Direct Warming Frozen Embryo Transfer Outcomes in Assisted Reproductive Technology (DW-FET-RCT)

A Pragmatic, Multi-centre, Double-blinded, Two-arm Randomized Controlled Trial on a Direct Warming Frozen Embryo Transfer in Assisted Reproductive Technologies Treatment Outcome

The goal of this clinical trial is to evaluate whether the direct warming method for frozen embryo transfers (FET) can improve live birth and pregnancy outcomes in women aged 18-45 undergoing IVF treatments. The main questions it aims to answer are:

• Does the direct warming method achieve a similar or higher clinical success rate for FET compared to the conventional multi-step method?
• Is the direct warming method more cost-effective than the conventional method?

Researchers will compare the direct warming method to the conventional multi-step method to see if the former leads to better pregnancy outcomes and reduced procedural time.

Participants will:

• Undergo either the one-step or conventional embryo thawing procedure.
• Complete standard clinical follow-ups for pregnancy, including ultrasound scans and pregnancy tests.

Study Overview

• Status: Not yet recruiting
• Conditions: In Vitro Fertilization (IVF); Assisted Reproductive Techniques; Cryopreservation of Embryos; Frozen Embryo Transfer (FET); Pregnancy Outcome After in Vitro Fertilization (IVF)
• Intervention / Treatment: Other: Direct Warming Method; Other: Conventional Multi-step Thawing Method

Detailed Description

This clinical trial explores a novel direct warming method for frozen embryo transfer (FET), aimed at improving both clinical and operational outcomes in assisted reproductive technologies (ART). The method was designed to simplify and accelerate the embryo thawing process, reducing the time needed for thawing while eliminating the use of cryoprotectants commonly required in conventional thawing methods. This innovation has the potential to offer a more efficient and cost-effective alternative to standard FET procedures.

The primary focus of this trial is to compare the clinical effectiveness of the direct warming method against the conventional multi-step thawing process. In particular, the study seeks to determine whether the new method yields comparable or superior outcomes in terms of clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR), and live birth rate (LBR), while also assessing its overall cost-effectiveness.

Study Design and Technical Details

This study employs a randomized controlled design, with participants being allocated into either the intervention group (direct warming method) or the control group (conventional multi-step thawing). The direct warming method streamlines the thawing process to just 3 minutes, in contrast to the conventional method, which requires multiple stages and takes approximately 20 minutes. By using only an embryo culture medium without cryoprotectants, the direct warming method reduces both complexity and potential risks associated with handling and cryoprotectant toxicity.

Key Objectives

• Primary Objective: To evaluate the clinical efficacy of the direct warming method in achieving comparable or higher success rates for FET as compared to conventional multi-step thawing.
• Secondary Objective: To assess the cost-effectiveness of the direct warming method by comparing the consumable and time costs across different centers.

Expected Impact and Innovation

The direct warming method challenges the traditional multi-step thawing approach, offering a faster and simpler alternative without compromising clinical outcomes. By minimizing the need for cryoprotectants and reducing the complexity of the thawing process, the new method is expected to enhance the overall efficiency of FET procedures while maintaining or improving pregnancy success rates. Additionally, the cost and time savings associated with the direct warming method may make it a viable option for IVF clinics worldwide, driving standardization and consistency across clinical settings.

• Study Type: Interventional
• Enrollment (Estimated): 578
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yiu Leung D Chan, DPhil; Phone Number: (852) 3505 3199; Email: drdcyl16@cuhk.edu.hk
• Study Contact Backup: Name: Waner Wu, MPhil; Phone Number: (852) 3505 1764; Email: wanerwu@link.cuhk.edu.hk

