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

Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology

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Referencias

References to studies included in this review

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estudios excluidos
otras referencias

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Brugnon 2010

Methods	Randomisation: computer generated random list Blinded: no Size: 52 D2 55 D5‐6 Single centre: Clermont Ferrand Université d'Auvergne, Biologie de la reproduction CECOS EA 975, Clermont Ferrand, France
Participants	Criteria: If more than 5 oocytes were retrieved and 3 top quality embryos (3 4 blastomeres, < 20% fragmentation without multinuclear blastomeres) were observed at day 2, the couples were included in the study. Cause/duration: NA. Previous Treatment:NA. Fert rate: NA. Blast rate: NA
Interventions	Ov Stim: NS Luteal support: NS Media: Sequential commercial brand Culture method: NS AHA: N SET
Outcomes	Cumulative pregnancy rate (D2 versus D5/6) 51.9 versus 49.1%. Clinical pregnancy rate per ET (D2 versus D5/6): 46.2% versus 41.8%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random list
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Low risk
Other bias	Unclear risk	Not stated

Bungum 2003

Methods	Randomisation: sealed envelope on day3 Blinded: no Size 118 separate women D3 57 D5 61 No dropouts Single centre: Denmark Power calc: Yes retrospective Therapeutic
Participants	Criteria: D3 3 or more 8‐cell embryos <20% fragmentation, <40, BMI<30, FSH<12 Age: D3 31.3 D5 31.2 Cause/duration: NS Previous Treatment: first or second cycle: D3 84% D5 88% ICSI: D3 51% D5 64% (lower blast rate in ICSI than IVF) FSH: D3 6.5 D5 6.5 #eggs: D3 12.8±4.4 D5 13.5±5.3 Fert rate: D3 60.2% D5 60.7% Blast rate: 55.2% ET policy: 2 embryos both groups #ET: D3 2.0 D5 1.96 (2 patients D5 had 1 only due to lack of blasts) Pregnancy determination: HCG + US 7 weeks
Interventions	Ov Stim: GnRHa long + rFSH + HCG 35hr Luteal support: prog vaginal Media: G1/G2 Vitrolife Culture method: microdrops low oxygen incubator AHA: NS
Outcomes	Primary a) LB: NS b) preg/OPU/ET/woman: D3 63.2% (36/57) D5 52.5% (32/61) c) multiple rate: D3 41.6% (15/36) D5 40.6% (13/32) Secondary a) Imp: D3 43.9% (50/114) D5 36.7% (44/120) b) miscarriage pre 12 weeks: D3 15% 6/36 D5 29.2% 12/32 c) embryo freeze: D3 95% (3.4±2.4) D5 59% (1.3±1.6) d) embryo utilisation: NS e) ET rate: 100% both f) high order rate: nil g) monozygotic twin: NS
Notes	Prognosis: good 3 or more 8C D3 Lower blast rate in ICSI than IVF Outcome no advantage of Blast culture for this selected group Letter sent and reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sealed envelope
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Coskun 2000

Methods	Randomisation: enrolled consecutively sealed envelope until day of fert check Blinded: no Size: 201 separate women randomised and analysed: D3 101 D5 100 Single centre: Uni clinic in Israel Power calc: NS Therapeutic
Participants	Criteria: 4 or more zygotes Age: D3 30.7 D5 30.4 Primary/Secondary: NS Cause/duration ‐ similar except for Unexp: D3 15% D5 6% Previous Treatment: NS ICSI: D3 67% D5 64% FSH: NS Criteria: 4 or more fert eggs #eggs: NS Fert rate: D3 68%, D5 67% Blast rate: 28% 197/703 (77% patients had at least 1) (lower in male infertility patients 26%) ET policy: 2 for both D3 and D5 But women with at least 6 attempts had up to 3 embryos transferred #ET: D3 2.3 (±0.6), D5 2.2 (±0.5) Pregnancy determination: HCG + ultrasound
Interventions	Ov Stim: GnRH down regulation hMG + 36hr trigger Luteal support: prog IM Media: Sequential Medicult to D3 and G1/G2 for D5 Culture method: NS AHA: NS
Outcomes	Primary a) LB (ongoing) per OPU and ET: D3 33/101 D5 35/100 b) preg OPU: D3 39% (39/101) D5 39% (39/100) b) preg/ET: D3 39% (39/101), D5 39% (39/100) c) multiple preg: D3 13/39 33% D5 15/39 38% Secondary a) Imp: D3 21% (50/235) D5 24% (52/218) not sig b) miscarriage: D3 5/39 D5 3/39 c) embryo freeze: No D5 freezing d) embryo utilisation: NS e) embryo transfer rate: D3 101/101 100% D5 100/100 100% e) cancellation rate: D3 0%, D5 0% f) high order: D3 1/39 D5 0/39 g) monozygotic twins: NS
Notes	Prognosis: good 4 or more zygotes Young women Good ET policy Mixture of media brands 100% ET rate therefore all stages transferred Low blast rate High implantation rate considering No dropouts unusual
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Low risk
Other bias	High risk	Reported no provision for Day 5 freezing

