Published 11 March 2019
Results described as 'practice-changing', as large Chinese trial finds freeze-all transfers associated with higher live birth rates than fresh in good prognosis ovulatory patients.
Hard on the heels of a meta-analysis which found benefit only in IVF high responders and of other trials drawing similar or neutral conclusions, a new large-scale RCT from China has for the first time found that an elective freeze-all strategy in IVF does actually improve outcome in terms of live birth and risk of OHSS.(1) The results of the trial - as reflected in an accompanying Lancet editorial from the past chairman of the ASRM - suggest that the door is at least now open for the wider uptake of freeze-all, with some promise of evidence that improved outcomes may indeed be possible.(2)
The trial was substantial: 1650 female IVF patients at 21 academic fertility centres in China, each with regular cycles, having a first cycle of treatment and randomly assigned to either fresh or frozen single blastocyst transfer. They were described by the authors as 'ovulatory women with good prognosis'. Transfer in those allocated to freeze-all was 'at least four weeks' after blastocyst vitrification.
The primary endpoint was singleton live birth and results showed a significant benefit in favour of the elective FETs - 50.4% LBR vs 39.9%, a relative risk calculated as 1.26 (CI 1.14-1.41, p<0.0001). The authors report that the difference 'was associated with higher rates of implantation, clinical pregnancy, and ongoing pregnancy than was fresh single blastocyst transfer'. This higher rate of implantation, they suggested, could depend on three factors: an embryo with greater implantation competency, a more receptive endometrium, and improved developmental synchrony between the embryo and the endometrium. This third factor has long been suggested as a possible explanation for a less than optimal implantation rate in fresh embryo transfers. 'Ovarian stimulation and possibly the resultant supra-physiological oestrogen concentrations might have a detrimental effect on endometrial development compared with the endometrium in natural cycles,' they write.
Rates of OHSS were similarly found in favour of the freeze-all transfers, with four of the 825 cases diagnosed in the freeze-all group and nine/825 in the fresh (though not statistically significant). However, there was a down-side to the results in a higher rate of pre-eclampsia found in the freeze-all patients than in the fresh (3.1% vs 1.0%), an effect which raised questions for the wider application of a freeze-all strategy.
Indeed, wrote former ASRM chairman Christos Coutifaris in a Lancet commentary, 'the question is whether an [overall] 11·9% absolute percentage point improvement in the livebirth rate (from 41·3% to 53·2%) following delayed transfer of vitrified blastocysts justifies the observed increase in perinatal complications and supports the recommendation of elective frozen embryo transfer for all blastocyst-stage embryos'. Coutifaris seemed to remain on the side of caution, noting that the 40% LBR found with the fresh transfers is still 'clinically excellent', yet without the greater pre-eclampsia risk.
The authors, however, seem more persuaded by their results, noting 'the practice-changing implications of our findings' and that the transfer of a vitrified single blastocyst is 'better' for achieving a singleton live birth than a fresh transfer in women with good prognosis.
Freeze-all for all?
So, practice-changing? As the authors note, this is the first substantial randomised trial (or meta-analysis) to show a real live-birth benefit from deferred blastocyst transfer in a general ART population. Two important trials published by the New England Journal of Medicine found no advantage in freeze-all over fresh in ovulatory patients, and only in subjects with PCOS.(3,4) A benefit favouring high responders was also found in a very recent meta-analysis involving more than 5000 subjects.(5) Indeed, PCOS and a high response to stimulation are noted by Coutifaris in his Lancet commentary as the current indications for a freeze-all strategy. And he adds that there are still other 'unresolved issues' before recommending the wider uptake of 'elective FET for all' - in the emotional and financial costs of the delay, in poor ovarian response, and performance in the older ART patient. Nevertheless, despite the caution and the still patchy data, freeze-all seems to be increasingly adopted - and, according to anecdotal and short reports, is yielding acceptable rates of live birth in a wide cross-section of patients.
1. Wei D, Liu J-Y, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet 2019.
2. Coutifaris C. Elective frozen embryo transfer for all? Lancet 2019.
3. 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.
4. Chen Z-J, Shi Y, Sun Y, et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med 2016; 375: 523–533.
5. 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.