Freezing All Embryos Versus Fresh Embryo Transfer in In-Vitro Fertilisation – a Multicentre Randomised Controlled Trial in the UK (E-Freeze)

Background: Embryos created following in-vitro fertilisation (IVF) are usually replaced within the uterus within a few days (fresh embryo transfer). It has been suggested that elective freezing of all embryos followed by transfer at a later date (freeze-all) could make treatment safer and more effective. The aim of this trial was to compare the clinical and cost-effectiveness of a strategy of freeze-all versus fresh embryo transfer. Methods: A two arm, non-blinded, parallel group pragmatic randomised trial was conducted across 18 IVF clinics in the UK. Couples undergoing IVF, where the woman was <42 years of age were randomised (1:1 allocation ratio) to either freeze-all or a fresh embryo transfer, provided they had at least 3 good quality embryos. The primary outcome was healthy baby rate (term singleton live birth with appropriate weight for gestation) (ISCTRN: 61225414). Findings: Between 2016 and 2019, 619 couples were randomised (309 to freeze-all and 310 to fresh transfer). Of these, 307 and 309 couples in the freeze-all and fresh transfer arms were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the freeze-all group compared to the fresh embryo transfer group: healthy baby rate {20.3 % (62/307) versus 24.4% (75/309); Risk Ratio (RR), 95% Confidence Interval (CI): 0.84, 0.62 to 1.15}]; ovarian hyperstimulation (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06), and miscarriage (14.3% versus 12.9%; RR 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the freeze-all group. The freeze-all approach was more costly and was unlikely to be cost-effective in a UK NHS context. Interpretation: This study provides no evidence to support the adoption of a routine policy of freezing all embryos in preference to fresh embryo transfer in order to improve infant outcomes. Clinical Trial Registration Details: The trial was registered with the International Standard Randomised Controlled Trial Register (ISRCTN61225414) as was conducted as per published protocol. Funding Information: NIHR HTA, UK (13/115/82). Declaration of Interests: PH, JK, report receipt of funding from NIHR, during the conduct of the study. JB, CC,EJ, KS report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. AM reports grants from NIHR personal fees from Merck Serono, personal fees from Ferring, and Cooks, outside the submitted work. SB reports grants from NIHR HTA, during the conduct of the study and remuneration from Oxford University Press for role as Editor in Chief of Human Reproduction Open. DB reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. YC reports personal fees from Merck Serono, personal fees from Ferring, outside the submitted work. EJ reports membership of the HTA Commissioning Board (2013–16), the NIHR HTA General Board (2016–17) and is a member of the NHS England and NIHR partnership programme (2019 to present). RM reports other private practice fees from Manchester Fertility, personal fees from Merck, personal fees from Ferring, personal fees from Gedeon Richter, outside the submitted work. GS reports non-financial support and other from Merck KGaA, Darmstadt, Germany, outside the submitted work. ST reports personal fees from CooperSurgical International, personal fees from Parallabs, outside the submitted work. Other Authors’ Competing Interests: None declared. Ethics Approval Statement: The E-Freeze trial protocol was approved by the North of Scotland Research Ethics Service (NoSRES) Committee (Study Ref: 15/NS/0114). Local approval and site-specific assessments were obtained from each participating site.