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Transferência de embrião no estágio de clivagem versus no estágio de blastocisto na reprodução assistida

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Appendices

Appendix 1. CGF search

CGFG search strategy (18.04.16)

Keywords CONTAINS "day 2"or"day 3"or "day 3 embryo transfer" or "day 4 embryo transfer" or "cleavage stage" or "cleavage transfer" or "pronuclear morphology" or "early cleavage assessment" or "early cleavage medium" or "early cleavage status" or Title CONTAINS "day 2"or"day 3"or "day 3 embryo transfer" or "day 4 embryo transfer" or "cleavage stage" or "cleavage transfer" or "pronuclear morphology" or "early cleavage assessment" or "early cleavage medium" or "early cleavage status"

AND

Keywords CONTAINS "day 5" or "day 5 transfer" or "day 6 transfer" or "Blastocyst" or "blastocyst culture technique" or "blastocyst media" or "blastocyst stage" or "blastocyst transfer" or Title CONTAINS "day 5" or "day 5 transfer" or "day 6 transfer" or "Blastocyst" or "blastocyst culture technique" or "blastocyst media" or "blastocyst stage" or "blastocyst transfer" (136 hits)

Appendix 2. CENTRAL search

1 MESH DESCRIPTOR Embryo Transfer EXPLODE ALL TREES 886
2 MESH DESCRIPTOR Fertilization in Vitro EXPLODE ALL TREES 1737
3 MESH DESCRIPTOR Sperm Injections, Intracytoplasmic EXPLODE ALL TREES 437
4 MESH DESCRIPTOR Oocyte Donation EXPLODE ALL TREES 61
5 (embryo transfer*):TI,AB,KY 1790
6 (in vitro fertili?ation):TI,AB,KY 1801
7 (intracytoplasmic sperm injection*):TI,AB,KY 941
8 ((ivf or icsi)):TI,AB,KY 3235
9 ET:TI,AB,KY 18137
10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 21997
11 (day 2):TI,AB,KY 2969
12 (day 3):TI,AB,KY 3497
13 48*:TI,AB,KY 53104
14 72*:TI,AB,KY 33864
15 cleav*:TI,AB,KY 733
16 pronuclear:TI,AB,KY 48
17 day2:TI,AB,KY 11
18 day3:TI,AB,KY 15
19 ((early adj3 embryo*)):TI,AB,KY 83
20 ((day two or day three)):TI,AB,KY 426
21 MESH DESCRIPTOR Cleavage Stage, Ovum EXPLODE ALL TREES 62
22 #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 86461
23 MESH DESCRIPTOR Blastocyst EXPLODE ALL TREES 129
24 Blastocyst*:TI,AB,KY 481
25 ((day 5 or day 6)):TI,AB,KY 3509
26 ((day5 or day6)):TI,AB,KY 9
27 ((day five or day six)):TI,AB,KY 229
28 #23 OR #24 OR #25 OR #26 OR #27 4120
29 #10 AND #22 AND #28 303

Appendix 3. MEDLINE search

MEDLINE (18.04.2016)

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/ or exp oocyte donation/ (36008)
2 embryo transfer$.tw. (9137)
3 in vitro fertili?ation.tw. (18546)
4 intracytoplasmic sperm injection$.tw. (5560)
5 (ivf or icsi).tw. (21404)
6 ET.tw. (188210)
7 or/1‐6 (231210)
8 day 2.tw. (18667)
9 day3.tw. (35)
10 48$.tw. (531140)
11 72$.tw. (345751)
12 cleav$.tw. (162019)
13 pronuclear.tw. (2060)
14 day 3.tw. (24496)
15 day2.tw. (33)
16 (early adj3 embryo$).tw. (23848)
17 (day two or day three).tw. (2469)
18 exp Cleavage Stage, Ovum/ (2136)
19 or/8‐18 (1041484)
20 exp Blastocyst/ (22554)
21 Blastocyst$.tw. (17851)
22 (day 5 or day 6).tw. (30007)
23 (day5 or day6).tw. (28)
24 (day five or day six).tw. (1441)
25 or/20‐24 (62035)
26 7 and 19 and 25 (4010)
27 randomized controlled trial.pt. (413691)
28 controlled clinical trial.pt. (90548)
29 randomized.ab. (343328)
30 placebo.tw. (173474)
31 clinical trials as topic.sh. (176165)
32 randomly.ab. (247064)
33 trial.ti. (149327)
34 (crossover or cross‐over or cross over).tw. (66966)
35 or/27‐34 (1033793)
36 exp animals/ not humans.sh. (4227002)
37 35 not 36 (950680)
38 26 and 37 (272)

