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. 2022 May 19;5(5):CD002118.
doi: 10.1002/14651858.CD002118.pub6.

Cleavage-stage versus blastocyst-stage embryo transfer in assisted reproductive technology

Demián Glujovsky  1 , Andrea Marta Quinteiro Retamar  2 , Cristian Roberto Alvarez Sedo  3 , Agustín Ciapponi  4 , Simone Cornelisse  5 , Deborah Blake  6
Affiliations

Cleavage-stage versus blastocyst-stage embryo transfer in assisted reproductive technology

Demián Glujovsky et al. Cochrane Database Syst Rev. .

Abstract

Background: Advances in embryo culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer. The rationale for blastocyst-stage 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 transfer improves the live birth rate (LBR) per fresh transfer, and other associated outcomes, compared with cleavage-stage (day 2 to 3) embryo transfer.

Search methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL, from inception to October 2021. 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 IVF with blastocyst-stage embryo transfer versus IVF with cleavage-stage embryo transfer.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were LBR per fresh transfer and cumulative clinical pregnancy rates (cCPR). Secondary outcomes were clinical pregnancy rate (CPR), multiple pregnancy, high-order multiple pregnancy, miscarriage (all following first embryo transfer), failure to transfer embryos, and whether supernumerary embryos were frozen for transfer at a later date (frozen-thawed embryo transfer). We assessed the overall quality of the evidence for the main comparisons using GRADE methods.

Main results: We included 32 RCTs (5821 couples or women). The live birth rate following fresh transfer was higher in the blastocyst-stage transfer group (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06 to 1.51; I2 = 53%; 15 studies, 2219 women; low-quality evidence). This suggests that if 31% of women achieve live birth after fresh cleavage-stage transfer, between 32% and 41% would do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR. A post hoc analysis showed that vitrification could increase the cCPR. This is an interesting finding that warrants further investigation when more studies using vitrification are published. The CPR was also higher in the blastocyst-stage transfer group, following fresh transfer (OR 1.25, 95% CI 1.12 to 1.39; I2 = 51%; 32 studies, 5821 women; moderate-quality evidence). This suggests that if 39% of women achieve a clinical pregnancy after fresh cleavage-stage transfer, between 42% and 47% will probably do so after fresh blastocyst-stage transfer. We are uncertain whether blastocyst-stage transfer increases multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; I2 = 30%; 19 studies, 3019 women; low-quality evidence) or miscarriage rates (OR 1.12, 95% CI 0.90 to 1.38; I2 = 24%; 22 studies, 4208 women; low-quality evidence). This suggests that if 9% of women have a multiple pregnancy after fresh cleavage-stage transfer, between 8% and 12% would do so after fresh blastocyst-stage transfer. However, a sensitivity analysis restricted only to studies with low or 'some concerns' for risk of bias, in the subgroup of equal number of embryos transferred, showed that blastocyst transfer probably increases the multiple pregnancy rate. Embryo freezing rates (when there are frozen supernumerary embryos for transfer at a later date) were lower in the blastocyst-stage transfer group (OR 0.48, 95% CI 0.40 to 0.57; I2 = 84%; 14 studies, 2292 women; 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; I2 = 36%; 17 studies, 2577 women; moderate-quality evidence). This suggests that if 1% of women have no embryos transferred in planned fresh cleavage-stage transfer, between 2% and 4% probably have no embryos transferred in planned fresh blastocyst-stage transfer. The evidence was of low quality for most outcomes. The main limitations were serious imprecision and serious risk of bias, associated with failure to describe acceptable methods of randomisation.

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 of both than fresh cleavage-stage transfer. We are uncertain whether blastocyst-stage transfer improves the cCPR derived from fresh and frozen-thawed cycles following a single oocyte retrieval. Although there is a benefit favouring blastocyst-stage transfer in fresh cycles, more evidence is needed to know whether the stage of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage. They should also evaluate women with a poor prognosis to enable those undergoing assisted reproductive technology (ART) and service providers to make well-informed decisions on the best treatment option available.

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Conflict of interest statement

Demián Glujovsky is part of medical staff of a fertility clinic and undertakes private practice within those premises.

Andrea Quinteiro Retamar is the egg donor coordinator of a fertility clinic and undertakes private practice within those premises.

Simone Cornelisse is the lead author of excluded study Cornelisse 2018 and took no part in assessing it for this review.

Cristian Alvarez Sedo, Agustín Ciapponi, and Deborah Blake have no conflicts of interest to declare.

