Fresh versus frozen embryo transfers for assisted reproduction

Review question

Is a freeze-all strategy in IVF and ICSI treatments safe and effective in comparison to conventional IVF and ICSI treatment?


Background

Conventionally, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments consist of a fresh embryo transfer directly after ovarian hyperstimulation, which is used in order to retrieve oocytes in the IVF/ICSI procedure. In the conventional IVF/ICSI treatment fresh embryo transfer is possibly followed by one or more frozen embryo transfers in subsequent cycles when enough embryos are available. Alternatively, one can opt to 'freeze all' suitable embryos, and transfer frozen embryos in subsequent cycles only, which is also known as the 'freeze all' strategy. In the "freeze all" strategy all embryos are frozen to be transferred at later time point when the ovaries are not stimulated. Therefore, this method could reduce the risk of ovarian hyperstimulation syndrome (OHSS, an overreaction to fertility drugs) as OHSS is more severe when pregnancy occurs. Furthermore, studies have suggested that a woman's hormonal response to fertility drugs could affect the lining of the womb making it difficult for an embryo to implant. Thus, it could be beneficial to freeze the embryos and transfer them later when the lining of the womb is not affected by fertility drugs.

In the past decade, an increasing number of clinics have applied the 'freeze all' strategy as a standard treatment strategy in their practice. In practice, the 'freeze all' strategy and the conventional strategy can vary technically.

We compared the effectiveness and safety of these treatment strategies in women undergoing assisted reproductive technology.


Study characteristics

We examined all research published in the scientific literature up to 23 September 2020.

We included 15 randomised controlled trials (experiments where each person has an equal chance of being chosen to receive the treatment or a comparator) in the review. We were able to combine and analyse the results of eight trials, with a total of 4712 women.
 

Key results

There is probably little or no difference in cumulative live birth rate and ongoing pregnancy rate between the 'freeze all' strategy and the conventional IVF/ICSI strategy. 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 57% and 63%. Not performing a fresh transfer, as is done in a freeze-all strategy, might lower the OHSS risk for women at risk of OHSS. Our findings suggest that if the OHSS rate is 3% following a conventional IVF/ICSI strategy, the rate following a 'freeze all' strategy would be 1%. We are uncertain whether the 'freeze all' strategy has any effect on the risk of miscarriage, multiple pregnancy rate, and time to pregnancy compared to conventional IVF/ICSI.

We also evaluated differences in risks for mother and child. The 'freeze all' strategy may increase the risk of hypertensive disorders of pregnancy, the risk of having a large-for-gestational-age baby, and may result in a higher birth weight of the children born. Caution is needed in drawing conclusions from this as the analysis is based on very low number of events.


Quality of the evidence

The evidence was of moderate quality for cumulative live birth rate and low quality for safety outcomes. The low quality was generally due to serious imprecision in view of the relatively few events, serious unexplained heterogeneity, meaning that the results across trials varied widely, and due to risk of bias within the included trials.

Authors' conclusions: 

We found moderate-quality evidence showing that one strategy is probably not superior to the other in terms of cumulative live birth rate and ongoing pregnancy rate. The risk of OHSS may be decreased in the 'freeze all' strategy. Based on the results of the included studies, we could not analyse time to pregnancy. It is likely to be shorter using a conventional IVF/ICSI strategy with fresh embryo transfer in the case of similar cumulative live birth rate, as embryo transfer is delayed in a 'freeze all' strategy. The risk of maternal hypertensive disorders of pregnancy, of having a large-for-gestational-age baby and a higher birth weight of the children born may be increased following the 'freeze all' strategy. We are uncertain if 'freeze all' strategy reduces the risk of miscarriage, multiple pregnancy rate or having a small-for-gestational-age baby compared to conventional IVF/ICSI.

Read the full abstract...
Background: 

In vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments conventionally consist of a fresh embryo transfer, possibly followed by one or more cryopreserved embryo transfers in subsequent cycles. An alternative option is to freeze all suitable embryos and transfer cryopreserved embryos in subsequent cycles only, which is known as the 'freeze all' strategy. This is the first update of the Cochrane Review on this comparison.

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, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials from inception until 23 September 2020 for relevant studies, checked references of publications found, and contacted study authors to obtain additional data.

Selection criteria: 

Two review authors (TZ and MZ) independently selected studies for inclusion, assessed risk of bias, and extracted study data. We included randomised controlled trials comparing a 'freeze all' strategy with a conventional IVF/ICSI strategy including a fresh embryo transfer in women undergoing IVF or ICSI treatment.

Data collection and analysis: 

The primary outcomes were cumulative live birth rate and ovarian hyperstimulation syndrome (OHSS). Secondary outcomes included effectiveness outcomes (including ongoing pregnancy rate and clinical pregnancy rate), time to pregnancy and obstetric, perinatal and neonatal outcomes.

Main results: 

We included 15 studies in the systematic review and eight studies with a total of 4712 women in the meta-analysis. The overall evidence was of moderate to low quality. We graded all the outcomes and downgraded due to serious risk of bias, serious imprecision and serious unexplained heterogeneity. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study during the interim analysis, unit of analysis error, and absence of adequate study termination rules. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes, which is reflected in the cautious language below.

There is probably little or no difference in cumulative live birth rate between the 'freeze all' strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.08, 95% CI 0.95 to 1.22; I2 = 0%; 8 RCTs, 4712 women; moderate-quality evidence). This suggests that for a cumulative live birth rate of 58% following the conventional strategy, the cumulative live birth rate following the 'freeze all' strategy would be between 57% and 63%.

Women might develop less OHSS after the 'freeze all' strategy compared to the conventional IVF/ICSI strategy (OR 0.26, 95% CI 0.17 to 0.39; I2 = 0%; 6 RCTs, 4478 women; low-quality evidence). These data suggest that for an OHSS rate of 3% following the conventional strategy, the rate following the 'freeze all' strategy would be 1%.

There is probably little or no difference between the two strategies in the cumulative ongoing pregnancy rate (OR 0.95, 95% CI 0.75 to 1.19; I2 = 31%; 4 RCTs, 1245 women; moderate-quality evidence). 

We could not analyse time to pregnancy; by design, time to pregnancy is shorter in the conventional strategy than in the 'freeze all' strategy when the cumulative live birth rate is comparable, as embryo transfer is delayed in a 'freeze all' strategy. We are uncertain whether the two strategies differ in cumulative miscarriage rate because the evidence is very low quality (Peto OR 1.06, 95% CI 0.72 to 1.55; I2 = 55%; 2 RCTs, 986 women; very low-quality evidence) and cumulative multiple-pregnancy rate (Peto OR 0.88, 95% CI 0.61 to 1.25; I2 = 63%; 2 RCTs, 986 women; very low-quality evidence). The risk of hypertensive disorders of pregnancy (Peto OR 2.15, 95% CI 1.42 to 3.25; I2 = 29%; 3 RCTs, 3940 women; low-quality evidence), having a large-for-gestational-age baby (Peto OR 1.96, 95% CI 1.51 to 2.55; I2 = 0%; 3 RCTs, 3940 women; low-quality evidence) and a higher birth weight of the children born (mean difference (MD) 127 g, 95% CI 77.1 to 177.8; I2 = 0%; 5 RCTs, 1607 singletons; moderate-quality evidence) may be increased following the 'freeze all' strategy. We are uncertain whether the two strategies differ in the risk of having a small-for-gestational-age baby because the evidence is low quality (Peto OR 0.82, 95% CI 0.65 to 1.05; I2 = 64%; 3 RCTs, 3940 women; low-quality evidence).

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