Appendix 4. EMBASE search

EMBASE (18.04.2016)

1 exp embryo transfer/ (23824)

2 exp fertilization in vitro/ (42931)

3 exp intracytoplasmic sperm injection/ (15087)

4 exp oocyte donation/ (3307)

5 embryo transfer$.tw. (13659)

6 in vitro fertili?ation.tw. (23385)

7 intracytoplasmic sperm injection$.tw. (7307)

8 (ivf or icsi).tw. (34559)

9 ET.tw. (549055)

10 or/1‐9 (612746)

11 day 2.tw. (26857)

12 day3.tw. (375)

13 48$.tw. (758206)

14 72$.tw. (501641)

15 cleav$.tw. (182785)

16 pronuclear.tw. (2422)

17 day 3.tw. (35731)

18 day2.tw. (254)

19 (early adj3 embryo$).tw. (25993)

20 (day two or day three).tw. (4136)

21 exp oocyte cleavage/ (2702)

22 or/11‐21 (1429399)

23 exp BLASTOCYST/ (18376)

24 Blastocyst$.tw. (22053)

25 (day 5 or day 6).tw. (41160)

26 (day5 or day6).tw. (271)

27 (day five or day six).tw. (2124)

28 or/23‐27 (66323)

29 10 and 22 and 28 (6457)

30 Clinical Trial/ (856738)

31 Randomized Controlled Trial/ (398937)

32 exp randomization/ (70252)

33 Single Blind Procedure/ (21917)

34 Double Blind Procedure/ (127696)

35 Crossover Procedure/ (46777)

36 Placebo/ (273267)

37 Randomi?ed controlled trial$.tw. (133653)

38 Rct.tw. (19983)

39 random allocation.tw. (1511)

40 randomly allocated.tw. (24417)

41 allocated randomly.tw. (2100)

42 (allocated adj2 random).tw. (751)

43 Single blind$.tw. (17185)

44 Double blind$.tw. (160672)

45 ((treble or triple) adj blind$).tw. (539)

46 placebo$.tw. (230656)

47 prospective study/ (329881)

48 or/30‐47 (1560826)

49 case study/ (37386)

50 case report.tw. (303496)

51 abstract report/ or letter/ (955992)

52 or/49‐51 (1289953)

53 48 not 52 (1519996)

54 29 and 53 (713)

Appendix 5. PsycINFO search

PsycINFO (18.04.2016)

1 exp reproductive technology/ (1554)
2 embryo transfer$.tw. (105)
3 in vitro fertili?ation.tw. (617)
4 intracytoplasmic sperm injection$.tw. (44)
5 (ivf or icsi).tw. (483)
6 ET.tw. (108660)
7 or/1‐6 (110440)
8 day 2.tw. (1598)
9 day3.tw. (1)
10 48$.tw. (60219)
11 72$.tw. (37004)
12 cleav$.tw. (2937)
13 pronuclear.tw. (13)
14 day 3.tw. (1377)
15 day2.tw. (4)
16 (early adj3 embryo$).tw. (526)
17 (day two or day three).tw. (292)
18 exp embryo/ (1541)
19 or/8‐18 (101907)
20 Blastocyst$.tw. (65)
21 (day 5 or day 6).tw. (1633)
22 (day5 or day6).tw. (1)
23 (day five or day six).tw. (139)
24 or/20‐23 (1836)
25 7 and 19 and 24 (13)

Appendix 6. CINAHL search

CINAHL (18.04.16)

#

Query

Results

S20

S9 AND S14 AND S19

66

S19

S15 OR S16 OR S17 OR S18

24,644

S18

TX(day five or day six)

23,967

S17

TX blastocyst*

706

S16

TX morula

8

S15

(MM "Blastocyst")

