Impact case study database

One in six couples are infertile. In vitro fertilisation (IVF) is a routine treatment for most forms of infertility. However, it is time consuming and emotionally demanding for couples, with rates of livebirth per cycle in high income countries of 25-40% (depending on prognostic factors, in particular a woman’s age). Costs per cycle are relatively high, and NHS provision is limited; across the UK, 60% of cycles are couple-funded, though with considerable geographic variation. Providers often use surrogate markers of success (including fertilisation or pregnancy rate) in marketing to couples. Hence couples, funders and stakeholders have identified the need to determine which IVF treatments work best and in which circumstances. Randomised controlled trials (RCTs) in reproductive medicine rarely, if ever, have adequate power to detect reasonable target differences in the key outcome of live-birth rates; indeed, only 2% of meta-analyses of such RCTs have been shown to have sufficient power in this respect. Moreover, no previous observational studies had explored whether the associations between the number of embryo transfers and various outcomes differed according to maternal age.

To address these research challenges, Lawlor and colleagues have undertaken a series of analyses using a comprehensive UK-wide dataset of all IVF cycles taking place since 2003. This body of research has demonstrated the following.

Determined the effect of single, two or three embryo transfers on live-birth success and perinatal outcomes [1]. Multiple embryo transfer increases clinical pregnancy rates, incentivising providers and patients. Yet, multiple pregnancy arising from multiple embryo transfer is associated with adverse outcomes for the baby. Lack of evidence on the balance between live-birth success and adverse perinatal outcomes with different numbers of embryos transferred in one treatment led to widespread variation in embryo transfer practice nationally and globally. By 2010 it was recognised (by couples, clinicians and funders) that the question of whether it was best to transfer one or more embryos was of paramount importance and two large RCTs were funded (one in the UK and one in Australia). Both of these RCTs were stopped early because of failure to recruit. The UK trial recruited just 23 of a planned 700 participants, and the Australian trial just 27 of a planned 1000 participants. Recruitment was poor because of couple treatment preferences – for double embryo transfer in the UK and single in Australia. In any case, neither trial would have addressed the best practice for women aged over 37 years, since they were excluded. Previous observational studies also lacked power to detect effects in women over the age of 40 years, for whom a double transfer may be the last opportunity to complete a family of two children.

Using data on 124,148 IVF cycles, which resulted in 33,514 live-births, Lawlor and colleagues showed that in women younger than 40 years, a single fresh embryo transfer, followed by subsequent single frozen transfer, resulted in an equivalent live-birth rate and lower risk of harm (fewer multiple births, preterm births and small for gestational age babies), compared with those occurring following a double embryo transfer. Furthermore, for the first time, they showed that in women aged 40 years or older, double embryo transfer resulted in a higher live-birth rate and lower risk of harm than single embryo transfers [1]. In both age groups, transfer of three embryos reduced live-birth rates and increased adverse outcomes [1]. It was recommended that single embryo transfer should be the routine approach in women younger than 40 years and a double embryo transfer the norm in those older than 40 years, with triple transfers phased out.

Determined the benefit of repeat treatment cycles, including how many cycles were required to obtain a live-birth rate similar to that in couples conceiving naturally, and whether it was worth continuing with further cycles if an initial cycle failed to yield oocytes [2]. Using prospectively collected UK-wide data on over 150,000 women collected over nearly a decade from 2003, Lawlor and colleagues showed that the cumulative live-birth rate in all women continued to increase up to nine cycles. In women younger than 40 years (and of any age using donor eggs), couples could achieve a cumulative live-birth rate (68%) similar to that of couples conceiving naturally with six cycles [2]. This provided the evidence for funding more than one or two cycles and has made demonstrable differences in Scotland where up to three cycles per couple are now NHS-funded. The research also challenged traditional assumptions that low or zero egg retrievals in a cycle implied that further cycles should be limited as live-birth was unlikely. Contrary to these assumptions, Lawlor’s team found that egg retrieval for each cycle was independent; in other words, zero retrieval in one cycle did not influence live-birth success in subsequent cycles [2].

Identified accurate predictors of live-birth success using data from 144,018 IVF cycles. Lawlor and colleagues identified key characteristics associated with live-birth rates relating to couples (e.g. woman’s age, nature and duration of infertility) and treatments (e.g. use of donor eggs and intracytoplasmic sperm injection (ICSI)) . In addition, they elucidated how these factors interacted with each other – for example, the increased live-birth rates with donor eggs were apparent at all ages but strongest at older ages, and ICSI increased live-birth rates in those with male-related infertility [3]. The prediction model these researchers developed was found to predict outcomes with greater accuracy than the existing model, not just in their original research but also in an external validation study they carried out on 130,960 cycles in the UK[4]. They have also produced an online tool and smart phone app based on their prediction model, for use by couples and clinicians.