Natural Cycle Versus Hormone Replacement Therapy Cycle for a Frozen-thawed Embryo Transfer in PGT Patients

Natural Cycle Versus Hormone Replacement Therapy Cycle for a Frozen-thawed Embryo Transfer in PGT Patients: A Randomized Trial

The aim of the current study is to compare miscarriage rates (before 8 weeks) between a true natural cycle (awaiting spontaneous LH surge) and a hormone replacement therapy cycle prior to blastocyst transfer in preimplantation genetic testing (PGT) patients, with biopsy on day 5 of embryonic development. The advantage of performing the study in PGT patients is the exclusion of aneuploidy as a cause of miscarriage.

Study Overview

• Status: Recruiting
• Conditions: Miscarriage; Frozen Embryo Transfer; Natural Cycle; Hormone Replacement Therapy Cycle; Preimplantation Genetic Screening; Euploid Embryos
• Intervention / Treatment: Drug: Estradiol Valerate; Drug: Micronized progesterone

• Study Type: Interventional
• Enrollment (Estimated): 522
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1090
    • Recruiting
    • Centre for Reproductive Medicine UZ Brussel
    • Contact: Elsie Nulens; Phone Number: +32 2 477 66 48; Email: Studieverpleegkundigen_CRG@UZBrussel.be
    • Sub-Investigator: Christophe Blockeel, MD, PhD
    • Principal Investigator: Caroline Roelens, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• BMI under 35 kg/m2
• Regular menstrual cycle pattern (i.e. 24-35 days cycle)
• First, second and third ICSI-PGT cycle
• First frozen embryo transfer cycle following a fresh ICSI-PGT attempt
• PGT with trophectoderm biopsy on day 5 of embryonic development
• Signed informed consent

Exclusion Criteria:

• Oligo-amenorrhea
• BMI above 35
• Contraindications for the use of hormonal replacement therapy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Natural cycle; Patients are asked to perform a blood sample, with evaluation of serum estradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH), on the first or second day of the menstrual cycle. If these serum hormonal values are considered basal for the beginning of the follicular phase, patients are asked to come back on day 10 to 12 of the cycle for blood sample and transvaginal ultrasound scan in order to assess follicular growth. The timing of ovulation is determined based on a combination of ultrasonography features (the presence of a dominant follicle and adequate endometrium) and endocrine hormonal values in serum blood samples. Ovulation is generally defined as an, at least, 180% increase of LH compared to the mean level in the previous 24h. Frozen-warmed blastocyst transfer will take place six days following the spontaneous LH surge.
Experimental: Hormone replacement therapy cycle; Patients are asked to perform a blood sample, with evaluation of serum estradiol (E2), progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on the first or second day of the menstrual cycle. If these values are considered basal for the beginning of the follicular phase, estrogen supplementation (Estradiol valerate, Progynova® 3x2mg/day) is started to induce proliferation of the endometrium. Blood sample and transvaginal ultrasound are thereafter performed ten to fourteen days later. If the endometrium is considered adequate (generally considered if triple line and above 6,5 mm thickness), embryo transfer is scheduled on the sixth day of progesterone (vaginal micronized progesterone, Utrogestan® 2x200mg twice a day) supplementation. In case of escape spontaneous ovulation embryo transfer will be performed considering the presumable time of ovulation.	Drug: Estradiol Valerate; Estradiol valerate will be started in the beginning of the menstrual cycle in order to induce proliferation of the endometrium.; Other Names: Progynova; Drug: Micronized progesterone; If the endometrium is considered adequately proliferated, micronized progesterone is administered and frozen-thawed blastocyst transfer will take place on the 6th day of supplementation.; Other Names: Utrogestan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miscarriage rate before 8 weeks of gestation	a spontaneous loss of a clinical pregnancy before 8 weeks of gestational age, in which the embryo(s) is/are nonviable and is/are (not) spontaneously absorbed or expelled from the uterus per initiated embryo transfer cycle and per positive hCG	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miscarriage rate after 8 weeks of gestation	a spontaneous loss of a clinical pregnancy after 8 weeks but before 22 completed weeks of gestational age, in which the embryo(s) or fetus(es) is/are nonviable and is/are not spontaneously absorbed or expelled from the uterus per initiated embryo transfer cycle and per positive hCG	22 weeks
Clinical pregnancy rate	a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy per initiated embryo transfer cycles	7 weeks
Ongoing pregnancy rate	the number of pregnancies after 20 weeks of gestation per initiated embryo transfer cycle	20 weeks

Collaborators and Investigators

• Sponsor: CRG UZ Brussel

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2019
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 5, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 14, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: natural cycle; FET; miscarriage; frozen-thawed embryo transfer; hormone replacement therapy cycle
• Additional Relevant MeSH Terms: Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Abortion, Spontaneous; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Progestins; Estradiol; Progesterone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate
• Other Study ID Numbers: HRT_NC-FET; 2018-003156-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No