a brown-blue colour.

      Work package 3: OMICS studies on endometrial samples Omics- refer to the application of
      high-throughput techniques which simultaneously examine changes in different molecular
      compartments: genomics, transcriptomics, proteomics, metabolomics etc. The understanding of
      human endometrial physiology and pathophysiology is being revolutionised by the use of
      omics-; however, current understanding of different complex phenotypes related to fertility
      remains incomplete, inconsistent and without strong clinical application.

      A Pipelle biopsy of the endometrium involves passing a narrow plastic tube through the cervix
      to obtain a sample by aspiration. It is routinely used in the NHS to rule out endometrial
      hyperplasia/carcinoma in women suffering from heavy menstrual bleeding or postmenopausal
      bleeding.

      The investigators hypothesise that women who suffered recurrent reproductive failure may have
      altered transcriptomics, proteomics, and metabolomics profiles in their endometrium.
      Identifying these changes may provide diagnostic and prognostic markers for future
      pregnancies.
    

Intervention name(s): Chromohysteroscopy; Endometrial biopsy (Pipelle)
Intervention type(s): Diagnostic Test; Diagnostic Test
Intervention description(s): Standard hysteroscopy followed by injection of a dye, in this case iodine.; A narrow plastic tube (Pipelle) is passed through the cervix to aspirate a sample of endometrial tissue.
Other intervention name(s): Endometrial sampling
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        A cohort of women who suffered unexplained recurrent miscarriage will be sub grouped in two
        study populations: women who suffered two or more miscarriages and women who suffered five
        or more miscarriages (extreme recurrent miscarriage cohort). A total of 60 women will be
        recruited for the study investigations (30 for chromohysteroscopy and 30 for endometrial
        biopsy).

        We will select a very narrow phenotype in order to increase the study's sensitivity and
        power. Participants will be 18-35 years old, not pregnant and regularly menstruating in
        order to reduce the age effect on the pregnancy outcome. They will be diagnosed as having
        unexplained recurrent miscarriage by undertaking the standard miscarriage investigations.
      
Biospecimen description: 
      Endometrial samples taken during the implantation window (mid luteal phase, timed based on LH
      surge).
    
Keywords: embryo implantation; endometrial receptivity; chromohysteroscopy; transcriptomics; proteomics; metabolomics; implantation window; luteal phase