The Outcome of Two Protocols Used to Prepare Endometrium for Frozen Embryo Transfer

Infertility Clinical Trial

Official title:

A Randomized Controlled Study to Compare the Outcome of Two Protocols Used to Prepare the Endometrium for Frozen Embryo Transfer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04507022
• Other study ID #: RFC041120190008
• Status: Completed
• Phase: Phase 4
• Start date: August 12, 2020
• Est. completion date: February 5, 2021

Study information

• Verified date: October 2020
• Source: Rahem Fertility Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a RCT to test the outcome of two protocols used for preparation of the endometrium for frozen blastocyst embryo transfer

Description:

Receptive endometrium and a good quality embryo at the blastocyst developmental stage are prerequisites for a successful implantation to occur. Blastocyst freezing techniques and survival have witnessed huge improvements in the last years. Trials to improve the outcome of frozen embryo transfer (FET) are not to be stopped. The transfer of a good quality blastocyst represents a vital part of the process. Optimization of endometrial receptivity and implantation is an everlasting challenge.

Hormone replacement therapy (HRT) is now proven to be successful for preparation of the endometrium to receive the vitrified warmed embryos. Most HRT protocols give estradiol (E2) first to reach a satisfactory endometrial thickness, then followed by progesterone to mimic the natural cycles. E2 is mostly given for 10 to 14 days and this duration might be prolonged to reach a satisfactory endometrial thickness without adversely affecting the outcome. Trans-vaginal ultrasound assessment of the endometrial thickness before the start of P supplementation has been traditionally used to predict FET cycle outcome. Clinical pregnancy rates (CPR) and live birth rates (LBR) were found to decrease for each millimetre of endometrial thickness below 7 mm. Endometrial thickness however of 9 mm was reported to be among major factors affecting LBR after FET in a large set of data.

Further, there is a recent concept that endometrial compaction (decreased thickness) between the end of estrogen phase and the day of ET has favorable impact on the outcome of FET. Different modalities were proposed to enhance endometrial compaction. One of these modalities was to decrease the dose of estrogen so as to change the estrogen- progesterone ratio as well as help in preventing further endometrial growth.

Aromatase inhibitor (AI) can be used to decrease estrogen before starting P supplementation. Additionally, there were also reports that their use had been associated with improved implantation. It appears interesting to combine the easy scheduled HRT protocol with aromatase inhibitor to maximize FET outcome.

This proposed protocol has not been tested before. In current study, HRT plus AI will be compared with HRT only. In both groups, daily intramuscular P will be given for luteal support as it was shown to give the highest ongoing pregnancy rate in FET cycles.

We did a secondary follow up analysis of some exploratory outcomes (not preregistered). These outcomes were analyzed after publication and they include Live birth rate, implantation rate, hypertensive disorders of pregnancy, large for gestation and congenital anomalies. The results of these outcomes are planned to be presented elsewhere. For openness and transparency, we felt the importance to report this follow up in the registry.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 112
• Est. completion date: February 5, 2021
• Est. primary completion date: February 5, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 37 Years

Eligibility

Inclusion Criteria:Inclusion criteria:

• Women aged from18 - 37 years old undergoing FET using good quality blastocysts vitrified on day 5(3 BB and more) (according to Gardner and Schoolcraft 1999) (8).

• Participants having at least one good quality blastocyst (3BB and more) available for transfer after warming.

• Participants having trilaminar endometrium of 9 mm after E2 preparation.

Exclusion Criteria:

• Women younger than 18 or older than 37 years old.

• Women who have uterine abnormality or pathology.

• Women who will not meet the inclusion criteria.

• Women who will refuse to participate in in the study.

Related Conditions & MeSH terms

• Infertility
• Infertility, Female
• Infertility, Male

Intervention

Drug:
• Estradiol Valerate
2mg three times daily
• Progesterone
100 mg daily intramuscular
• Aromatase inhibitor
2.5 mg twice daily for 5 days

Locations

Country	Name	City	State
Egypt	Rahem Fertility Center	Zagazig	Sharkia

Sponsors (1)

Lead Sponsor	Collaborator
Rahem Fertility Center

Country where clinical trial is conducted

Egypt, 

References & Publications (8)

Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles with the use of only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-arm randomized controlled noninferiority trial. Fertil Steril. 2018 Feb;109(2):266-275. doi: 10.1016/j.fertnstert.2017.11.004. Epub 2018 Jan 17. — View Citation

Gardner DK, Schoolcraft WB. Culture and transfer of human blastocysts. Curr Opin Obstet Gynecol. 1999 Jun;11(3):307-11. Review. — View Citation

Haas J, Smith R, Zilberberg E, Nayot D, Meriano J, Barzilay E, Casper RF. Endometrial compaction (decreased thickness) in response to progesterone results in optimal pregnancy outcome in frozen-thawed embryo transfers. Fertil Steril. 2019 Sep;112(3):503-509.e1. doi: 10.1016/j.fertnstert.2019.05.001. Epub 2019 Jun 24. — View Citation

Liu KE, Hartman M, Hartman A, Luo ZC, Mahutte N. The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers. Hum Reprod. 2018 Oct 1;33(10):1883-1888. doi: 10.1093/humrep/dey281. — View Citation

Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, Blockeel C. Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Hum Reprod. 2017 Nov 1;32(11):2234-2242. doi: 10.1093/humrep/dex285. Review. — View Citation

Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, Higdon HL 3rd, Kitawaki J, Lessey BA. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum Reprod. 2012 Mar;27(3):881-8. doi: 10.1093/humrep/der452. Epub 2012 Jan 13. — View Citation

Pan Y, Hao G, Wang Q, Liu H, Wang Z, Jiang Q, Shi Y, Chen ZJ. Major Factors Affecting the Live Birth Rate After Frozen Embryo Transfer Among Young Women. Front Med (Lausanne). 2020 Mar 24;7:94. doi: 10.3389/fmed.2020.00094. eCollection 2020. — View Citation

Sekhon L, Feuerstein J, Pan S, Overbey J, Lee JA, Briton-Jones C, Flisser E, Stein DE, Mukherjee T, Grunfeld L, Sandler B, Copperman AB. Endometrial preparation before the transfer of single, vitrified-warmed, euploid blastocysts: does the duration of estradiol treatment influence clinical outcome? Fertil Steril. 2019 Jun;111(6):1177-1185.e3. doi: 10.1016/j.fertnstert.2019.02.024. Epub 2019 Apr 24. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ongoing Pregnancy Rate	visualization of fetal cardiac pulsation by ultrasound	at 12 weeks of gestation
Secondary	endometrial compaction	change in endometrial thickness	from the end of estradiol phase to the day of embryo transfer up to 11 days
Secondary	clinical pregnancy rate	visualization of fetal cardiac pulsation by ultrasound	6 weeks gestation
Secondary	Live birth rate	The birth of at least one newborn that exhibits any sign of life	24 weeks
Secondary	Implantation rate	The number of gestational sacs observed divided by the number of embryos transferred expressed as a percentage, %	6 weeks gestation
Secondary	Number of participants with Hypertensive disorders of pregnancy	gestational hypertension or preeclampsia	20 weeks gestation till postpartum
Secondary	Number of participants with Large for gestational age	A birth weight greater than the 90th centile of the sex-specific birth weight for a given gestational age reference.	from gestation till delivery]
Secondary	Rate of Congenital anomalies	Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth or later in life.	during pregnancy and after birth (one month after birth)