Assessing the Endometrial Environment in Recurrent Pregnancy Loss and Unexplained Infertility

Phase 2

Completed

• Conditions: Recurrent Pregnancy Loss; Unexplained Infertility
• Interventions: Diagnostic Test: Uterine ERA and microbiome testing; Drug: Oral antibiotics and vaginal probiotics

• Registration Number: NCT03401918
• Lead Sponsor: 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.

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 Timeline

• Study Start: 2017-08-01
• Study First Submitted: 2018-01-01
• Study First Submitted QC: 2018-01-09
• Study First Posted: 2018-01-17
• Primary Completion: 2021-07-01
• Study Completion: 2021-07-01
• Results First Submitted: 2022-04-04
• Status Verified: 2022-05
• Results First Submitted QC: 2022-05-10
• Last Update Submitted: 2022-05-10
• Results First Posted: 2022-05-13
• Last Update Posted: 2022-05-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 41

Inclusion Criteria

Not provided

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patients with recurrent pregnancy loss or unexplained infertility	Uterine ERA and microbiome testing	Patients with recurrent pregnancy loss or unexplained infertility will have an assessment of the uterine environment at the time of implantation, followed by testing of uterine endometrial gene expression using the ERA test and the uterine micro biome. Those 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.
Patients with recurrent pregnancy loss or unexplained infertility	Oral antibiotics and vaginal probiotics	Patients with recurrent pregnancy loss or unexplained infertility will have an assessment of the uterine environment at the time of implantation, followed by testing of uterine endometrial gene expression using the ERA test and the uterine micro biome. Those 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.
Healthy Control Patients	Uterine ERA and microbiome testing	Patients who have had a normal delivery and no history of infertility or recurrent pregnancy loss will have assessment of the uterine environment at the time of implantation.

Primary Outcome Measures

Name	Time	Method
Normalized Microbiome Bacterial Sequencing	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
Abnormal Endometrial Receptivity Array	1 month	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.
Abnormal Microbiome Bacterial Sequencing	1 month	The primary outcome will abnormal microbiome results. An abnormal microbiome will be defined as less then 90% lactobacilli on DNA sequencing
Normalized Endometrial Receptivity Array	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

Trial Locations

Locations (1)

Reproductive Endocrinology and Infertility Center at Stanford University; 🇺🇸 Sunnyvale, California, United States