Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology

Demián Glujovsky; Debbie Blake; Ariel Bardach; Cindy Farquhar

doi:10.1002/14651858.CD002118.pub4

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Figure 1

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

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Figure 2

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

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Figure 3

Forest plot of comparison: 1 Live birth rate, outcome: 1.1 Live birth per couple.

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Figure 4

Forest plot of comparison: 2 Clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple.

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Figure 5

Forest plot of comparison: 3 Cumulative pregnancy rate, outcome: 3.1 cumulative pregnancy rate from fresh and frozen transfers.

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Figure 6

Funnel plot of comparison: 1 Live birth rate, outcome: 1.1 Live birth per couple.

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Figure 7

Funnel plot of comparison: 2 Clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple.

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Analysis 1.1

Comparison 1 Live birth rate, Outcome 1 Live birth per couple.

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Analysis 1.2

Comparison 1 Live birth rate, Outcome 2 Live birth per couple: grouped by number of embryos transferred.

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Analysis 1.3

Comparison 1 Live birth rate, Outcome 3 Live birth rate per couple: grouped by prognosis.

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Analysis 1.4

Comparison 1 Live birth rate, Outcome 4 Live birth rate: grouped by day of randomisation.

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Analysis 2.1

Comparison 2 Clinical pregnancy rate, Outcome 1 clinical pregnancy rate per couple.

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Analysis 2.2

Comparison 2 Clinical pregnancy rate, Outcome 2 clinical pregnancy rate per couple: grouped by number of embryos transferred.

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Analysis 2.3

Comparison 2 Clinical pregnancy rate, Outcome 3 clinical pregnancy rate per couple: grouped by prognosis.

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Analysis 2.4

Comparison 2 Clinical pregnancy rate, Outcome 4 clinical pregnancy rate per couple: grouped by day of randomisation.

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Analysis 3.1

Comparison 3 Cumulative pregnancy rate, Outcome 1 cumulative pregnancy rate from fresh and frozen transfers.

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Analysis 4.1

Comparison 4 Multiple‐pregnancy rate, Outcome 1 multiple‐pregnancy rate per couple.

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Analysis 4.2

Comparison 4 Multiple‐pregnancy rate, Outcome 2 multiple‐pregnancy rate per couple: grouped by number of embryo transfer.

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Analysis 4.3

Comparison 4 Multiple‐pregnancy rate, Outcome 3 multiple‐pregnancy rate per couple: grouped by prognosis.

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Analysis 4.4

Comparison 4 Multiple‐pregnancy rate, Outcome 4 high order pregnancies (more than 2 gestational sacs) per couple.

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Analysis 4.5

Comparison 4 Multiple‐pregnancy rate, Outcome 5 high order pregnancy: grouped by number of embryos transferred.

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Analysis 4.6

Comparison 4 Multiple‐pregnancy rate, Outcome 6 high order pregnancies: grouped by prognosis.

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Analysis 4.7

Comparison 4 Multiple‐pregnancy rate, Outcome 7 multiple‐pregnancy rate per pregnancy.

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Analysis 4.8

Comparison 4 Multiple‐pregnancy rate, Outcome 8 high order pregnancies per total pregnancies.

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Analysis 5.1

Comparison 5 Miscarriage rate, Outcome 1 miscarriage rate per couple.

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Analysis 5.2

Comparison 5 Miscarriage rate, Outcome 2 miscarriage rate per pregnancy.

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Analysis 6.1

Comparison 6 Embryo freezing rate, Outcome 1 embryo freezing per couple.

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Analysis 6.2

Comparison 6 Embryo freezing rate, Outcome 2 Embyro freezing per couple: grouped by number of embryos transferred.

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Analysis 6.3

Comparison 6 Embryo freezing rate, Outcome 3 Embryo freezing per couple: grouped by prognostic factors.

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Analysis 7.1

Comparison 7 Failure to transfer embryos rate per couple, Outcome 1 Failure to transfer any embryos per couple.

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Analysis 7.2

Comparison 7 Failure to transfer embryos rate per couple, Outcome 2 Failure to transfer any embryos per couple: grouped by prognostic factors.

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Analysis 7.3

Comparison 7 Failure to transfer embryos rate per couple, Outcome 3 Failure to transfer any embryos per couple: grouped by number of embryos transferred.

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Table 1. Culture techniques of included studies

Trial	Culture Tech Day 2/3	Culture Tech Day 5/6
Brugnon 2010	G series™ medium (Vitrolife, Sweden)	G series™ medium (Vitrolife, Sweden)
Bungum 2003	Sequential G1 VItrolife	Sequential G1/G2 Vitrolife
Coskun 2000	Sequential Medicult	Sequential G1/G2 Vitrolife
Devreker 2000	NS	NS
Elgindy 2011	NS	NS
Emiliani 2003	In‐house sequential (based on G1/G2)	In‐house sequential (based on G1/G2)
Fisch 2007
Frattarelli 2003	Sequential NS	Sequential NS
Gardner 1998a	Single Hams F10 In‐house	Sequential G1/G2 In‐house
Hreinsson 2004	Vitro life IVF	Sequential G1/G2 or CCM Vitrolife
Karaki 2002	Medicult	Sequential G1/G2 Vitrolife
Kolibianakis 2004	Sequential G1 Vitrolife	Sequential G1/G2 Vitrolife
Levitas 2004	NS	Sequential ‐ G1/G2 Vitrolife
Levron 2002	NS	NS
Livingstone 2002	Sequential ‐ Sydney IVF Cook	Sequential ‐ Sydney IVF Cook
Motta 1998	Sequential ‐ Irvines P1	Sequential ‐ Irvines P1 then Blast media
Pantos 2004
Papanikolaou 2005	Sequential ‐ Vitrolife G1/G2 GII or GIII	Sequential ‐ Vitrolife G1/G2 GII or GIII
Papanikolaou 2006	Assume Sequential ‐ Vitrolife G1/G2	Assume Sequential ‐ Vitrolife G1/G2
Rienzi 2002	Sequential G1 Vitrolife	Sequential G1/G2 Vitrolife
Schillaci 2002	NS	NS
Ten 2011	NS	NS
Van der Auwera 2002	Sequential both Cook and Vitrolife	Sequential both Cook and Vitrolife

Table 1. Culture techniques of included studies

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Table 2. Blastocyst and implantation rate (in Day 5 to 6 transfers)

Study	Blastocyst rate	Implantation D2/3	Implantation D5/6	Other
Brugnon 2010	Not stated	24/52 46.2%	23/55 41.8%
Bungum 2003	55.2%	50/114 43.9%	44/120 36.7%	2/61 patients had only 1 blastocyst
Coskun 2000	28%	50/235 21.3%	52/218 23.9%	77% patients had at least 1 blastocyst
Devreker 2000	Not stated	1/34 2.9%	8/19 42.1%
Elgindy 2011	97%	71/197 36%	53/280 19%
Emiliani 2003	48%	57/197 28.9%	50/168 29.8%
Fisch 2007	Not stated	11/12 92%	4/8 50%
Frattarelli 2003	Not stated	18/69 26.1%	23/53 43.4%
Gardner 1998	46.5%	64/174 36.8%	53/95 55.8%	85% patients had at least 2 blastocysts
Hreinsson 2004	33%	29/139 20.9%	24/114 21.1%	2 morula replace (one implanted). 60% preg rate when top quality blasts transferred
Karaki 2002	33%	37/291 12.7%	37/142 26.1%	9/80 cancelled due to lack of blastocysts (unselected)
Kolibiankis 2004	50.7%	96/234 41.0%	94/226 41.6%
Levitas 2004	43%	4/56 7.1%	10/24 4.2%	Day 5‐7 26% cancelled due to lack of blastocysts (poor prog)
Levron 2002	34.2%	53/137 38.7%	20/99 20.2%	6.5% cancelled due to lack of blastocysts (good prog)
Livingstone 2002	not stated
Motta 1998	Not stated	51/262 19.5%	36/120 30.0%	6/58 cycles cancelled D5 no blastocysts
Pantos 2004	44.6%	15.8%	15.8%
Papanikolaou 2005	Not stated	35/170 20.6%	59/158 37.3%	4/158 women had only 1 blast transferred due to lack of availability and 1 had it on request.
Papanikolaou 2006	Not stated	38/156 24%	58/149 38.9%	Number of patients with no embryos avail D3: 8 and D5: 11
Rienzi 2002	44.8%	34/96 35.4%	38/100 38.0%	Good prognosis
Schillaci 2002	60.3%	23/168 13.7%	26/110 23.6%	Unselected population nil cancellations D5
Ten 2011	Not stated	21/54 38.9%	26/56 46.4%	Good prognosis
Van der Auwera	44.7%	31/106 29.2%	41/90 45.6%	27% cancellation D5 (unselected population)

Table 2. Blastocyst and implantation rate (in Day 5 to 6 transfers)

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Table 3. Mean number of embryos transferred

Study ID	Day 2/3	Day 5/6
Brugnon 2010	1	1
Bungum 2003	2.00	1.97
Coskun 2000	2.3	2.2
Devreker 2000	2.83	1.73
Elgindy 2010	2.8	1.97
Emiliani 2003	2.1	1.9
Fisch 2007	1	1
Frattarelli 2003	2.96	2.04
Gardner 1998	3.7	2.2
Hreinsson J	1.8	1.9
Karaki 2002	3.5	2.0
Kolibiankis 2004	1.9	1.8
Levitas 2004	3.4	1.9
Levron 2002	3.1	2.3
Livingstone	2.0	1.0
Motta 1998	4.6	2.3
Pantos 2004	4	3.4
Papanikolaou 2005	2	1.97
Papanikolaou 2006	1	1
Rienzi 2002	2.0	2.0
Schillaci 2002	2.8	1.8
Ten 2011	2	2
Van der Auwera 2002	1.86	1.87

Table 3. Mean number of embryos transferred

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Comparison 1. Live birth rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth per couple Show forest plot	12	1510	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.40 [1.13, 1.74]

2 Live birth per couple: grouped by number of embryos transferred Show forest plot	12		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

2.1 more cleavage stage than blastocyst embyros transferred	6	483	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [1.03, 2.23]
2.2 single embryo transfer	2	458	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.46 [0.98, 2.19]
2.3 equal number of embryos transferred	6	1027	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.35 [1.04, 1.75]
3 Live birth rate per couple: grouped by prognosis Show forest plot	12	1510	Odds Ratio (M‐H, Random, 95% CI)	1.37 [1.01, 1.85]

3.1 good prognostic factors	8	1126	Odds Ratio (M‐H, Random, 95% CI)	1.43 [0.99, 2.07]
3.2 poor prognostic factors	2	77	Odds Ratio (M‐H, Random, 95% CI)	1.99 [0.49, 8.04]
3.3 unselected group	2	307	Odds Ratio (M‐H, Random, 95% CI)	1.05 [0.56, 1.97]
4 Live birth rate: grouped by day of randomisation Show forest plot	12	1510	Odds Ratio (M‐H, Random, 95% CI)	1.37 [1.01, 1.85]

4.1 randomisation at start of cycle	5	819	Odds Ratio (M‐H, Random, 95% CI)	1.25 [0.90, 1.73]
4.2 randomised on day of OPU and day 1 after OPU	3	245	Odds Ratio (M‐H, Random, 95% CI)	0.97 [0.37, 2.58]
4.3 randomised Day 2 to 3 post OPU	2	364	Odds Ratio (M‐H, Random, 95% CI)	2.17 [1.42, 3.33]
4.4 day of randomisation unstated	2	82	Odds Ratio (M‐H, Random, 95% CI)	1.68 [0.65, 4.38]

Comparison 1. Live birth rate

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Comparison 2. Clinical pregnancy rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 clinical pregnancy rate per couple Show forest plot	23	3241	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.14 [0.99, 1.32]

2 clinical pregnancy rate per couple: grouped by number of embryos transferred Show forest plot	23		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 equal numbers of ET	11	1854	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.99, 1.44]
2.2 more cleavage stage than blastocyst embryos transfered	12	1387	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.86, 1.33]
2.3 Single embryo transfer	3	478	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.84, 1.82]
3 clinical pregnancy rate per couple: grouped by prognosis Show forest plot	23	3241	Odds Ratio (M‐H, Random, 95% CI)	1.13 [0.92, 1.40]

3.1 Good prognostic factors	14	1756	Odds Ratio (M‐H, Random, 95% CI)	1.15 [0.83, 1.58]
3.2 Poor prognostic factors	2	77	Odds Ratio (M‐H, Random, 95% CI)	2.59 [0.75, 8.92]
3.3 Unselected group	7	1408	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.81, 1.25]
4 clinical pregnancy rate per couple: grouped by day of randomisation Show forest plot	23	3241	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.99, 1.32]

4.1 Randomised start of cycle	7	1371	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.95, 1.49]
4.2 Randomised on day of OPU or day 1	8	892	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.76, 1.31]
4.3 Randomised on day 2 to 3	4	537	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [1.13, 2.23]
4.4 Day of randomisation unstated	4	441	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.57, 1.25]

Comparison 2. Clinical pregnancy rate

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Comparison 3. Cumulative pregnancy rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 cumulative pregnancy rate from fresh and frozen transfers Show forest plot	4	527	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.58 [1.11, 2.25]

Comparison 3. Cumulative pregnancy rate

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Comparison 4. Multiple‐pregnancy rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 multiple‐pregnancy rate per couple Show forest plot	16	2481	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.92 [0.71, 1.19]