337

S14

S10 OR S11 OR S12 OR S13

42,864

S13

TX pronuclear

3

S12

(MM "Cleavage Stage, Ovum")

7

S11

TX (day two or day three)

41,824

S10

TX cleavage

1,086

S9

S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8

4,298

S8

TX intracytoplasmic sperm injection*

278

S7

TX embryo* N3 transfer*

897

S6

TX ovar* N3 hyperstimulat*

375

S5

TX ovari* N3 stimulat*

288

S4

TX IVF or TX ICSI

1,527

S3

(MM "Fertilization in Vitro")

1,599

S2

TX vitro fertilization

3,285

S1

TX vitro fertilisation

3,285

Appendix 7. EBM reviews

EBM Reviews ‐ Cochrane Central Register of Controlled Trials (18.04.2016)

#1MESH DESCRIPTOR Embryo Transfer EXPLODE ALL TREES886

#2MESH DESCRIPTOR Fertilization in Vitro EXPLODE ALL TREES1737

#3MESH DESCRIPTOR Sperm Injections, Intracytoplasmic EXPLODE ALL TREES437

#4MESH DESCRIPTOR Oocyte Donation EXPLODE ALL TREES61

#5(embryo transfer*):TI,AB,KY1790

#6(in vitro fertili?ation):TI,AB,KY1801

#7(intracytoplasmic sperm injection*):TI,AB,KY941

#8((ivf or icsi)):TI,AB,KY3235

#9ET:TI,AB,KY18137

#10#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #921997

#11(day 2):TI,AB,KY2969

#12(day 3):TI,AB,KY3497

#1348*:TI,AB,KY53104

#1472*:TI,AB,KY33864

#15cleav*:TI,AB,KY733

#16pronuclear:TI,AB,KY48

#17day2:TI,AB,KY11

#18day3:TI,AB,KY15

#19((early adj3 embryo*)):TI,AB,KY83

#20((day two or day three)):TI,AB,KY426

#21MESH DESCRIPTOR Cleavage Stage, Ovum EXPLODE ALL TREES62

#22#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #2186461

#23MESH DESCRIPTOR Blastocyst EXPLODE ALL TREES129

#24Blastocyst*:TI,AB,KY481

#25((day 5 or day 6)):TI,AB,KY3509

#26((day5 or day6)):TI,AB,KY9

#27((day five or day six)):TI,AB,KY229

#28#23 OR #24 OR #25 OR #26 OR #274120

#29#10 AND #22 AND #28303

Appendix 8. ClinicalTrials.gov search

ClinicalTrials.gov search strategy (11.05.16)

"embryo" and "day" and "transfer" (262 hits)

OR

"blastocyst" and "transfer" (87 hits)

Appendix 9. WHO portal (ICTRP) search

WHO portal (ICTRP) search strategy (12.05.16)

"embryo" and "day" and "transfer" (3 hits)

OR

"blastocyst" and "transfer" (24 hits)

Study flow diagram: Results of search from review inception to 2016
Figuras y tablas -
Figure 1

Study flow diagram: Results of search from review inception to 2016

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

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

Forest plot of comparison: 1 Blastocyst versus cleavage stage transfer: Live birth rate, outcome: 1.1 Live birth per couple.
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Blastocyst versus cleavage stage transfer: Live birth rate, outcome: 1.1 Live birth per couple.

Forest plot of comparison: 2 Blastocyst versus cleavage stage transfer: Cumulative pregnancy rate following fresh and frozen transfer, outcome: 2.5 Cumulative pregnancy rate from fresh and frozen transfers: grouped by vitrification or slow freezing.
Figuras y tablas -
Figure 5

Forest plot of comparison: 2 Blastocyst versus cleavage stage transfer: Cumulative pregnancy rate following fresh and frozen transfer, outcome: 2.5 Cumulative pregnancy rate from fresh and frozen transfers: grouped by vitrification or slow freezing.

Forest plot of comparison: 2 Blastocyst versus cleavage stage transfer: Clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple.
Figuras y tablas -
Figure 6

Forest plot of comparison: 2 Blastocyst versus cleavage stage transfer: Clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple.

