Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology New search for studies and content updated (conclusions changed)

Abstract

Abstract Background

Advances in cell culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage stage embryo transfer to blastocyst stage transfer. The rationale for blastocyst transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates.

Objectives

To determine whether blastocyst stage (day 5 to 6) embryo transfers improve the live birth rate, and other associated outcomes, compared with cleavage stage (day 2 to 3) embryo transfers.

Search methods

We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2016, Issue 4), MEDLINE, EMBASE, PsycINFO, CINAHL, and Bio extracts from inception to 4th April 2016. We also searched registers of ongoing trials and the reference lists of studies retrieved.

Selection criteria

We included randomised controlled trials (RCTs) which compared the effectiveness of blastocyst versus cleavage stage transfers.

Data collection and analysis

We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and cumulative clinical pregnancy rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos, and embryo freezing. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.

Main results

We included 27 RCTs (4031 couples or women).

The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I2 = 45%, low quality evidence) following fresh transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer.

There was no evidence of a difference between the groups in rates per couple of cumulative pregnancy following fresh and frozen‐thawed transfer after one oocyte retrieval (OR 0.89, 95% CI 0.64 to 1.22; 5 RCTs, 632 women, I2 = 71%, very low quality evidence).

The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR 1.30, 95% CI 1.14 to 1.47; 27 RCTs, 4031 women, I2 = 56%, moderate quality evidence). This suggests that if 36% of women achieve clinical pregnancy after fresh cleavage stage transfer, between 39% and 46% would do so after fresh blastocyst stage transfer.

There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs, 3019 women, I2 = 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I2 = 0%, low quality evidence). These data are incomplete as under 70% of studies reported these outcomes.

Embryo freezing rates were lower in the blastocyst transfer group (OR 0.48, 95% CI 0.40 to 0.57; 14 RCTs, 2292 women, I2 = 84%, low quality evidence). This suggests that if 60% of women have embryos frozen after cleavage stage transfer, between 37% and 46% would do so after blastocyst stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 RCTs, 2577 women, I2 = 36%, moderate quality evidence). This suggests that if 1% of women have no embryos transferred in (planned) fresh cleavage stage transfer, between 2% and 4% will have no embryos transferred in (planned) fresh blastocyst stage transfer.

The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias.

Authors' conclusions

There is low quality evidence for live birth and moderate quality evidence for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates derived from fresh and frozen‐thawed cycles following a single oocyte retrieval, but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable couples or women undergoing assisted reproductive technology (ART) and service providers to make well informed decisions on the best treatment option available.

Author(s)

Demián Glujovsky, Cindy Farquhar, Andrea Marta Quinteiro Retamar, Cristian Roberto Alvarez Sedo, Deborah Blake

Abstract

Plain language summary

Blastocyst versus cleavage stage embryo transfer in assisted conception

Review question

We aimed to determine whether blastocyst stage (day 5 to 6) embryo transfer improves live birth rates following fresh transfer and cumulative pregnancy rates (following fresh and frozen‐thawed cycles) compared with cleavage stage (day 2 to 3) transfer.

Background

Embryos from assisted reproductive technologies (ARTs, e.g. in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), thawed embryo cycles) are commonly transferred into a woman’s uterus at either the cleavage stage (day 2 to 3 after egg collection) or blastocyst stage (day 5 to 6 after egg collection). Until recently, most ART cycles transferred embryos at cleavage stage, however there has been a trend to transferring embryos at the blastocyst stage as this timing is about the same as natural cycle embryos moving into the uterus.

Study characteristics

We included 27 randomised controlled trials (RCTs), which included 4031 women. The evidence is current to April 2016.

Key results

There was low quality evidence for live birth and moderate for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates (i.e. pregnancies from both fresh and thawed cycles deriving from a single egg collection procedure), but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative rates of live birth and pregnancy. There was no evidence of a difference between the groups in multiple pregnancy and miscarriage rates, but the quality of evIdence was low. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable ART consumers and service providers to make well informed decisions on the best treatment option available.

Quality of the evidence

The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias.

Author(s)

Demián Glujovsky, Cindy Farquhar, Andrea Marta Quinteiro Retamar, Cristian Roberto Alvarez Sedo, Deborah Blake

Reviewer's Conclusions

Authors' conclusions

Implications for practice

There is low quality evidence that blastocyst stage transfer is associated with higher rates of live birth and clinical pregnancy than cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates (derived from fresh and thawed cycles) but the evidence for this outcome was of very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on the cumulative rate.

Implications for research

Although this review provides evidence that there is a significant difference in live birth rates from fresh cycles in favour of blastocyst transfer compared to cleavage stage transfer cycles, findings for cumulative clinical pregnancy rates (derived from fresh and thawed cycles) still raise questions. Further new studies of blastocyst cycles must report live birth and cumulative live birth rates and miscarriage rates to enable consumers and service providers to make well informed decisions on the best treatment option. Finally, more studies with single embryo transfer are also needed in order to evaluate the best option with the fewest adverse event rates.

Based on the results of this review, we recommend the following to ensure valuable data are produced.

  • Adherence to Consolidated Standards of Reporting Trials (CONSORT) recommendations for RCTs, especially methods of concealment (Begg 1996).
  • Research into best patient selection and inclusion criteria; consider prognostic factors such as age, outcomes from previous cycles.
  • Same media composition and brand for both groups up to the cleavage stage.
  • Explicit prespecified embryo transfer policies for both groups; preferably single embryo transfer.
  • Long‐term follow‐up reports of cumulative live birth rates (including embryo thaws) presented as a survival analysis.
  • Research into improved blastocyst cryopreservation techniques, e.g. vitrification.
  • Application of blastocyst culture for single embryo transfer.
  • Reporting of miscarriage, live birth, and cumulative pregnancy rates.

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