2 multiple‐pregnancy rate per couple: grouped by number of embryo transfer Show forest plot	16		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Equal number of embryos transferred	8	1672	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.75, 1.46]
2.2 More cleavage stage than blastocyst embryos transferred	8	809	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.49, 1.13]
2.3 Single embryo transfer	1	351	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.17]
3 multiple‐pregnancy rate per couple: grouped by prognosis Show forest plot	16	2481	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.70, 1.18]

3.1 Good prognostic factors	11	1498	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.63, 1.22]
3.2 Poor prognostic factors	1	54	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.14, 5.81]
3.3 Unselected	4	929	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.62, 1.47]
4 high order pregnancies (more than 2 gestational sacs) per couple Show forest plot	12	2035	Odds Ratio (M‐H, Fixed, 95% CI)	0.44 [0.15, 1.33]

5 high order pregnancy: grouped by number of embryos transferred Show forest plot	12	2035	Odds Ratio (M‐H, Fixed, 95% CI)	0.44 [0.15, 1.33]

5.1 Equal number of embryos transferred	8	1672	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.28]
5.2 More cleavage stage than blastocyst embryos transferred	4	363	Odds Ratio (M‐H, Fixed, 95% CI)	0.46 [0.14, 1.49]
6 high order pregnancies: grouped by prognosis Show forest plot	12	2035	Odds Ratio (M‐H, Fixed, 95% CI)	0.44 [0.15, 1.33]

6.1 Good prognostic factors	9	1385	Odds Ratio (M‐H, Fixed, 95% CI)	0.29 [0.08, 1.06]
6.2 Poor prognostic factors	1	54	Odds Ratio (M‐H, Fixed, 95% CI)	4.2 [0.16, 107.89]
6.3 Unselected	2	596	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 multiple‐pregnancy rate per pregnancy Show forest plot	14		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 high order pregnancies per total pregnancies Show forest plot	12		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. Multiple‐pregnancy rate

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Comparison 5. Miscarriage rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 miscarriage rate per couple Show forest plot	14	2127	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.14 [0.84, 1.55]

2 miscarriage rate per pregnancy Show forest plot	14		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 5. Miscarriage rate

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Comparison 6. Embryo freezing rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 embryo freezing per couple Show forest plot	11	1729	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.88 [2.35, 3.51]

2 Embyro freezing per couple: grouped by number of embryos transferred Show forest plot	11	1729	Odds Ratio (M‐H, Random, 95% CI)	4.06 [2.49, 6.60]

2.1 equal number of embryos transferred	7	1118	Odds Ratio (M‐H, Random, 95% CI)	4.35 [2.11, 8.97]
2.2 more cleavage stage than blastocyst embryos transferred	4	611	Odds Ratio (M‐H, Random, 95% CI)	3.95 [2.09, 7.46]
3 Embryo freezing per couple: grouped by prognostic factors Show forest plot	10	1486	Odds Ratio (M‐H, Random, 95% CI)	4.17 [2.41, 7.21]

3.1 good prognostic factors	6	612	Odds Ratio (M‐H, Random, 95% CI)	6.39 [3.12, 13.10]
3.2 poor prognostic factors	0	0	Odds Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 unselected	4	874	Odds Ratio (M‐H, Random, 95% CI)	2.60 [1.31, 5.16]

Comparison 6. Embryo freezing rate

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Comparison 7. Failure to transfer embryos rate per couple

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to transfer any embryos per couple Show forest plot	16	2459	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.24, 0.51]

2 Failure to transfer any embryos per couple: grouped by prognostic factors Show forest plot	16	2459	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.24, 0.51]

2.1 good prognostic factors	9	1315	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.35, 1.27]
2.2 poor prognostic factors	2	77	Odds Ratio (M‐H, Fixed, 95% CI)	0.20 [0.04, 1.08]
2.3 unselected	5	1067	Odds Ratio (M‐H, Fixed, 95% CI)	0.27 [0.17, 0.43]
3 Failure to transfer any embryos per couple: grouped by number of embryos transferred Show forest plot	16		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 equal number of embryos transferred	7	1321	Odds Ratio (M‐H, Fixed, 95% CI)	0.37 [0.23, 0.61]
3.2 more cleavage stage than blastocyst embryos tranferred	8	787	Odds Ratio (M‐H, Fixed, 95% CI)	0.23 [0.11, 0.46]
3.3 single embryo transfer	1	351	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.28, 1.81]

Comparison 7. Failure to transfer embryos rate per couple

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