Funnel plot of comparison: 1 Blastocyst versus cleavage stage transfer: Live birth rate, outcome: 1.1 Live birth per couple.
Figuras y tablas -
Figure 7

Funnel plot of comparison: 1 Blastocyst versus cleavage stage transfer: Live birth rate, outcome: 1.1 Live birth per couple.

Funnel plot of comparison: 2 Blastocyst versus cleavage stage transfer: Clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple.
Figuras y tablas -
Figure 8

Funnel plot of comparison: 2 Blastocyst versus cleavage stage transfer: Clinical pregnancy rate, outcome: 2.1 clinical pregnancy rate per couple.

Comparison 1 Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer, Outcome 1 Live birth per couple.
Figuras y tablas -
Analysis 1.1

Comparison 1 Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer, Outcome 1 Live birth per couple.

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.
Figuras y tablas -
Analysis 1.2

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.

Comparison 1 Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer, Outcome 3 Live birth rate per couple: grouped by prognosis.
Figuras y tablas -
Analysis 1.3

Comparison 1 Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer, Outcome 3 Live birth rate per couple: grouped by prognosis.

Comparison 1 Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer, Outcome 4 Live birth rate: grouped by day of randomisation.
Figuras y tablas -
Analysis 1.4

Comparison 1 Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer, Outcome 4 Live birth rate: grouped by day of randomisation.

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.
Figuras y tablas -
Analysis 2.1

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.

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.
Figuras y tablas -
Analysis 2.2

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.

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.
Figuras y tablas -
Analysis 2.3

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.

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.
Figuras y tablas -
Analysis 2.4

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.

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.
Figuras y tablas -
Analysis 2.5

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.

Comparison 3 Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer, Outcome 1 Clinical pregnancy rate per couple.
Figuras y tablas -
Analysis 3.1

Comparison 3 Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer, Outcome 1 Clinical pregnancy rate per couple.

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.
Figuras y tablas -
Analysis 3.2

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.

Comparison 3 Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer, Outcome 3 Clinical pregnancy rate per couple: grouped by prognosis.
Figuras y tablas -
Analysis 3.3

Comparison 3 Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer, Outcome 3 Clinical pregnancy rate per couple: grouped by prognosis.

Comparison 3 Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer, Outcome 4 Clinical pregnancy rate per couple: grouped by day of randomisation.
Figuras y tablas -
Analysis 3.4

Comparison 3 Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer, Outcome 4 Clinical pregnancy rate per couple: grouped by day of randomisation.

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 1 Multiple pregnancy rate per couple.
Figuras y tablas -
Analysis 4.1

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 1 Multiple pregnancy rate per couple.

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 2 Multiple pregnancy rate per couple: grouped by number of embryo transfer.
Figuras y tablas -
Analysis 4.2

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 2 Multiple pregnancy rate per couple: grouped by number of embryo transfer.

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 3 Multiple pregnancy rate per couple: grouped by prognosis.
Figuras y tablas -
Analysis 4.3

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 3 Multiple pregnancy rate per couple: grouped by prognosis.

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 4 Multiple pregnancy rate per couple: grouped by day of randomisation.
Figuras y tablas -
Analysis 4.4

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 4 Multiple pregnancy rate per couple: grouped by day of randomisation.

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 5 High order pregnancies (more than 2 gestational sacs) per couple.
Figuras y tablas -
Analysis 4.5

Comparison 4 Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer, Outcome 5 High order pregnancies (more than 2 gestational sacs) per couple.

Comparison 5 Blastocyst versus cleavage stage transfer: Miscarriage rate following fresh transfer, Outcome 1 Miscarriage rate per couple.
Figuras y tablas -
Analysis 5.1

Comparison 5 Blastocyst versus cleavage stage transfer: Miscarriage rate following fresh transfer, Outcome 1 Miscarriage rate per couple.

Comparison 6 Blastocyst versus cleavage stage transfer: Embryo freezing rate per couple, Outcome 1 Embryo freezing per couple.
Figuras y tablas -
Analysis 6.1

Comparison 6 Blastocyst versus cleavage stage transfer: Embryo freezing rate per couple, Outcome 1 Embryo freezing per couple.

