Deferring frozen embryo transfers for at least one menstrual cycle following a failed fresh transfer or with freeze-all has become ‘standard practice’ according to a new meta-analysis. Results from that analysis and from a new RCT suggest that outcomes may be best with no deferment.
The cryopreservation of embryos in an IVF/ICSI cycle is now a routine procedure, with usage and success rates both increasing. Indeed, one meta-analysis from 2019 reported live birth rates approaching or even exceeding those obtained from fresh embryo transfers. The latest preliminary data from SART show that more than one—third of all cycles performed in the USA in 2019 were with eggs or embryos all frozen for future use. An even higher proportion of FETs was found by ESHRE’s EIM Consortium in its preliminary presentation of European results for 2018, while in the UK the latest figures from the HFEA show that FETs made up just 10% of all IVF cycles in 1991 but 41% in 2019. The EIM and HFEA data did not specify what proportion of these frozen cycles were freeze-all, but David Adamson, in his Annual Meeting presentation of 2017 world data for ICMART, did report that 21.6% of all aspirations were freeze-all. This reflects a substantial trend over time and wide acceptance of a routine practice aiming ostensibly to overcome the detrimental effects of ovarian stimulation, especially in women at high risk of OHSS.
However, while the evidence in support of FET is strong and getting stronger, the elective deferral and timing of frozen transfers is described in the new meta-analysis as an ‘empirical’ strategy, ‘based on suggestions rather than solid scientific evidence’ and which may unnecessarily delay time to pregnancy, ‘causing frustration and decreased quality of life to couples’.(1)
The aim of the meta-analysis was thus to review the current evidence on the timing of FET – whether following a failed fresh transfer or in a freeze-all programme it might better be offered immediately after a stimulated cycle without compromising LBR, or whether a transfer delay is equally effective.
The results of the review - of 15 studies - found a slightly and just significantly higher live birth and clinical pregnancy rates from frozen transfers performed in the first cycle (immediate) than in second/subsequent cycles (postponed) (pooled OR of 1.20 for LBR and 1.22 for clinical PR). These are not huge differences, but the authors concluded that routinely postponing transfer for at least one menstrual cycle does not appear to be ‘scientifically supported’ and that the results may indicate a need for a rethink in clinical practice. However, they acknowledge that their findings are based on retrospective cohort studies limited by low quality evidence and selection bias, hence their warning that the results ‘be interpreted with caution’.
However, a randomised trial published after this meta-analysis does appear to provide more robust evidence that immediate transfer is indeed associated with significantly higher LBRs than a delayed approach.(2) The RCT, carried out in China, is described as the first to investigate the timing of frozen embryo transfers, and its authors are emphatic in their recommendations: they conclude that FETs should be done immediately following a stimulated IVF cycle to improve LBR.
The meta-analysis was based on studies (up to March 2020) involving 6304 immediate and 13,851 postponed cycles which included subfertile women aged 18 to 46 years with any indication for IVF/ICSI treatment (except oocyte donation). The primary outcome was LBR, with implantation, pregnancy, clinical pregnancy rates and miscarriage as secondary endpoints.
Results showed that 12 studies (of low to moderate quality) reported no difference in LBR between immediate and postponed FET; two (moderate quality) found a statistically significant increase in LBR with an immediate approach; and one small study (very low quality) reported better LBR with postponed. Trends in rates for secondary endpoints followed a similar pattern. But what’s needed next, say the authors, are RCTs to provide high-grade data on cancellation rates, different endometrial preparation protocols and other factors which may influence LBR in transfer timing.
The RCT from China included 724 women who had been infertile for an average of three years and treated at two fertility centres, with transfers performed in a first menstrual cycle (n = 362) or delayed to the second/later cycle (n = 362). Results showed that those randomised to the immediate transfer group had a significantly higher ongoing pregnancy and LBR than those in the delayed group (ongoing PR = 49.6% vs 41.5%; LBR = 47.2% vs 37.7%; with a miscarriage rate of 13.2% vs 24.2%).
What the two studies clearly have in common is that they each report a higher LBR for immediate embryo transfers than for postponed, but neither can offer a water-tight explanation. The RCT results are described as ‘unexpected’ by the authors, who suggest one possible explanation for the poorer outcomes in deferred transfers as the ‘anxiety or emotional state’ of patients having to wait. However, anxiety levels were not measured in the study so it remains unknown if they were more stressed or not.
One well rehearsed question is the effect of stimulation on endometrial receptivity. Or could it be that the embryos transferred earlier (in the first cycle) are of better quality? The Danish meta-analysts did attempt to investigate this through subgroup analysis but were limited by sample size. These and other knowledge gaps, they say, leave ample opportunity for further RCTs, particularly with respect to cancellation rates in each of the two approaches and patient preference. In the meantime, the message from the meta-analysis authors is that, while delaying FET for at least one menstrual cycle after a failed fresh transfer or with freeze-all is now routine practice, it may well be ‘inexpedient’. But, they warn, with so much data on safety and cancellation rates missing, immediate FET should ‘not be performed at any cost’, even in cases where any delay seems unnecessary.
1. Bergenheim S, Saupstad M, Pistoljevic N, et al. Immediate versus postponed frozen embryo transfer after IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 2021; 27: 623–642; doi:10.1093/humupd/dmab00
2. Li H, Sun X, Yang J, et al. Immediate versus delayed frozen embryo transfer in patients following a stimulated IVF cycle: a randomised controlled trial; Human Reprod 2021; 36: 1832–1840. doi:10.1093/humrep/deab071