Recurrent Pregnancy Loss, Unexplained Infertility
Conditions
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.
Interventions
DIAGNOSTIC_TESTUterine ERA and microbiome testing
Uterine fluid and endometrial biopsy collection to test uterine endometrial receptivity array and microbiome.
DRUGOral 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.
Sponsors
Instituto Valenciano de Infertilidad, IVI VALENCIA
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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. |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients With Recurrent Pregnancy Loss or Unexplained Infertility 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. | 25 |
| Healthy Control Patients 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. | 16 |
| Total | 41 |
Baseline characteristics
| Characteristic | Patients With Recurrent Pregnancy Loss or Unexplained Infertility | Healthy Control Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 16 Participants | 41 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants | 2 Participants | 15 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 25 Participants | 16 Participants | 41 Participants |
| Sex: Female, Male Female | 25 Participants | 16 Participants | 41 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 16 |
| other Total, other adverse events | 0 / 25 | 0 / 16 |
| serious Total, serious adverse events | 0 / 25 | 0 / 16 |
Outcome results
Primary
Abnormal Endometrial Receptivity Array
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.
Time frame: 1 month
Population: No endometrial receptivity array data were collected because the microbiome assay failed validation and further testing was not done.
Primary
Abnormal Microbiome Bacterial Sequencing
The primary outcome will abnormal microbiome results. An abnormal microbiome will be defined as less then 90% lactobacilli on DNA sequencing
Time frame: 1 month
Population: No participants were analyzed because the assay failed validation and the results are uninterpretable.
Primary
Normalized Endometrial Receptivity Array
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
Time frame: 3-6 months
Population: Data were not collected for this outcome measure as the study did not continue to the treatment phase.
Primary
Normalized Microbiome Bacterial Sequencing
The primary outcome will be normal microbiome results defined as \>90% lactobacilli after oral antibiotics and vaginal probiotics after initially abnormal microbiome results
Time frame: 3-6 months
Population: Data were not collected for this outcome measure as the study did not continue to the treatment phase.