Comparison 7 Blastocyst versus cleavage stage transfer: Failure rate to transfer embryos (per couple), Outcome 1 Failure to transfer any embryos (per couple).
Figuras y tablas -
Analysis 7.1

Comparison 7 Blastocyst versus cleavage stage transfer: Failure rate to transfer embryos (per couple), Outcome 1 Failure to transfer any embryos (per couple).

Summary of findings for the main comparison. Blastocyst stage versus cleavage stage embryo transfer for assisted reproductive technology

Blastocyst stage versus cleavage stage embryo transfer for assisted reproductive technology

Population: Couples with subfertility
Settings: Assisted reproductive technology
Intervention: Blastocyst stage embryo transfer
Comparison: Cleavage stage embryo transfer

Outcomes per couple

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Cleavage stage embryo transfer

Blastocyst stage

Live birth rate

286 per 1000

372 per 1000

(324 to 421)

OR 1.48
(1.20 to 1.82)

1630

(13 studies)

⊕⊕⊝⊝
low1

Cumulative pregnancy rate

481 per 1000

452 per 1000

(372 to 530)

OR 0.89

(0.64 to 1.22)

632

(5 studies)

⊕⊝⊝⊝
very low2,3,4

I2 = 71%, attributable to the use of vitrification in one study and slow freezing in the other four

Clinical pregnancy rate

362 per 1000

425 per 1000
(393 to 455)

OR 1.30
(1.14 to 1.47)

4031
(27 studies)

⊕⊕⊝⊝
moderate2

Multiple pregnancy rate

122 per 1000

127 per 1000
(103 to 156)

OR 1.05
(0.83 to 1.33)

3019
(19 studies)

⊕⊕⊝⊝
low1

Miscarriage rate

68 per 1000

78 per 1000
(68 to 119)

OR 1.15
(0.88 to 1.50)

2917
(18 studies)

⊕⊕⊝⊝
low2,3

Embryo freezing rate

594 per 1000

412 per 1000

(369 to 455)

OR 0.48

(0.40 to 0.57)

2292

(14 studies)

⊕⊕⊝⊝
low2,4

I2 = 84%. Direction of effect largely consistent

Failure rate to transfer any embryos

11 per 1000

26 per 1000

(19 to 37)

OR 2.50

(1.76 to 3.55)

2577

(17 studies)

⊕⊕⊕⊝
moderate2

I2 = 36%

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded two levels for very serious risk of bias: several studies did not describe acceptable methods of sequence generation and/or allocation concealment, several at unclear or high risk of attrition bias, none clearly had blinded outcome assessment, moreover sensitivity analysis restricted to five studies with clear description of allocation concealment results in a non‐significant effect (OR 1.38, 95% CI 0.96 to 1.99).
2Downgraded one level for serious risk of bias: several studies did not describe acceptable methods of sequence generation and/or allocation concealment, several at unclear or high risk of attrition bias, none clearly had blinded outcome assessment.
3Downgraded one level for serious imprecision: findings compatible with benefit in either group or with no effect.
4Downgraded one level for serious inconsistency.

Figuras y tablas -
Summary of findings for the main comparison. Blastocyst stage versus cleavage stage embryo transfer for assisted reproductive technology
Table 1. Culture techniques of included studies

Trial

Culture technique day 2/3

Culture technique day 5/6

Aziminekoo 2015

Sydney IVF cleavage medium, Cook

Sydney IVF blastocyst medium

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)

Fernandez‐Shaw 2015

Sequential G1 Vitrolife

Sequential G1/G2 Vitrolife

Fisch 2007

NS

NS

Frattarelli 2003

NS

NS

Gaafar 2015

NS

NS

Gardner 1998

Single Hams F10 In‐house

Sequential G1/G2 In‐house

Hreinsson 2004

Vitrolife IVF

Sequential G1/G2 or CCM Vitrolife

Karaki 2002

Medicult

Sequential G1/G2 Vitrolife

Kaur 2014

Cleavage medium

G2 Plus media

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

CCM ‐ it is a trade mark from Vitrolife of medium for blastocyst culture
IVF ‐ in vitro fertilisation
NS ‐ not stated
G1/G2 ‐ sequential media from Vitrolife

Figuras y tablas -
Table 1. Culture techniques of included studies
Table 2. Blastocyst and implantation rate (in day 5 to 6 transfers)