Study Locations

• Hong Kong
  • Hong Kong SAR
    • Shatin, New Territories, Hong Kong SAR, Hong Kong
      • The Chinese University of Hong Kong
      • Contact: Phone Number: (852) 3505 1764
    • Shatin,NT, Hong Kong SAR, Hong Kong
      • The CUHK Medical centre
      • Contact: Yiu Leung, David Chan; Phone Number: +852 3946 6888; Email: drdcyl16@cuhk.edu.hk
• United Kingdom
  • London, United Kingdom
    • The Homerton Hospital
    • Contact: Priya Bhide; Phone Number: 020 8510 5555; Email: p.bhide@qmul.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Plan to undergo single embryo transfer (SET) during the FET cycle.
• Age between 18 and 45 years.
• Patients with at least one high-quality blastocyst available for transfer.
• Patients who have provided informed consent to participate in the study.

Exclusion Criteria:

• Patients with repeated implantation failure (RIF) or recurrent miscarriage (RM).
• Patients with known uterine anomalies or significant uterine pathology (e.g., fibroids, polyps).
• Patients who are unwilling or unable to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Direct Warming method; The blastocyst designated for thawing will be placed in a pre-warmed, direct warming medium for one minute. Afterward, the embryo is transferred into an embryo culture medium within a time-lapse system, where it remains until the patient is ready for the embryo transfer procedure. This direct warming method significantly reduces the total procedure time to approximately 3 minutes, making it about ten times faster than the conventional multi-step thawing method.	Other: Direct Warming Method; This intervention involves thawing vitrified blastocysts using a simplified, one-step direct warming method. The blastocyst is placed in a pre-warmed embryo culture medium for approximately one minute, then transferred directly into the embryo culture medium within a time-lapse system until ready for uterine transfer. The total thawing process takes approximately three minutes, reducing the duration and complexity of the procedure compared to conventional methods.; Other Names: One-step thawing
Placebo Comparator: Conventional multi-step thawing method; In the conventional multi-step thawing method, vitrified blastocysts are sequentially thawed using a series of pre-warmed thawing, dilution, and washing solutions. The blastocyst is first placed in a thawing solution for 1-3 minutes, followed by immersion in a dilution solution for 4-6 minutes to reduce cryoprotectant concentration. Finally, the blastocyst is transferred to a washing solution for 5-10 minutes for rehydration. The entire process takes approximately 30 minutes, after which the embryo is placed into an embryo culture medium in a time-lapse system until it is ready for embryo transfer.	Other: Conventional Multi-step Thawing Method; This intervention involves thawing vitrified blastocysts using a standard, multi-step process. The procedure includes sequential exposure of the blastocyst to different thawing solutions containing varying concentrations of cryoprotectants, followed by its transfer into an embryo culture medium in a time-lapse system. The overall process takes approximately 10-30 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Pregnancy Rate	Number of participants with at least one intrauterine gestational sac observed on ultrasound at 6-8 weeks of gestation following embryo transfer.	6-8 weeks post embryo transfer
Ongoing Pregnancy Rate (OPR)	Number of participants with a viable intrauterine pregnancy observed on ultrasound at 12 weeks of gestation.	12 weeks post embryo transfer
Live Birth Rate (LBR)	Number of participants who deliver a live infant after 24 weeks of gestation.	At delivery, approximately 9 months post embryo transfer
Cost-Effectiveness	A comparative analysis of the total costs, including costs of consumables (e.g., warming mediums, storage devices) and staff labor hours, associated with the direct warming method compared to the conventional multi-step thawing method. Costs will be measured in USD and analyzed at the end of the study period.	At the end of the study, approximately 4 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup Analysis of Warming Medium	Analysis of the clinical differences between brands of warming mediums assessing their impact on embryo survival rate.	Throughout the study period, approximately 4 years.
Subgroup Analysis of Storage Devices	Analysis of the clinical differences between brands of Storage Devices assessing their impact on embryo survival rate.	Throughout the study period, approximately 4 years.

