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 KurinczukStuart 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

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
4 Downloads (Pure)


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.

Original languageEnglish
Number of pages174
JournalHealth Technology Assessment
Issue number25
Early online date26 May 2022
Publication statusPublished - 26 May 2022


  • Embryo Transfer/methods
  • Female
  • Fertilization in Vitro/methods
  • Freezing
  • Humans
  • Live Birth
  • Male
  • Ovarian Hyperstimulation Syndrome
  • Pregnancy
  • Pregnancy Rate


Dive into the research topics of 'Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT'. Together they form a unique fingerprint.

Cite this