Study

Blastocyst rate

Implantation D2/3

Implantation D5/6

Other

Aziminekoo 2015

22.4%

21/173; 12.1%

22/152; 14.5%

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%

Fernandez‐Shaw 2015

67.7 %

20/71; 28.1%

36/84; 42.8%

Fisch 2007

Not stated

11/12; 92%

4/8; 50%

Frattarelli 2003

Not stated

18/69; 26.1%

23/53; 43.4%

Gaafar 2015

Not stated

Not stated

Not stated

Gardner 1998

46.5%

64/174; 36.8%

53/95; 55.8%

85% women had at least 2 blastocysts

Hreinsson 2004

33%

29/139; 20.9%

24/114; 21.1%

2 morula replaced (one implanted). 60% pregnancy 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)

Kaur 2014

Not stated

66/309; 21.4%

102/290; 35.2%

Kolibianakis 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 prognosis)

Levron 2002

34.2%

53/137; 38.7%

20/99; 20.2%

6.5% cancelled due to lack of blastocysts (good prognosis)

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 available 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 2002

44.7%

31/106; 29.2%

41/90; 45.6%

27% cancellation D5 (unselected population)

Figuras y tablas -
Table 2. Blastocyst and implantation rate (in day 5 to 6 transfers)
Table 3. Mean number of embryos transferred

Study ID

Day 2/3

Day 5/6

Aziminekoo 2015

2.8

2.6

Brugnon 2010

1

1

Bungum 2003

2.00

1.97

Coskun 2000

2.3

2.2

Devreker 2000

2.83

1.73

Elgindy 2011

2.8

1.97

Emiliani 2003

2.1

1.9

Fernandez‐Shaw 2015

1.5

1.4

Fisch 2007

1

1

Frattarelli 2003

2.96

2.04

Gaafar 2015

NS

NS

Gardner 1998

3.7

2.2

Hreinsson 2004

1.8

1.9

Karaki 2002

3.5

2.0

Kaur 2014

2.04

1.93

Kolibianakis 2004

1.9

1.8

Levitas 2004

3.4

1.9

Levron 2002

3.1

2.3

Livingstone 2002

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

NS ‐ not stated

Figuras y tablas -
Table 3. Mean number of embryos transferred
Comparison 1. Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Live birth per couple Show forest plot

13

1630

Odds Ratio (M‐H, Fixed, 95% CI)

1.48 [1.20, 1.82]

2 Live birth per couple: grouped by number of embryos transferred Show forest plot

12

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 More cleavage stage than blastocyst embryos transferred

6

483

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [1.03, 2.22]

2.2 Single embryo transfer

2

458

Odds Ratio (M‐H, Fixed, 95% CI)

1.47 [0.98, 2.20]

2.3 Equal number of embryos transferred

6

1027

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [1.04, 1.75]

3 Live birth rate per couple: grouped by prognosis Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 good prognostic factors

8

1126

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [1.18, 1.93]

3.2 poor prognostic factors

2

77

Odds Ratio (M‐H, Fixed, 95% CI)

2.05 [0.53, 7.96]

3.3 unselected group

3

427

Odds Ratio (M‐H, Fixed, 95% CI)

1.36 [0.91, 2.02]

4 Live birth rate: grouped by day of randomisation Show forest plot

13

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 randomisation at start of cycle

5

819

Odds Ratio (M‐H, Fixed, 95% CI)

1.26 [0.93, 1.70]

4.2 randomised on day of OPU and day 1 after OPU

4

365

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [0.87, 2.06]

4.3 randomised day 2 to 3 post‐OPU

2

364

Odds Ratio (M‐H, Fixed, 95% CI)

2.17 [1.42, 3.33]

4.4 day of randomisation unstated

2

82

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [0.67, 4.39]

Figuras y tablas -
Comparison 1. Blastocyst versus cleavage stage transfer: Live birth rate following fresh transfer
Comparison 2. Blastocyst versus cleavage stage transfer: Cumulative pregnancy rate following fresh and frozen transfer

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

5

632

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.64, 1.22]

2 Cumulative pregnancy rate per couple: grouped by number of embryos transferred Show forest plot

4

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 single embryo transfer

1

107

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.39, 1.79]