Figures

1
1
Study flow diagram: results of search from review inception to 2020 (update of the flow diagram published in 2016)
2
2
Forest plot of comparison: 1 Blastocyst‐ versus cleavage‐stage transfer: live birth rate, outcome: 1.1 live birth per couple
3
3
Forest plot of comparison: 2 Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple
4
4
Funnel plot of comparison: 1 Blastocyst‐ versus cleavage‐stage transfer: live birth rate, outcome: 1.1 live birth per couple
5
5
Funnel plot of comparison: 2 Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple
1.1
1.1. Analysis
Comparison 1: Blastocyst‐ versus cleavage‐stage transfer: live birth rate following fresh transfer, Outcome 1: Live birth per couple
1.2
1.2. Analysis
Comparison 1: Blastocyst‐ versus cleavage‐stage transfer: live birth rate following fresh transfer, Outcome 2: Live birth per couple: grouped by number of embryos transferred
1.3
1.3. Analysis
Comparison 1: Blastocyst‐ versus cleavage‐stage transfer: live birth rate following fresh transfer, Outcome 3: Live birth rate per couple: grouped by prognosis
1.4
1.4. Analysis
Comparison 1: Blastocyst‐ versus cleavage‐stage transfer: live birth rate following fresh transfer, Outcome 4: Live birth rate: grouped by day of randomisation
2.1
2.1. Analysis
Comparison 2: Blastocyst‐ versus cleavage‐stage transfer: cumulative pregnancy rate following fresh and frozen transfer, Outcome 1: Cumulative pregnancy rate from fresh and frozen transfers
2.2
2.2. Analysis
Comparison 2: Blastocyst‐ versus cleavage‐stage transfer: cumulative pregnancy rate following fresh and frozen transfer, Outcome 2: Cumulative pregnancy rate per couple: grouped by number of embryos transferred
2.3
2.3. Analysis
Comparison 2: Blastocyst‐ versus cleavage‐stage transfer: cumulative pregnancy rate following fresh and frozen transfer, Outcome 3: Cumulative pregnancy rate per couple: grouped by prognosis
2.4
2.4. Analysis
Comparison 2: Blastocyst‐ versus cleavage‐stage transfer: cumulative pregnancy rate following fresh and frozen transfer, Outcome 4: Cumulative pregnancy rate: grouped by day of randomisation
2.5
2.5. Analysis
Comparison 2: Blastocyst‐ versus cleavage‐stage transfer: cumulative pregnancy rate following fresh and frozen transfer, Outcome 5: Cumulative pregnancy rate from fresh and frozen transfers: grouped by vitrification or slow freezing
3.1
3.1. Analysis
Comparison 3: Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy following fresh transfer, Outcome 1: Clinical pregnancy rate per couple
3.2
3.2. Analysis
Comparison 3: Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy following fresh transfer, Outcome 2: Clinical pregnancy rate per couple: grouped by number of embryos transferred
3.3
3.3. Analysis
Comparison 3: Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy following fresh transfer, Outcome 3: Clinical pregnancy rate per couple: grouped by prognosis
3.4
3.4. Analysis
Comparison 3: Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy following fresh transfer, Outcome 4: Clinical pregnancy rate per couple: grouped by day of randomisation
3.5
3.5. Analysis
Comparison 3: Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy following fresh transfer, Outcome 5: Clinical pregnancy rate per couple: TLS (with algorithm) cleavage stage versus conventional blastocyst stage
3.6
3.6. Analysis
Comparison 3: Blastocyst‐ versus cleavage‐stage transfer: clinical pregnancy following fresh transfer, Outcome 6: Clinical pregnancy rate per couple: TLS (with algorithm) cleavage stage versus TLS (with algorithm) blastocyst stage
4.1
4.1. Analysis
Comparison 4: Blastocyst‐ versus cleavage‐stage transfer: multiple pregnancy following fresh transfer, Outcome 1: Multiple pregnancy rate per couple
4.2
4.2. Analysis
Comparison 4: Blastocyst‐ versus cleavage‐stage transfer: multiple pregnancy following fresh transfer, Outcome 2: Multiple pregnancy rate per couple: grouped by number of embryos transferred
4.3
4.3. Analysis
Comparison 4: Blastocyst‐ versus cleavage‐stage transfer: multiple pregnancy following fresh transfer, Outcome 3: Multiple pregnancy rate per couple: grouped by prognosis
4.4
4.4. Analysis
Comparison 4: Blastocyst‐ versus cleavage‐stage transfer: multiple pregnancy following fresh transfer, Outcome 4: Multiple pregnancy rate per couple: grouped by day of randomisation
4.5
4.5. Analysis
Comparison 4: Blastocyst‐ versus cleavage‐stage transfer: multiple pregnancy following fresh transfer, Outcome 5: High‐order pregnancies (more than 2 gestational sacs) per couple
4.6
4.6. Analysis
Comparison 4: Blastocyst‐ versus cleavage‐stage transfer: multiple pregnancy following fresh transfer, Outcome 6: Multiple pregnancy rate per couple: TLS (with algorithm) cleavage stage versus conventional blastocyst stage
5.1
5.1. Analysis
Comparison 5: Blastocyst‐ versus cleavage‐stage transfer: miscarriage rate following fresh transfer, Outcome 1: Miscarriage rate per couple
6.1
6.1. Analysis
Comparison 6: Blastocyst‐ versus cleavage‐stage transfer: embryo freezing rate per couple, Outcome 1: Embryo freezing per couple
7.1
7.1. Analysis
Comparison 7: Blastocyst‐ versus cleavage‐stage transfer: failure rate to transfer embryos (per couple), Outcome 1: Failure to transfer any embryos (per couple)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Schillaci 2002 {published data only}
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Ten 2011 {published data only}
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Van der Auwera 2002 {published data only}
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References to studies excluded from this review

Bungum 2002 {published data only}
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Cornelisse 2018 {published data only}
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Green 2016 {published data only}
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Guerin 1991 {published data only}
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Holden 2017 {published data only}
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References to studies awaiting assessment

Clua Obrado 2020 {published data only}
    1. Clua Obrado E, Rodriguez I, Arroyo G, Martinez F, Latre L, Coroleu B, et al. Cleavage stage embryo transfer impairs cumulative live birth rates and time to livebirth as compared to blastocyst transfer in oocyte recipients. A randomized controlled trial. Human Reproduction 2020;35(Suppl 1):i2-i3.

References to ongoing studies

ChiCTR‐ICR‐15006184 {published data only}
    1. ChiCTR-ICR-15006184. Cumulative live birth rates after cleavage-stage versus blastocyst-stage embryo transfer: a multicenter, prospective, randomized controlled trial. www.chictr.org.cn/showprojen.aspx?proj=10698 (first received 29 March 2015).
Cornelisse 2021 {published data only}
    1. Cornelisse S, Ramos L, Arends B, Brink-van der Vlugt JJ, Bruin JP, et al. Comparing the cumulative live birth rate of cleavage-stage versus blastocyst-stage embryo transfers between IVF cycles: a study protocol for a multicentre randomised controlled superiority trial (the ToF trial). BMJ Open 2021;11:e042395. - PMC - PubMed
    1. NTR7034. ToF-studie Embryo transfer, day Three Or day Five, in good prognosis IVF cycles. www.who.int/trialsearch/Trial2.aspx?TrialID=NTR7034 (first received 19 February 2018).
ISRCTN48090543 {published data only}
    1. ISRCTN48090543. Trial comparing blastocyst transfer with cleavage stage transfer in women with increased maternal age [Blastocyst stage vs cleavage stage transfer in women with increased maternal age: a prospective randomised controlled trial]. trialsearch.who.int/?TrialID=ISRCTN48090543 (first received 28 December 2011).
NCT01107002 {published data only}
    1. NCT01107002. Comparison of 5 day embryo transfer with 2-3 day transfer in patients with previous in vitro fertilization failure. clinicaltrials.gov/ct2/show/NCT01107002 (first received 20 April 2010).
NCT02639000 {published data only}
    1. NCT02639000. Effects of blastocyst stage compared with cleavage stage embryo transfer in women below 39 years. clinicaltrials.gov/show/NCT02639000 (first received 23 December 2015).
NCT04210414 {published data only}
    1. NCT04210414. Cleave-stage transfer on day 3 versus day 5 transfer when only one embryo available (Cleave-blast). clinicaltrials.gov/show/NCT04210414 (first received 24 December 2019).
Neuhausser 2020 {published data only}
    1. Neuhausser WM, Vaughan DA, Sakkas D, Hacker MR, Toth T, Penzias A. Non-inferiority of cleavage-stage versus blastocyst-stage embryo transfer in poor prognosis IVF patients (PRECiSE trial): study protocol for a randomized controlled trial. Reproductive Health 2020;17(1):16. - PMC - PubMed
PACTR201402000773124 {published data only}
    1. PACTR201402000773124. Blastocyst versus day 2 transfer in low responders. www.who.int/trialsearch/Trial2.aspx?TrialID=PACTR201402000773124 (first received 18 February 2014).
PACTR201709002592834 {published data only}
    1. PACTR201709002592834. A randomized controlled trial of pregnancy outcome of sequential versus day 3 and day 5 embryo transfer in cases with recurrent implantation failure. www.who.int/trialsearch/Trial2.aspx?TrialID=PACTR201709002592834 (first received 7 September 2019).

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References to other published versions of this review

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