The study operated to a strict pre-agreed protocol, which has been published.1
Parts of this chapter have been reproduced with permission from the published protocol, Maheshwari et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
Infertility is common, affecting one in seven couples in the UK.2 The National Institute for Health and Care Excellence (NICE) recommends in vitro fertilisation (IVF) as the definitive treatment for prolonged unresolved infertility.3 The number of IVF treatments in the UK has continued to rise each year, from 6609 in 1999 to > 64,000 in 2013, resulting in > 20,000 pregnancies.4
In vitro fertilisation
In vitro fertilisation treatment involves a number of consecutive steps. Initially, each woman is given external hormone injections to develop multiple ovarian follicles. The growth of these follicles is monitored by serial transvaginal ultrasound scans and, when these follicles reach maturity, the eggs within them are harvested surgically. Retrieved eggs are mixed with sperm by one of two methods: IVF, where motile sperm are placed surrounding the eggs, or intracytoplasmic sperm injection (ICSI), where a single sperm is selected and injected into the egg. Eggs mixed with sperm are then incubated to create embryos. Conventionally, these embryos are allowed to develop in the laboratory for a few days before one or two of them are selected for transfer into the uterus (i.e. fresh-embryo transfer) on day 3 (the cleavage stage) or day 5 (the blastocyst stage). Additional embryos are frozen and stored for replacement at a later date without the need for ovarian stimulation (i.e. frozen-embryo transfer).
Concerns with in vitro fertilisation
Despite being a widely used treatment in the UK and around the world, there are a number of concerns about conventional IVF.
Static success rates
In vitro fertilisation success rates remain modest, with a mean live birth rate of 25% per treatment involving a fresh-embryo transfer. Data for three consecutive years (2010 to 2012) from the American4 and European registries5 suggest that there was no improvement in IVF live birth rates over the 3-year period.
Ovarian hyperstimulation syndrome
Exogenous hormones used for ovarian stimulation are associated with a risk of ovarian hyperstimulation syndrome (OHSS), which is exacerbated if a woman becomes pregnant following fresh-embryo transfer. Moderate to severe OHSS is a complication unique to IVF treatment, occurring in around 1–5% of treatments,6 and often requiring in-patient care, resulting in significant NHS costs. Severe OHSS is associated with significant morbidity (including ascites, pleural and pericardial effusion, respiratory failure and intensive care admission) and, rarely, death.
Poor obstetric and perinatal outcomes
Pregnancies resulting from IVF are associated with a higher rate of maternal and perinatal complications than pregnancies resulting from spontaneous conception. A systematic review7 has shown that babies, even singletons, conceived following IVF are more likely than babies conceived without IVF treatment to die during the perinatal period [risk ratio (RR) 1.87, 95% confidence interval (CI) 1.48 to 2.37], to be delivered preterm (RR 1.54, 95% CI 1.47 to 1.62), to have a low birthweight (RR 1.65, 95% CI 1.56 to 1.75) and to have congenital anomalies (RR 1.67, 95% CI 1.33 to 2.09). Women who become pregnant as a result of IVF are more likely than those who become pregnant as a result of spontaneous conception to develop pre-eclampsia (RR 1.49, 95% CI 1.39 to 1.59), bleeding in pregnancy (RR 2.49, 95% CI 2.30 to 2.69) and diabetes (RR 1.48, 95% CI 1.33 to 1.66) and to require a caesarean section (RR 1.56, 95% CI 1.51 to 1.60).
Although the absolute number of women with OHSS and pregnancy-related complications associated with IVF is relatively small, the increasing number of women receiving IVF4 has meant that the NHS burden of dealing with its short- and long-term complications is a serious and growing problem.
A possible cause of suboptimal live birth rates, as well as adverse maternal and perinatal outcomes, following IVF is the impact of the exogenous hormones used for ovarian stimulation on the lining of the uterine cavity. High levels of oestrogen produced by the ovary in response to this treatment affect uterine receptivity, reducing the chances of successful implantation and placentation. Suboptimal placentation may lead to obstetric and perinatal complications. It has been suggested that avoiding embryo transfer when the uterus is less receptive could improve success rates and reduce complications in pregnancy and delivery. Such a strategy also reduces the risk of OHSS by ensuring that a pregnancy does not occur in the presence of hyperstimulated ovaries.
Evidence supporting frozen-embryo transfer
It is already known that the risk of severe OHSS is greatly reduced by a policy of freezing all embryos, followed by frozen-embryo transfer, compared with fresh-embryo transfer.8 A systematic review of observational data9 showed that babies (singletons) conceived from frozen embryos have a reduced risk of perinatal morbidity (RR 0.68, 95% CI 0.48 to 0.96) and preterm delivery (RR 0.84, 95% CI 0.78 to 0.90), making IVF safer and more effective for women and babies.
Preliminary data from small randomised trials from the Islamic Republic of Iran10 and the USA11,12 in 2015 suggested that a strategy of not replacing embryos when they are created, but freezing them, followed by transferring thawed embryos into the uterus at a later date, improves pregnancy rates. A meta-analysis of data from these three randomised controlled trials (RCTs)8 has shown higher pregnancy rates following frozen-embryo transfer (odds ratio 1.32, 95% CI 1.10 to 1.59).
However, these existing trials have a number of significant limitations:
- They reported implausibly high pregnancy rates (e.g. 84% per embryo transfer), which are far in excess of those reported by national and international registries.4,5
- Key outcomes, including healthy baby, live birth, costs, safety and acceptability, were not measured by any of the trials.
- They were limited in terms of design, with highly selected populations, inadequate sample sizes and per-protocol analysis rather than intention to treat (ITT) and conduct, as all of the trials involved co-interventions that were not accounted for in the analysis.
One of the publications10 has been retracted on the grounds of serious methodological flaws. Hence, the evidence base, comprising two small trials, was not sufficiently robust to support a radical change in clinical practice. In addition, the results of these trials could not be directly applied to a UK setting because of very different regulatory and funding arrangements. There was, therefore, an urgent need to perform a definitive RCT in the UK evaluating elective freezing of embryos, followed by subsequent thawed frozen-embryo transfer, in terms of clinical effectiveness and cost-effectiveness.
Objective
Primary objective
The primary objective of the trial was to determine if a policy of freezing embryos, followed by thawed frozen-embryo transfer, results in a higher healthy baby rate than the current policy of transferring fresh embryos.
Secondary objectives
The secondary objectives of the trial were to assess if a policy of freezing embryos, followed by thawed frozen-embryo transfer, compared with the current policy of transferring fresh embryos, results in:
- fewer complications associated with IVF treatment and pregnancy
- greater cost-effectiveness from a health service and broader societal perspective.