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Assessing the Endometrial Environment in Recurrent Pregnancy Loss and Unexplained Infertility

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ClinicalTrials.gov Identifier: NCT03401918
Recruitment Status : Recruiting
First Posted : January 17, 2018
Last Update Posted : January 17, 2018
Sponsor:
Collaborator:
Instituto Valenciano de Infertilidad, IVI VALENCIA
Information provided by (Responsible Party):
Ruth Bunker Lathi, Stanford University

Brief Summary:
The purpose of this study is to determine if patients with recurrent pregnancy loss or unexplained infertility have an altered uterine gene expression or uterine microbiome (micro-organism composition) during the window of embryo implantation. Furthermore we would like to assess for women with an abnormal uterine gene expression whether vaginal progesterone medication improves or alters gene expression and for women with an abnormal microbiome whether antibiotic treatment followed by probiotic treatment normalizes the microbiome.

Condition or disease Intervention/treatment Phase
Recurrent Pregnancy Loss Unexplained Infertility Diagnostic Test: Uterine ERA and microbiome testing Drug: Oral antibiotics and vaginal probiotics Phase 2

Detailed Description:

Recurrent pregnancy loss and unexplained infertility are emotional and difficult diagnoses. Despite a thorough medical investigation, many cases of recurrent pregnancy loss and infertility remain unexplained. Understanding endometrial factors that may contribute to these diseases may lead to improved treatment options in the future. The purpose of this study is to determine if patients with recurrent pregnancy loss or unexplained infertility have an altered uterine gene expression or uterine microbiome (micro-organism composition) during the window of embryo implantation. Furthermore we would like to assess for women with an abnormal uterine gene expression whether vaginal progesterone medication improves or alters gene expression and for women with an abnormal microbiome whether antibiotic treatment followed by probiotic treatment normalizes the microbiome.

A standard evaluation for infertility includes a uterine cavity evaluation, evaluation for ovarian reserve testing, and for patients with recurrent pregnancy loss parental testing for uterine infection, chromosome analysis, autoimmune and thyroid screening. This standard workup, however, does not include a molecular or microbial assessment of the endometrium. Endometrial factors may contribute to unexplained infertility or recurrent pregnancy loss however the extent of this is unknown.

We are recruiting patients who have recurrent pregnancy loss, unexplained infertility, and healthy control patients who have had a term delivery in order to compare differences between these groups.

Subjects will undergo an endometrial biopsy that will specifically test the receptivity of your endometrium as well as identify the bacterial composition of the uterine environment (microbiome). The endometrial receptivity array and microbiome testing will be performed at no cost. The endometrial receptivity array provides information on the receptivity of a patient's endometrium to the implantation of an embryo. This may yield additional information regarding the etiology of a patient's infertility and/or recurrent pregnancy loss. If this testing is abnormal we may repeat the biopsy after vaginal progesterone supplementation to see if this normalizes the results. If the microbiome is abnormal we may repeat the biopsy after oral antibiotics and vaginal probiotics to see if this normalizes your microbiome results.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Assessing the Endometrial Environment in Recurrent Pregnancy Loss and Unexplained Infertility
Actual Study Start Date : September 6, 2017
Estimated Primary Completion Date : July 1, 2018
Estimated Study Completion Date : May 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Comparing the microbiome and ERA in RPL and infertility

In this arm we will assess the uterine environment at the time of implantation in recurrent pregnancy loss patients and unexplained infertility patients and compare the environment in these patient populations to healthy parous controls.

We will test the uterine endometrial gene expression using the ERA test and the uterine micro biome.

Diagnostic Test: Uterine ERA and microbiome testing
Uterine fluid and endometrial biopsy collection to test uterine endometrial receptivity array and microbiome.

Experimental: The impact of progesterone and antibiotics/probiotics
In this arm, recurrent pregnancy loss and unexplained infertility patients who have abnormal results (an abnormal microbiome or an abnormal ERA) will have the option to undergo treatment followed by retesting of the uterine environment. For an abnormal ERA suggesting a pre-receptive result, luteal phase vaginal progesterone supplementation will be offered prior to re-testing of the ERA. For an abnormal microbiome a combination of oral antibiotics and vaginal probiotics will be offered prior to re-testing the uterine microbiome.
Drug: Oral antibiotics and vaginal probiotics
For subjects with abnormal microbiome results, oral antibiotics and vaginal probiotic treatment will be offered followed by a repeat uterine microbiome biopsy.




Primary Outcome Measures :
  1. abnormal microbiome bacterial sequencing [ Time Frame: 1 month ]
    The primary outcome will abnormal microbiome results. An abnormal microbiome will be defined as less then 90% lactobacilli on DNA sequencing

  2. abnormal endometrial receptivity array [ Time Frame: 1 months ]
    The second primary outcome will be abnormal endometrial receptivity array defined as non-receptive (pre or post receptive) based on RNA sequencing of an endometrial gene array.

  3. normalized microbiome bacterial sequencing [ Time Frame: 3-6 months ]
    The primary outcome will be normal microbiome results defined as >90% lactobacilli after oral antibiotics and vaginal probiotics after initially abnormal microbiome results

  4. normalized endometrial receptivity array [ Time Frame: 3-6 months ]
    The primary outcome will be normal endometrial receptivity array results defined as receptive after luteal phase progesterone support after initially abnormal endometrial receptivity array results



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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion/Exclusion Criteria:

  1. Recurrent Pregnancy Loss

    Inclusion:

    • Age 18-45
    • 3 or more SABs including biochemical pregnancies OR 2 or more SABs if one is documented to be euploid

    Exclusion:

    • irregular menstrual cycles
    • Submucosal fibroid >3cm
    • Stage 3-4 endometriosis
    • BMI >40
    • IUD within the last 3 months
  2. Unexplained infertility Patients

    Inclusion:

    • TTC x >= 1 year
    • At least one SA with TMS >10 mil within last 2 years
    • At least one patent fallopian tube documented by HSG or SHG
    • Cycle length 25-35 days

    Exclusion:

    • Irregular menstrual cycles
    • Submucosal fibroid >3cm
    • Stage 3-4 endometriosis
    • BMI >40
    • IUD within the last 3 months
    • Less then 2 SABs including biochemical pregnancies
  3. Healthy control patients

Inclusion:

  • Patients who present for fertility preservation, sex selection, same sex couples needing fertility care, preconception counseling
  • 1 or more live births

Exclusion:

  • Irregular menstrual cycles
  • Submucosal fibroid >3cm
  • Stage 3-4 endometriosis
  • BMI >40
  • IUD within the last 3 months
  • Less then 2 SABs including biochemical pregnancies
  • No history of RPL or infertility

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03401918


Locations
United States, California
Reproductive Endocrinology and Infertility Center at Stanford University Recruiting
Sunnyvale, California, United States, 94087
Contact: Sara J Churchill, MD    617-513-4997    sarajc@stanford.edu   
Sponsors and Collaborators
Stanford University
Instituto Valenciano de Infertilidad, IVI VALENCIA

Responsible Party: Ruth Bunker Lathi, SSOCIATE PROFESSOR OF OBSTETRICS AND GYNECOLOGY (REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY) AT THE STANFORD UNIVERSITY MEDICAL CENTER, Stanford University
ClinicalTrials.gov Identifier: NCT03401918     History of Changes
Other Study ID Numbers: 40761
First Posted: January 17, 2018    Key Record Dates
Last Update Posted: January 17, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Infertility
Abortion, Spontaneous
Fetal Death
Abortion, Habitual
Genital Diseases, Male
Genital Diseases, Female
Pregnancy Complications
Death
Pathologic Processes
Anti-Bacterial Agents
Antibiotics, Antitubercular
Progesterone
Anti-Infective Agents
Antitubercular Agents
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs