Freeze-all ‘may be of no benefit’ in terms of ongoing pregnancy rate

Published 20 April 2021

A single-centre RCT involving more than 200 couples found ongoing pregnancy rate ‘significantly lower’ in the freeze-all group than in those following a conventional approach. Alessia Galimberti, one of our newly recruited writers, reports.*

A freeze-all transfer strategy in IVF has been associated with a significantly lower cumulative ongoing pregnancy rate than a conventional approach in a single centre RCT from the Netherlands.(1) The study, which took place between 2013 and 2015 in a general IVF population (‘with any indication for IVF’), concludes that ‘there might be no benefit of a freeze-all strategy’ in this patient group, although the authors concede that the findings must yet be balanced against those in sub-groups and the potential safety benefits (and harms) for mothers and infants.

Freeze-all has now become a routine approach in many IVF clinics, with several reviews and meta-analyses appearing so far to support the procedure as a strategy to avoid the effects of ovarian stimulation on endometrial receptivity and the risk of OHSS.(2)

The authors of this latest RCT were also behind a Cochrane review published in 2017 on ‘fresh versus frozen embryo transfers’ which concluded that the risk of OHSS was significantly lower with a freeze-all strategy but with no evidence of better results in terms of cumulative LBRs when compared to fresh transfers.(3)

Now, these findings have been tested in an open label, two arm, parallel group RCT in 204 couples randomly assigned to the freeze-all (n=102) or conventional strategy (n=102) just before the start of down-regulation. Unlike other freeze-all RCTs so far conducted, this was a broad subfertile population all having their first IVF treatment, even if with a poor prognosis and regardless of the number of follicles or available embryos.

Data analysis of pregnancy outcomes showed that cumulative ongoing pregnancy rate per woman was significantly lower in the freeze-all group than in the conventional (19% vs 31%). Cumulative live birth, clinical pregnancy and biochemical pregnancy rates were similarly reduced (18% vs 28%, 19% vs 33%, 24% vs 41%). Moreover, time to pregnancy within 12 months after randomisation was higher in the freeze-all arm (46.9 weeks vs 39.6 weeks). In addition, except for the risk of OHSS which was developed by three women in the conventional strategy group, no significant differences were found in the rate of miscarriage, ectopic or multiple pregnancy, birthweight, preterm births and congenital abnormalities.

Despite its increasing use and the growing number of studies, the relative efficacy and safety of IVF treatment with a freeze all strategy is still unclear when compared to conventional approaches. Earlier studies have found outcome benefits in high responders, but, overall, freeze-all has been thought justified in selected clinical scenarios, such as in PGT-A or OHSS prevention.(4)

A recently published update to the Cochrane review included analysis of eight trials, with a total of 4712 subjects.(5) The authors found with moderate-quality evidence that one strategy is probably not superior to the other in terms of cumulative LBR and ongoing pregnancy rate, thus confirming the conclusions of the RCT. On safety, it has been shown that the risk of maternal hypertensive disorders of pregnancy, or of having a large-for-gestational-age and a higher birth weight baby is greater with freeze all. A 2019 meta-analysis, despite finding a significantly lower risk of OHSS with elective FET, also found that the risk of pre-eclampsia was higher than with fresh embryo transfers.(6)

The latter, it was proposed, may be related to endometrial preparation with exogenous progesterone and prolonged estrogen use during artificial FET cycles, or to the absence of circulating corpus luteum vasoactive factors, causing probable deficient circulatory adaptations during early gestation.

Meanwhile, it remains to be seen how these latest and future findings will adapt the currently favourable response to freeze-all. But certainly, the efficacy of a freeze-all strategy in subgroups of patients, different stages of embryo development, and different freezing protocols needs yet to be established. And even if as in this latest trial (and as the authors insist) routine freeze-all does not improve LBRs, outcome must always be balanced by safety factors, and it seems the evidence is not yet sufficient to do that.

* Alessia Galimberti is a senior embryologist working at the Infertility Center of the Papa Giovanni XXIII Hospital in Bergamo, Italy. This her first report for FoR.

1. Wong KM, van Wely M, Verhoeve HR, et al. Transfer of fresh or frozen embryos: a randomised controlled trial. Hum Reprod 2021; 36: 998-1006.
2. Sciorio R, Esteves SC. Clinical utility of freeze-all approach in ART treatment: A mini-review. Cryobiology 2020; 92: 9-14.
3. 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(3: CD011184.
4. Roque M, Haahr T, Esteves SC, Humaidan P. The ‘Big Freeze’: freeze-all should not be used for everyone
Human Reprod 2018; 33: 1577–1578.
5. Zaat T, Zagers M, Mol F, et al. Fresh versus frozen embryo transfers in assisted reproduction
Cochrane Database Syst Rev 2021; 2: CD011184.
6. Roque M, Haahr T, Geber S, et al. 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.

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