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong

Publications and helpful links

General Publications

• Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM, Vanderpoel S, Racowsky C. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. 2017 Mar 1;23(2):139-155. doi: 10.1093/humupd/dmw038.
• Canosa S, Parmegiani L, Charrier L, Gennarelli G, Garello C, Granella F, Evangelista F, Monelli G, Guidetti D, Revelli A, Filicori M, Bongioanni F. Are commercial warming kits interchangeable for vitrified human blastocysts? Further evidence for the adoption of a Universal Warming protocol. J Assist Reprod Genet. 2022 Jan;39(1):67-73. doi: 10.1007/s10815-021-02364-1. Epub 2021 Nov 30.
• Wang SF, Seifer DB. Age-related increase in live-birth rates of first frozen thaw embryo versus first fresh transfer in initial assisted reproductive technology cycles without PGT. Reprod Biol Endocrinol. 2024 Apr 13;22(1):42. doi: 10.1186/s12958-024-01210-0.
• Parmegiani L, Beilby KH, Arnone A, Bernardi S, Maccarini AM, Nardi E, Cognigni GE, Filicori M. Testing the efficacy and efficiency of a single "universal warming protocol" for vitrified human embryos: prospective randomized controlled trial and retrospective longitudinal cohort study. J Assist Reprod Genet. 2018 Oct;35(10):1887-1895. doi: 10.1007/s10815-018-1276-4. Epub 2018 Aug 3.
• Schiewe MC, Anderson RE. Vitrification: the pioneering past to current trends and perspectives of cryopreserving human embryos, gametes and reproductive tissue. Journal of Biorepository Science for Applied Medicine. 2017;5:57-68.
• Jiang VS, Cherouveim P, Naert MN, Dimitriadis I, Souter I, Bormann CL. Live birth outcomes following single-step blastocyst warming technique - optimizing efficiency without impacting live birth rates. J Assist Reprod Genet. 2024 May;41(5):1193-1202. doi: 10.1007/s10815-024-03069-x. Epub 2024 Mar 13.
• Liebermann J, Hrvojevic K, Hirshfeld-Cytron J, Brohammer R, Wagner Y, Susralski A, Jasulaitis S, Chan S, Takhsh E, Uhler M. Fast and furious: pregnancy outcome with one-step rehydration in the warming protocol for human blastocysts. Reprod Biomed Online. 2024 Apr;48(4):103731. doi: 10.1016/j.rbmo.2023.103731. Epub 2023 Nov 23.
• Manns JN, Katz S, Whelan J, Patrick JL, Holt T, Merline AM, et al. VALIDATION OF A NEW, ULTRA-FAST BLASTOCYST WARMING TECHNIQUE REDUCES WARMING TIMES TO 1 MIN AND YIELDS SIMILAR SURVIVAL AND RE-EXPANSION COMPARED TO BLASTOCYSTS WARMED USING A STANDARD METHOD. Fertility and Sterility.
• Yan G, Yao Y, Yang W, Lu L, Wang L, Zhao D, Zhao S. An all-37 degrees C thawing method improves the clinical outcomes of vitrified frozen-thawed embryo transfer: a retrospective study using a case-control matching analysis. Arch Gynecol Obstet. 2023 Jun;307(6):1991-1999. doi: 10.1007/s00404-023-07029-1. Epub 2023 Apr 12.
• Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature. 1983 Oct 20-26;305(5936):707-9. doi: 10.1038/305707a0.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2025
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: November 19, 2024
• First Submitted That Met QC Criteria: December 15, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 6, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: In Vitro Fertilization; Cryopreservation; Frozen Embryo Transfer; Assisted Reproductive Technologies; Direct Warming Method; Cost-effectiveness in ART; Embryo Warming
• Other Study ID Numbers: 2024.132-T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD will not be shared due to concerns regarding participant confidentiality and privacy. Additionally, the informed consent process did not include provisions for the sharing of individual-level data with third parties. Furthermore, local regulatory restrictions limit the ability to distribute sensitive health data outside the study team.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No