Effect of Endometrial Biopsy on in Vitro Fertilization Pregnancy Rates - a Multicenter Study

Study Overview
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Brief Summary
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Animal and clinical studies have suggested that local tissue trauma can promote the process of an embryo implanting in the uterine cavity. The clinical studies have been performed in patients with a history of previously failed treatments using in vitro fertilization; a process of stimulating many eggs from a women and removing them from the body, to allow fertilisation with sperm to occur in a laboratory setting. The embryos are then replaced into the uterine cavity. This study questions whether endometrial biopsy (placing a small straw like catheter through the cervix and into the uterine cavity to take a sample of tissue via suction into the bore of the catheter), within 5-10 days of starting a cycle of in vitro fertilization, will improve pregnancy outcome for patients in the first or second cycle of treatment. The hypothesis is that endometrial biopsy will improve pregnancy outcome. The study is a randomized multicentre study involving 3 Canadian fertility centres.

Detailed Description
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Although the data are preliminary, there are studies suggesting that mild endometrial trauma in the cycle preceding IVF increases pregnancy rates, at least in women with recurrent implantation failure. Whether endometrial biopsy could promote implantation and improve pregnancy rates in the larger population of women undergoing IVF has yet to be explored. The present study will address this question and examine the impact of endometrial biopsies on IVF outcomes in the context of a randomized controlled trial. The optimal timing of the endometrial biopsy in the cycle preceding IVF has not been determined, but the majority of the studies have included a biopsy in the mid-luteal phase of the preceding cycle. In order to allow an adjuvant therapy to IVF that would be considered tolerable to a subject, and applicable to a large infertile women population, it was determined that a single endometrial biopsy, performed approximately 1 week prior to the start of controlled ovarian hyperstimulation (COH) in an IVF cycle, would be the simplest, most flexible, and generalizable intervention to study its effects on pregnancy rates. All other components of the IVF treatment will remain constant with approximately 8-12 days of ovarian stimulation, human chorionic gonadotrophin (HCG) trigger being administered in that time frame and oocyte retrieval occuring 36 hours later from trigger. The embryo transfer will take place either day 3 or day 5 after oocyte retrieval.

Official Title
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Effect of Endometrial Biopsy on in Vitro Fertilization Pregnancy Rates - a Randomized, Multicenter Study

Conditions
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Infertility, Pregnancy

Intervention / Treatment
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* Device: Endometrial Biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women undergoing first or second IVF cycle, with or without ICSI Age 18-39 BMI 18-35 kg/m2 Uterine cavity evaluation (hysterosalpingogram, sonohysterogram, hysteroscopy) in the preceding 24 months Early follicular phase (Day 2 or Day 3) serum FSH, evaluated in the preceding 6 months ONE of the following: Non- oral contraceptive pill (non-OCP) subjects: Documented LH surge 9-11 days prior to enrollment Current OCP subjects: OCP use for ≥ 10 days Use of long GnRH agonist or GnRH antagonist protocol Subject able to give informed consent Exclusion Criteria: Prior enrolment in this study Any prior early follicular phase serum FSH level ≥12 IU/L Previous poor ovarian response, defined as prior IVF cycle cancelled for poor response, or ≤4 oocytes retrieved IVF for pre-implantation genetic diagnosis (PGD) or fertility preservation Diabetes mellitus or uncontrolled thyroid disease Abnormal uterine cavity, such as unresected submucosal fibroids, uterine septum, Mullerian anomaly such as bicornuate or unicornuate uterus or intrauterine adhesions Hydrosalpinx that has not been removed or surgically ligated Any contraindication to endometrial biopsy Office hysteroscopy or other uterine procedure planned or performed during cycle preceding IVF stimulation Use of surgically retrieved sperm

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Endometrial Biopsy<br>Endometrial biopsy performed within 5-10 days prior to starting controlled ovarian stimulation, as part of in vitro fertilization treatment. | Device: Endometrial Biopsy<br>* An endometrial biopsy is performed using a sampling device known as a pipelle catheter which is introduced into the uterine cavity. The inner core is withdrawn creating suctional pressure into the hollow bore of the cavity, which allows acquisition of endometrial tissue upon rotation in the cavity. This is removed and the tissue sent for pathologic examination.<br>* Other names: Endometrial sampling;|
| No Intervention: Without Biopsy<br>Those proceeding with in vitro fertilization routinely, without an endometrial biopsy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Pregnancy Rate | Clinical pregnancy rate, defined as transvaginal ultrasound documentation of fetal heartbeat at five weeks gestation. | Five weeks gestation, as dated from the egg retrieval | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Implantation Rate | The number of gestational sacs seen at ultrasound, divided by the total number of embryos transferred | Five weeks gestation, as dated from the egg retrieval | 
| Live Birth Delivery Rate | Live birth delivery rate will be the number of live birth deliveries expressed per 100 initiated cycles, aspiration cycles or embryo transfer cycles, for which the denominator (initiated, aspirated or embryo transfer cycles) will be specified. Live birth delivery will include deliveries that resulted in at least one live birth. The delivery of a singleton, twin or other multiple births will be registered as one delivery. | Within twelve months of the cycle start date | 
| Fertilization Rate | Fertilization rate will be the number of zygotes resulting from insemination by IVF or injection by intracytoplasmic sperm injection, expressed as a ratio to the total number of oocytes inseminated or injected. | 24 hours after egg retrieval | 
| Normal Fertilization Rate | Normal fertilization rate will be the number of normal zygotes resulting from insemination by IVF or injection by ICSI, expressed as a ratio to the total number of oocytes inseminated or injected. | 24 Hours from egg retrieval | 
| Endometrial Thickness | As assessed by transvaginal ultrasound, the maximum dimension of the endometrial cavity echo in an antero-posterior plane. | Day of administration of human chorionic gonadotropin (8-12 days into ovarian stimulation) | 
| Endometrial Pattern | The endometrial pattern will be categorised as either trilaminar (triple stipe pattern) or hyperechoic (diffusely echogenic)at the time of transvaginal ultrasound assessment. | Day of administration of human chorionic gonadotropin (8-12 days into ovarian stimulation) | 
| Percentage of subjects with embryos cryopreserved | Total number of participants with embryos in excess, that met criteria for cryopreservation | At the latest, day 6 after egg retrieval | 
| The number of embryos cryopreserved per subject | The number of embryos each individual participant had in excess, meeting criteria for cryopreservation | At the latest, day 6 after egg retrieval | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endometrial Biopsy, Endometrial Sampling, In Vitro Fertilization, Pregnancy, Implantation