Title: E-FREEZE: a randomised controlled trial evaluating the clinical and cost-effectiveness of a policy of freezing all embryos followed by thawed frozen embryo transfer, compared with a policy of fresh embryo transfer in women undergoing in-vitro fertilization
Funder: Chief Scientist Office, Scotland

Abstract: In-vitro fertilization (IVF) involves several steps. Initially, hormones are used to stimulate the ovaries to produce eggs which are harvested surgically. Next, embryos are created outside the body by mixing eggs with sperm. Embryos are grown in culture for a few days before transfer within the uterus (fresh embryo transfer). Despite improvements in technology, IVF success rates remain low (25% live birth rate). There are concerns about maternal and perinatal outcomes. Systematic reviews have shown poorer outcomes in pregnancies following IVF, particularly after fresh embryo transfer. The process of IVF also incurs a risk of ovarian hyperstimulation syndrome (OHSS) which can cause serious maternal morbidity and rarely, mortality. It has been suggested that avoiding fresh embryo transfer by freezing all good quality embryos with the intention of thawing and subsequent replacement into the uterus at a later stage (thawed frozen embryo transfer) may lead to improved pregnancy rates and fewer complications. Good quality embryos are defined as those with 6–8 cells grade 3/3 or above using the agreed national grading scheme on day 3. However, the existing evidence base from three small randomised trials (and the resulting meta-analysis) is inadequate to justify such a radical change in practice. A two-arm parallel group randomised controlled trial is proposed across ten IVF centres in the UK. Women under 42 years of age undergoing their first IVF treatment, with at least 3 good quality embryos, will be randomised to receiving either thawed frozen embryo transfer or fresh embryo transfer, within 3 months of egg collection. Embryo freezing and subsequent replacement of spare embryos is now an established part of IVF and is endorsed by NICE. The trial population has been chosen in line with NICE guidance as to who should be offered NHS funded treatment. A single episode of thawed frozen embryo transfer (following freezing of all good quality embryos) will be compared to a single episode of fresh embryo transfer with the primary outcome comprising a healthy baby: a live singleton baby born at term with an appropriate weight for gestation (AGA). A composite primary outcome has been chosen to reflect safety (single, term and AGA) and effectiveness (live birth) as the goal of modern IVF is accepted to be a healthy baby and a healthy mother (with no OHSS). With 90% power and a two-sided 5% level of statistical significance, we will need to randomise 1,086 women (543 in each arm) over a 2 year period to show an absolute difference in the primary outcome of at least 9% (e.g. from 25% to 34%), between fresh and thawed frozen embryo transfer respectively. Such a difference was considered to be clinically important by an expert panel of clinicians in order to recommend a change in clinical practice, considering the extra time, effort and cost involved in freezing all embryos. A full economic evaluation will assess the costs and consequences of the new strategy compared with standard practice. The trial data will be combined with modelling to estimate the long term costs of health and social care using a previously developed decision analytic model. The assembled team comprises experienced clinicians from IVF units, clinical academics, scientists, clinical embryologists, user representatives and clinical trial methodologists (statisticians, epidemiologists and health economists) in order to conduct the definitive trial of the highest quality.

Lay abstract: One in seven couples experience difficulty in conceiving. Many of them will require in-vitro fertilization (IVF) which is recommended by NICE as the effective treatment for infertility. IVF involves hormone injections to stimulate a woman’s ovaries to produce a number of eggs which are removed by a minor operation. The eggs are then mixed with sperm to create embryos in the laboratory. Conventionally, these embryos are replaced within the womb a few days after they are created (fresh embryo transfer). Remaining good quality embryos are available to be frozen such that they can be thawed and transferred at a later date (thawed frozen embryo transfer). Until recently it has been universally believed that a fresh embryo has the best chance of resulting in a pregnancy. Thawed frozen embryo transfers have therefore generally only been used where the transfer of a fresh embryo has been unsuccessful, or when a woman has decided to return for a second pregnancy. Although this way of providing IVF is still the one which is most widely used, associated pregnancy rates are low (25% live birth rate) despite a number of technological advances. In addition, pregnancies resulting from IVF treatment incur an increased risk of complications to mother and baby. These risks appear to be higher after fresh as opposed to frozen embryo transfer. Over the last decade, embryo freezing techniques have improved substantially and recent research suggests that transfer of thawed frozen embryos could lead to higher pregnancy rates as well as fewer complications (both for the mother and the baby) as compared to fresh embryo transfer. An alternative policy which could potentially improve IVF outcomes and reduce complications, therefore, is to avoid fresh embryo transfer, freeze all good quallity embryos followed by thawing and replacing them at a later date. However, the existing evidence base is not robust enough to justify such a major change in the way IVF is provided. Hence we propose a large multicentre randomised controlled trial across approximately12 IVF centres in the UK to evaluate the clinical effectiveness and economic value of a policy of freezing all good quality embryos followed by thawed frozen embryo transfer, compared with the current practice of fresh embryo transfer in women undergoing IVF. We plan to conduct this project over a four year period starting in 2015. This project will be coordinated by the National Perinatal Epidemiology Unit Clinical Trials Unit and will involve multiple IVF centres from across the country. We will recruit 1,086 women (543 will have fresh embryo transfer and 543 will have all created good quality embryos frozen to be thawed and transferred later) over a 2 year period. All resulting pregnancies will be followed up until delivery (details of sample size calculation are provided in detailed protocol). The proposed outcome measures address both safety (safety of women undergoing IVF i.e. OHSS, complication in pregnancy - miscarriages, preterm delivery and low birth-weight baby) as well as effectiveness of the IVF treatment (pregnancy rates). Since changing the way IVF is currently delivered will have cost implications, we will also assess the short and longer term costs of both embryo transfer policies from both a health service as well as a broader societal perspective.

Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH