Transfer of thawed frozen embryo versus fresh embryo to improve the
healthy baby rate in women undergoing IVF: the E-Freeze RCT
Authors: 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 
Published: May 2022

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.