Fresh versus frozen embryo transfers in assisted reproduction

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 methods: 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.

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.

Conflict of interest statement

Kai Mee Wong: none known Madelon van Wely: none known Femke Mol: none known Sjoerd Repping: none known Sebastiaan Mastenbroek is principal investigator of one of the ongoing studies.

Figures

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.1 Live birth rate.

Figure 5

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.2 OHSS.

Figure 6

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.3 Ongoing pregnancy rate.

Figure 7

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.4 Clinical pregnancy rate.

Figure 8

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.5 Multiple pregnancy rate.

Figure 9

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.6 Miscarriage rate.

Figure 10

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.7 Pregnancy complications.

Figure 11

Forest plot of comparison: 1 Freeze‐all vs conventional IVF, outcomes per woman, outcome: 1.8 Birth weight of babies born.

Figure 12

Forest plot of comparison: 3 Freeze‐all vs conventional IVF, congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated, outcome: 3.1 Congenital abnormalities.

Analysis 1.1

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 1 Live birth rate.

Analysis 1.2

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 2 OHSS.

Analysis 1.3

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 3 Ongoing pregnancy rate.

Analysis 1.4

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 4 Clinical pregnancy rate.

Analysis 1.5

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 5 Multiple pregnancy rate.

Analysis 1.6

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 6 Miscarriage rate.

Analysis 1.7

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 7 Pregnancy complications.

Analysis 1.8

Comparison 1 Freeze‐all versus conventional IVF, outcomes per woman, Outcome 8 Birth weight of babies born.

Analysis 2.1

Comparison 2 Freeze‐all versus conventional IVF, adverse events per clinical pregnancy, Outcome 1 Multiple pregnancy.

Analysis 2.2

Comparison 2 Freeze‐all versus conventional IVF, adverse events per clinical pregnancy, Outcome 2 Miscarriage.

Analysis 2.3

Comparison 2 Freeze‐all versus conventional IVF, adverse events per clinical pregnancy, Outcome 3 Pregnancy complications.

Analysis 3.1

Comparison 3 Freeze‐all versus conventional IVF, congenital abnormalities per live‐born children plus number of foetuses therapeutically terminated, Outcome 1 Congenital abnormalities.