Published 28 January 2019
As another meta-analysis finds only limited outcome benefit from frozen embryo transfers, US data indicate that 25% of all cycles in 2016 were freeze-all.
It was Paul Devroey and colleagues in Brussels who first promoted the idea of segmentation to remove the risk of OHSS in IVF.(1) The strategy, wrote Devroey, ' is to freeze all of the oocytes or embryos for later use', and thereby (along with an agonist trigger) avoid the negative impact of OHSS, 'which for the individual with OHSS is substantial'. 'The concept of an OHSS-free clinic,' added Devroey, 'has become a reality.'
Since then, the safety factor to which he alluded has been confirmed in several trials and meta-analyses. An updated Cochrane review of 2017, for example, concluded - despite 'low-quality evidence' - that 'not performing a fresh transfer lowers the OHSS risk for women at risk of OHSS'.(2) That review included 1892 eligible subjects in its comparison, providing only modest conclusions, even with respect to safety.
Today, however, the segmentation concept - 'freeze-all', elective FET - has moved on, and safety is not its only objective. With a suggestion originating in the early 2000s that the high hormone levels derived from a stimulated IVF cycle would encourage a non-receptive, out-of-phase endometrium, the concept arose that adopting a freeze-all approach would not only minimise the risk of OHSS but even improve pregnancy rates in the general IVF population.
Yet despite time and a huge universal shift towards elective FET, the evidence for its outcome benefit remains sparse. Indeed, the latest meta-analysis of fresh vs frozen transfers, now involving 5379 eligible subjects and 11 trials, found eFET associated with a higher live birth rate only in hyper-responders.(3) There was no outcome difference between fresh and frozen in normal responders, nor in the cumulative LBR of the two overall groups.
Yet, as this Human Reproduction Update review euphemistically reports, 'several fertility clinics have adopted a liberal approach towards eFET, increasing its overall use'. There is no sure data on the extent of this increase, though the latest official figures from the USA report that, of the 263,577 ART cycles performed in 2016, 65,840 cycles (25%) were started 'with the intent of cryopreserving and storing all resulting eggs or embryos for potential future use'.(4) This is indeed remarkable growth - and these same US data, from this large population of registry patients, also show that the rates of pregnancy and live birth were higher for FET than with fresh embryos (56.3% vs 44.7%, and 45.9% vs 36.3%).
The CDC described the increase in the number of elective FET cycles between 2007 and 2016 as 'dramatic', rising steeply from almost zero to more than 60,000 cycles per year. ESHRE data from the EIM Consortium, presented provisionally for 2015 at last year's Annual Meeting, also revealed strong growth in the number of freeze-all cycles (up 7% on the previous year), and now accounting for 15% of all IVF cycles. However, unlike the US data, ESHRE figures did not find a higher pregnancy rate (per transfer) with the frozen cycles (30% vs 36%) - although in Britain the HFEA in its latest report did note that 'for the first time birth rates from frozen embryo cycles surpassed those from fresh'. Since 2014, the HFEA added, frozen IVF treatment cycles have increased by 39%.
In its summary of US activity for 2016 the CDC seems unequivocal - at least, based on its observational registry data - that rates of pregnancy and live birth are higher after frozen transfers than after fresh. Yet the clinical evidence for this 'dramatic' shift remains elusive. Indeed, the Update review from Humaidan's group in Denmark concluded that currently there are 'no clinical data supporting the indiscriminate use of eFET for all patients submitted to IVF/ICSI'. Yet as a strategy - and especially based on US figures - this is exactly what's now going on.
The trend is difficult to explain, other than by 'better results in our hands', a common riposte to the demand of an RCT. Or is it yet again a case of the trials running breathlessly to catch up with practice? The Danish reviewers called for future studies to explore freeze-all's 'causal' relationship with ovarian response, hormonal levels during stimulation, type of freezing and embryo developmental stage in pre-specified subgroups. The latest substantial trial we have - reported from Viet Nam last year - found no better rates of pregnancy or live birth from frozen FETs than from fresh.(5)
However, as in all previous reviews, this latest Update meta-analysis found that the risk of moderate/severe OHSS was significantly lower with eFET than with fresh embryo transfer (RR = 0.42). Their advice is thus that, taken together, their data suggest that a freeze-all policy should be individualised, presumably in favour of PCOS/hyper-responding patients and in 'line with modern patient handling approaches'.
1. Devroey P, Polyzos NP, Blockeel C. An OHSS-free clinic by segmentation of IVF treatment. Hum Reprod 2011; 26: 2593–2597.
2. Wong KM, Van Wely M, Mol F, et al. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2017 Mar 28;3:CD011184. doi: 10.1002/14651858.CD011184.pub2.
3. Roque M, Haahr T, Geber S. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2-14.5. Vuong LN, Dang VQ, Ho TM, et al. IVF transfer of fresh or frozen embryos in women without polycystic ovaries. N Engl J Med 2018; 378: 137–147.