Effect of Endometrial Biopsy on in Vitro Fertilization Pregnancy Rates - a Multicenter Study (EndoBx-IVF)

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

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.

Study Overview

• Status: Terminated
• Conditions: Infertility; Pregnancy
• Intervention / Treatment: Device: Endometrial Biopsy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5G 4X7
      • Pacific Centre for Reproductive Medicine
  • Ontario
    • Toronto, Ontario, Canada, M5T 2Z5
      • Mt. Sinai Hospital Centre for Fertility and Reproductive Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Endometrial Biopsy; Endometrial biopsy performed within 5-10 days prior to starting controlled ovarian stimulation, as part of in vitro fertilization treatment.	Device: Endometrial Biopsy; 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.; Other Names: Endometrial sampling; Endometrial pipelle biopsy
NO_INTERVENTION: Without Biopsy; Those proceeding with in vitro fertilization routinely, without an endometrial biopsy.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Jon Havelock
• Investigators: Principal Investigator: Jon C Havelock, MD, Pacific Centre for Reproductive Medicine and University of British Columbia

Publications and helpful links

General Publications

• Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril. 2003 Jun;79(6):1317-22. doi: 10.1016/s0015-0282(03)00345-5.
• Lejeune B, Lecocq R, Lamy F, Leroy F. Changes in the pattern of endometrial protein synthesis during decidualization in the rat. J Reprod Fertil. 1982 Nov;66(2):519-23. doi: 10.1530/jrf.0.0660519.
• Humphrey KW. The effects of some anti-oestrogens on the deciduoma reaction and delayed implantation in the mouse. J Reprod Fertil. 1968 Jul;16(2):201-9. doi: 10.1530/jrf.0.0160201. No abstract available.
• Gnainsky Y, Granot I, Aldo PB, Barash A, Or Y, Schechtman E, Mor G, Dekel N. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril. 2010 Nov;94(6):2030-6. doi: 10.1016/j.fertnstert.2010.02.022. Epub 2010 Mar 24.
• Raziel A, Schachter M, Strassburger D, Bern O, Ron-El R, Friedler S. Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure. Fertil Steril. 2007 Jan;87(1):198-201. doi: 10.1016/j.fertnstert.2006.05.062.
• Karimzadeh MA, Ayazi Rozbahani M, Tabibnejad N. Endometrial local injury improves the pregnancy rate among recurrent implantation failure patients undergoing in vitro fertilisation/intra cytoplasmic sperm injection: a randomised clinical trial. Aust N Z J Obstet Gynaecol. 2009 Dec;49(6):677-80. doi: 10.1111/j.1479-828X.2009.01076.x.
• Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril. 2008 May;89(5):1166-1176. doi: 10.1016/j.fertnstert.2007.05.064. Epub 2007 Aug 6.
• Karimzade MA, Oskouian H, Ahmadi S, Oskouian L. Local injury to the endometrium on the day of oocyte retrieval has a negative impact on implantation in assisted reproductive cycles: a randomized controlled trial. Arch Gynecol Obstet. 2010 Mar;281(3):499-503. doi: 10.1007/s00404-009-1166-1. Epub 2009 Jul 1.
• Katz VL. Diagnostic procedures. Imaging, endometrial sampling, endoscopy: indications and contraindications, complications. In: Katz VL, Lentz GM, Lobo RA, Gershenson DM, eds. Comprehensive Gynecology . 5th ed. Philadelphia, Pa: Mosby; 2007.
• Hilton J, Liu KE, Laskin CA, Havelock J. Effect of endometrial injury on in vitro fertilization pregnancy rates: a randomized, multicentre study. Arch Gynecol Obstet. 2019 Apr;299(4):1159-1164. doi: 10.1007/s00404-019-05044-9. Epub 2019 Jan 19.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): April 1, 2016

Study Registration Dates

• First Submitted: April 12, 2013
• First Submitted That Met QC Criteria: November 12, 2013
• First Posted (ESTIMATE): November 14, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 28, 2017
• Last Update Submitted That Met QC Criteria: November 24, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Pregnancy; In Vitro Fertilization; Implantation; Endometrial Biopsy; Endometrial Sampling
• Additional Relevant MeSH Terms: Infertility
• Other Study ID Numbers: EndoBx- IVF