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

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

Detailed Description
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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.

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

Conditions
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Infertility, Infertility, Female, Infertility, Male

Intervention / Treatment
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* Drug: Estradiol Valerate
* Drug: Progesterone
* Drug: Aromatase inhibitor


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 37 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: HRT Plus Aromatase Inhibitor<br>Hormone replacement treatment (HRT) will be used in all cases. Exogenous estradiol will be started on day 2 or 3 of the cycle. In all participants, 2 mg oral estradiol valerate, will be administered three times daily. Ultrasound evaluation of endometrium will be performed 10 to 12 days after starting E2. Trilaminar endometrium of 9 mm will be the targeted cutoff . If not yet ready, E2 supplementation will be continued with serial US assessment until the desired cutoff is achieved. Thereafter, participants will be randomized to two groups: Group A (HRT plus AI): will be given aromatase inhibitor for 5 days only (2.5 mg twice daily), along with the oral 6 mg E2. Then, daily intramuscular (IM) P in oil (100 mg IM P) will be started in addition to the daily dose of oral 6 mg E2. In both groups, embryos will be warmed on the 6th day of P supplementation. Before undergoing FET, endometrial thickness will be re-evaluated. IM P and 6mg E2 will be continued thereafter. | Drug: Estradiol Valerate<br>* 2mg three times daily<br>Drug: Progesterone<br>* 100 mg daily intramuscular<br>Drug: Aromatase inhibitor<br>* 2.5 mg twice daily for 5 days<br>|
| Active Comparator: HRT Only<br>Hormone replacement treatment (HRT) will be used in all cases. Exogenous estradiol will be started on day 2 or 3 of the cycle. In all participants, 2 mg oral estradiol valerate, will be administered three times daily. Ultrasound evaluation of endometrium will be performed 10 to 12 days after starting E2. Trilaminar endometrium of 9 mm will be the targeted cutoff . If not yet ready, E2 supplementation will be continued with serial US assessment until the desired cutoff is achieved. Thereafter, participants will be randomized to two groups Group B (HRT only): will be administered daily intramuscular (IM) P in oil (100 mg IM P) in addition to the daily dose of oral 6 mg E2. In both groups, embryos will be warmed on the 6th day of P supplementation. Before undergoing FET, endometrial thickness will be re-evaluated. IM P and 6mg E2 will be continued thereafter. | Drug: Estradiol Valerate<br>* 2mg three times daily<br>Drug: Progesterone<br>* 100 mg daily intramuscular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Pregnancy Rate | visualization of fetal cardiac pulsation by ultrasound | at 12 weeks of gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| endometrial compaction | change in endometrial thickness | from the end of estradiol phase to the day of embryo transfer up to 11 days | 
| clinical pregnancy rate | visualization of fetal cardiac pulsation by ultrasound | 6 weeks gestation | 
| Live birth rate | The birth of at least one newborn that exhibits any sign of life | 24 weeks | 
| Implantation rate | The number of gestational sacs observed divided by the number of embryos transferred expressed as a percentage, % | 6 weeks gestation | 
| Number of participants with Hypertensive disorders of pregnancy | gestational hypertension or preeclampsia | 20 weeks gestation till postpartum | 
| 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] | 
| 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) |