Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT

Maheshwari, Abha; Bari, Vasha; Bell, Jennifer L.; Bhattacharya, Siladitya; Bhide, Priya; Bowler, Ursula; Brison, Daniel; Child, Tim; Chong, Huey Yi; Cheong, Ying; Cole, Christina; Coomarasamy, Arri; Cutting, Rachel; Goodgame, Fiona; Hardy, Pollyanna; Hamoda, Haitham; Juszczak, Edmund; Khalaf, Yacoub; King, Andrew; Kurinczuk, Jennifer J.; Lavery, Stuart; Lewis-Jones, Clare; Linsell, Louise; Macklon, Nick; Mathur, Raj; Murray, David; Pundir, Jyotsna; Raine-Fenning, Nick; Rajkohwa, Madhurima; Robinson, Lynne; Scotland, Graham; Stanbury, Kayleigh; Troup, Stephen

Abstract

Background
Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it.

Objective
We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos.

Design
This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial.

Setting
Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019.

Participants
Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years.

Interventions
If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control).

Outcomes
The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State–Trait Anxiety Inventory scores.

Results
A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval –2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval –2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth.

Limitations
We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected.

Conclusion
When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer.

Trial registration
This trial is registered as ISRCTN61225414.

Citation

Maheshwari, A., Bari, V., Bell, J. L., Bhattacharya, S., Bhide, P., Bowler, U., …Troup, S. (2022). Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT. Health Technology Assessment, 26(25), 1-142. https://doi.org/10.3310/AEFU1104

• Journal Article Type: Article
• Acceptance Date: Aug 1, 2021
• Online Publication Date: May 1, 2022
• Publication Date: May 1, 2022
• Deposit Date: May 25, 2022
• Publicly Available Date: May 25, 2022
• Journal: Health Technology Assessment
• Print ISSN: 1366-5278
• Electronic ISSN: 2046-4924
• Publisher: NIHR Journals Library
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 25
• Pages: 1-142
• DOI: https://doi.org/10.3310/AEFU1104
• Keywords: Health Policy
• Public URL: https://nottingham-repository.worktribe.com/output/8221411
• Publisher URL: https://www.journalslibrary.nihr.ac.uk/hta/AEFU1104/#/abstract
• Additional Information: Copyright © 2022 Maheshwari et al. This work was produced by Maheshwari et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.