Fresh versus frozen embryo transfers for assisted reproduction

Review question

We reviewed the evidence about the effectiveness and safety of a 'freeze-all' strategy for women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) compared to a conventional IVF/ICSI strategy, in terms of cumulative live birth rate and risk of ovarian hyperstimulation syndrome (OHSS).

Background

Embryo transfer in IVF/ICSI can be performed using either fresh or frozen-thawed embryos. There are therefore two embryo transfer strategies in IVF: 1) the conventional IVF/ICSI strategy with a single transfer of fresh and one or more transfers of frozen-thawed embryos, and 2) the 'freeze-all' strategy with transfer of frozen-thawed embryos only, and no fresh embryo transfer. Differences in freezing technique and timing of cryopreservation and transfer exist within both transfer strategies. In the freeze-all strategy, embryo transfers are disengaged from ovarian stimulation in the ovarian stimulation cycle. This strategy may be beneficial, as the ovarian hyperstimulation is suggested to have a negative effect on the receptivity of the endometrium for embryo implantation. The freeze-all strategy would lower the risk of OHSS since pregnancies do not occur in the cycle with ovarian stimulation.

Study characteristics

We included four studies comparing a freeze-all strategy with a conventional IVF/ICSI strategy in a total of 1892 women undergoing assisted reproductive technology. The evidence is current to November 2016.

Key results

We found evidence showing seemingly no difference between the strategies in cumulative live birth rate per woman. Our findings suggest that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%. Time to pregnancy was not reported as an outcome in in the included studies, but it can be assumed to be shorter using a conventional IVF/ICSI strategy including fresh transfer in the case of similar cumulative live birth rates, as embryo transfer is delayed in a freeze-all strategy. Not performing a fresh transfer (freeze-all strategy) lowers the OHSS risk for women at risk of OHSS. Our findings suggest that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%.

Quality of the evidence

The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules.

Authors' conclusions: 

We found moderate-quality evidence showing that one strategy is not superior to the other in terms of cumulative live birth rates. Time to pregnancy was not reported, but it can be assumed to be shorter using a conventional IVF/ICSI strategy in the case of similar cumulative live birth rates, as embryo transfer is delayed in a freeze-all strategy. Low-quality evidence suggests that not performing a fresh transfer lowers the OHSS risk for women at risk of OHSS.

Read the full abstract...
Background: 

In general, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) implies a single fresh and one or more frozen-thawed embryo transfers. Alternatively, the 'freeze-all' strategy implies transfer of frozen-thawed embryos only, with no fresh embryo transfers. In practice, both strategies can vary technically including differences in freezing techniques and timing of transfer of cryopreservation, that is vitrification versus slow freezing, freezing of two pro-nucleate (2pn) versus cleavage-stage embryos versus blastocysts, and transfer of cleavage-stage embryos versus blastocysts.

In the freeze-all strategy, embryo transfers are disengaged from ovarian stimulation in the initial treatment cycle. This could avoid a negative effect of ovarian hyperstimulation on the endometrium and thereby improve embryo implantation. It could also reduce the risk of ovarian hyperstimulation syndrome (OHSS) in the ovarian stimulation cycle by avoiding a pregnancy.

We compared the benefits and risks of the two treatment strategies.

Objectives: 

To evaluate the effectiveness and safety of the freeze-all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology.

Search strategy: 

We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in November 2016 together with reference checking and contact with study authors and experts in the field to identify additional studies.

Selection criteria: 

We included randomised clinical trials comparing a freeze-all strategy with a conventional IVF/ICSI strategy which includes fresh transfer of embryos in women undergoing IVF or ICSI treatment.

Data collection and analysis: 

We used standard methodological procedures recommended by Cochrane. The primary review outcomes were cumulative live birth and OHSS. Secondary outcomes included other adverse effects (miscarriage rate).

Main results: 

We included four randomised clinical trials analysing a total of 1892 women comparing a freeze-all strategy with a conventional IVF/ICSI strategy. The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules.

There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.91 to 1.31; 4 trials; 1892 women; I2 = 0%; moderate-quality evidence). This suggests that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%.

The prevalence of OHSS was lower after the freeze-all strategy compared to the conventional IVF/ICSI strategy (OR 0.24, 95% CI 0.15 to 0.38; 2 trials; 1633 women; I2 = 0%; low-quality evidence). This suggests that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%.

The freeze-all strategy was associated with fewer miscarriages (OR 0.67, 95% CI 0.52 to 0.86; 4 trials; 1892 women; I2 = 0%; low-quality evidence) and a higher rate of pregnancy complications (OR 1.44, 95% CI 1.08 to 1.92; 2 trials; 1633 women; low-quality evidence). There was no difference in multiple pregnancies per woman after the first transfer (OR 1.11, 95% CI 0.85 to 1.44; 2 trials; 1630 women; low-quality evidence), and no data were reported for time to pregnancy.

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