2.2 equal number of embryos transferred

4

512

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.48, 0.99]

3 Cumulative pregnancy rate per couple: grouped by prognosis Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 good prognostic factors

2

205

Odds Ratio (M‐H, Fixed, 95% CI)

0.54 [0.30, 0.98]

3.2 unselected group

3

427

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.74, 1.61]

4 Cumulative pregnancy rate: grouped by day of randomisation Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 randomisation at start of cycle

3

414

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.54, 1.20]

4.2 randomised on day of OPU and day 1 after OPU

2

218

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.61, 1.83]

5 Cumulative pregnancy rate from fresh and frozen transfers: grouped by vitrification or slow freezing Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 slow freezing

4

512

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.48, 0.99]

5.2 vitrification

1

120

Odds Ratio (M‐H, Fixed, 95% CI)

2.44 [1.17, 5.12]

Figuras y tablas -
Comparison 2. Blastocyst versus cleavage stage transfer: Cumulative pregnancy rate following fresh and frozen transfer
Comparison 3. Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical pregnancy rate per couple Show forest plot

27

4031

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [1.14, 1.47]

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 embryo transfers

11

1854

Odds Ratio (M‐H, Fixed, 95% CI)

1.19 [0.99, 1.44]

2.2 more cleavage stage than blastocyst embryos transferred

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

27

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 good prognostic factors

15

2056

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [1.09, 1.56]

3.2 poor prognostic factors

3

195

Odds Ratio (M‐H, Fixed, 95% CI)

1.62 [0.84, 3.10]

3.3 unselected group

9

1780

Odds Ratio (M‐H, Fixed, 95% CI)

1.26 [1.04, 1.53]

4 Clinical pregnancy rate per couple: grouped by day of randomisation Show forest plot

25

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

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

10

1130

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.90, 1.46]

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]

Figuras y tablas -
Comparison 3. Blastocyst versus cleavage stage transfer: Clinical pregnancy following fresh transfer
Comparison 4. Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Multiple pregnancy rate per couple Show forest plot

19

3019

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.83, 1.33]

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

18

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 good prognostic factors

12

1798

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.83, 1.48]

3.2 poor prognostic factors

1

54

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.14, 5.81]

3.3 unselected

5

1049

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.65, 1.48]

4 Multiple pregnancy rate per couple: grouped by day of randomisation Show forest plot

17

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 randomised start of cycle

5

1172

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.59, 1.48]

4.2 randomised on day of OPU or day 1

7

846

Odds Ratio (M‐H, Fixed, 95% CI)

0.91 [0.60, 1.38]

4.3 randomised on day 2 to 3

3

382

Odds Ratio (M‐H, Fixed, 95% CI)

1.31 [0.79, 2.19]

4.4 day of randomisation unstated

2

175

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.06, 0.70]

5 High order pregnancies (more than 2 gestational sacs) per couple Show forest plot

13

2335

Odds Ratio (M‐H, Fixed, 95% CI)

0.45 [0.18, 1.15]

Figuras y tablas -
Comparison 4. Blastocyst versus cleavage stage transfer: Multiple pregnancy following fresh transfer
Comparison 5. Blastocyst versus cleavage stage transfer: Miscarriage rate following fresh transfer

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Miscarriage rate per couple Show forest plot

18

2917

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.88, 1.50]

Figuras y tablas -
Comparison 5. Blastocyst versus cleavage stage transfer: Miscarriage rate following fresh transfer
Comparison 6. Blastocyst versus cleavage stage transfer: Embryo freezing rate per couple

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Embryo freezing per couple Show forest plot

14

2292

Odds Ratio (M‐H, Fixed, 95% CI)

0.48 [0.40, 0.57]

Figuras y tablas -
Comparison 6. Blastocyst versus cleavage stage transfer: Embryo freezing rate per couple
Comparison 7. Blastocyst versus cleavage stage transfer: Failure rate to transfer embryos (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

17

2577

Odds Ratio (M‐H, Fixed, 95% CI)

2.50 [1.76, 3.55]

Figuras y tablas -
Comparison 7. Blastocyst versus cleavage stage transfer: Failure rate to transfer embryos (per couple)