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. 2022 May;26(25):1–142. doi: 10.3310/AEFU1104

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

Abha Maheshwari, Vasha Bari, Jennifer L Bell, Siladitya Bhattacharya, Priya Bhide, Ursula Bowler, Daniel Brison, Tim Child, Huey Yi Chong, Ying Cheong, Christina Cole, Arri Coomarasamy, Rachel Cutting, Fiona Goodgame, Pollyanna Hardy, Haitham Hamoda, Edmund Juszczak, Yacoub Khalaf, Andrew King, Jennifer J Kurinczuk, Stuart Lavery, Clare Lewis-Jones, Louise Linsell, Nick Macklon, Raj Mathur, David Murray, Jyotsna Pundir, Nick Raine-Fenning, Madhurima Rajkohwa, Lynne Robinson, Graham Scotland, Kayleigh Stanbury, Stephen Troup
PMCID: PMC9376799  PMID: 35603917

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.

FUNDING

This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

Plain language summary

During in vitro fertilisation, eggs and sperm are mixed in a laboratory to create embryos. An embryo is placed in the womb 2–5 days later (fresh-embryo transfer) and the remaining embryos are frozen for future use. Initial research suggested that freezing all embryos followed by thawing and replacing them a few weeks later could improve treatment safety and success. Although these data were promising, the data came from small studies and were not enough to change practice and policy. We conducted a large, multicentre, clinical trial to evaluate the two strategies: fresh-embryo transfer compared with later transfer of frozen embryos. We also compared the costs of both strategies during in vitro fertilisation treatment, pregnancy and delivery. This study was conducted across 18 clinics in the UK from 2016 to 2019, and 619 couples participated. Couples were allocated to one of two strategies: immediate fresh-embryo transfer or freezing of all embryos followed later by transfer of frozen embryo. The study’s aim was to find out which type of embryo transfer gave participants a higher chance of having a healthy baby. We found that freezing all embryos followed by frozen-embryo transfer did not lead to a higher chance of having a healthy baby. There were no differences between strategies in the number of live births, the miscarriage rate or the number of pregnancy complications. Fresh-embryo transfer was less costly from both a health-care and a patient perspective. A routine strategy of freezing all embryos is not justified given that there was no increase in success rates but there were extra costs and delays to embryo transfer.

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