Devreker 2000

Methods	Randomisation: "randomly allocated" Size: 23 separate women D2 12 D5 11 Single unit: Uni affiliated Belgium Power calc: NS Therapeutic
Participants	Criteria: <40y, >4 previous cycles Age: no diff Cause/duration: no diff Previous treatment: similar in both groups ICSI: NS FSH: NS #eggs: NS Fert rate: NS Blast rate: NS ET policy: max 3 for both groups #ET: D3 2.83 (34/12) D5 1.73 (19/11) Pregnancy determination: NS
Interventions	Ov Stim: NS Luteal support: NS Media: Sequential commercial brand Culture method: NS AHA: NS
Outcomes	Primary a) LB: D3 8.3% (1/12) D5 27.3% (3/11) b) preg/OPU: NS b) preg/ET: D3 8.3% (1/12) D5 36.4% (4/11) Secondary a) Imp: D3 3% (1/34) D5 42% (8/19) b) miscarriage: D1 0% D5 20% (1/4) c) embryo freeze: NS d) embryo utilisation: NS e) ET rate:100% both f) multiple rate: NS g) high order rate: NS h) b) monozygotic twin: NS
Notes	Prognosis: poor Abstract only Letter sent regarding randomisation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Unclear risk	Not stated
Other bias	Unclear risk	Not stated

Elgindy 2011

Methods	Randomisation: computer generated block randomisation Allocation: identical, sequentially numbered, dark‐sealed envelopes Size: 200 separate women D3 100 D5 100 Single unit: Uni affiliated Egypt Power calc: 95 women would be required to be able to reject the null hypothesis that the success rates are equal with a probability (power) of 0.8 and type‐I error probability of 0.05
Participants	Criteria: <35y, with regular cycles, serum day‐3 FSH concentration <9.5 IU/l and antral follicle count >6. At least at least four good‐quality embryos on day 3. Age: no diff Duration: no diff FSH: NS #eggs: NS Fert rate: NS #ET: D3 2.8 D5 1.96
Interventions	Ov Stim: long luteal‐phase GnRH agonist down regulation protocol and both recombinant FSH and human menopausal gonadotrophin Media: Sequential commercial brand Culture method: NS AHA: N
Outcomes	LB: D3 35% (35/100) D5 52% (52/100)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Prospective randomised controlled trial
Allocation concealment (selection bias)	Low risk
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Open label
Incomplete outcome data (attrition bias) All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Emiliani 2003

Methods	Randomisation: list with permuted blocks for each new cycle Blinded: NS Size: 171 separate women. But reported on 193 cycles D2 94 cycles 89 women D5 99 cycles 82 women 18 dropouts Single centre: Uni affiliated Belgium Power calc: Yes Therapeutic
Participants	Criteria: <39y, 3 or less previous cycles, 4 or more 2PN on day1 Age: D3 31±3 D5 32±4 Cause/duration: NS Previous treatment: D2 1.7+/‐0.9 D5 2.0+/‐ 1.0 ICSI: 67% both groups FSH:NS #eggs: D2 11.9±4.4 D5 12.0±4.9 Fert rate: D2 67.2% D5 67.5% Blast rate: 48.3% ET policy: D2 2‐3 depending on age and embryo quality D5 2 embryos #ET: D2 2.1±0.4 D5 1.9±0.3 Pregnancy determination: NS
Interventions	Ov Stim: GnRHa, hMG, HCG 36h Luteal support: NS Media: in‐house sequential media Culture method: 30ul microdrops low oxygen AHA: no
Outcomes	Primary a) LB/OPU: D2 44.1% (41/94) D5 33.3% (33/99) LB/woman D2 46.1% (41/89) D5 40.2% (33/82) Note that 5% D2 and 17% D5 were from same women LB/Per ET D2 44.1% (41/93) D5 37.1% (33/89) b) preg/OPU: D2 44.2% (46/94) D5 39.4% (39/99) Preg/randomised/cycle D2 44.2% (46/104) D5 36.4% (39/107) b) preg/ET D2 44.1% (46/93) D5 37.1% (39/89) c) multiple rate per preg: D2 22% (9/46) D5 36% (12/39) Secondary a) imp: D2 29% (57/197) D5 30% (50/168) b) miscarriage: D2 8.5% (4/46) D5 15.4% (6/39) c) embryo freeze: D2 73% cycles (4.3+/‐2.4) D5 54% cycles (3.3+/‐2.3) d) embryo utilisation: NS e) cancellation rate: D2 1.1% D5 10% (lack of blasts) f) high order rate: NS Cumulative delivery rate including thaws to date were: D2 50% D5 36.4% g) monozygotic twin: nil
Notes	Prognosis: mixed unselected Outcome: discontinued blast culture Gives cumulative fresh thaw rates. Not all different women ‐ per cycle data only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation list with permuted blocks for each new cycle
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	10 women were subsequently excluded for protocol violations
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Fisch 2007

Methods	Randomisation: N/A Blinded: N/A Size: 20 D3 8 D5 12 No dropouts Single centre: Private practice. USA Power calc: these are preliminary results and no ulterior study has been published (4 years later)
Participants	Criteria: D3 3 or more 8‐cell embryos <20% fragmentation, <40, BMI<30, FSH<12 Age: D3 31.3 D5 31.2 Cause/duration: NS Previous Treatment:first or second cycle:D3 84% D5 88% ICSI: D3 51% D5 64%(lower blast rate in ICSI than IVF) FSH: D3 6.5 D5 6.5 #eggs: D3 12.8+/‐4.4D5 13.5+/‐5.3 Fert rate: D3 60.2%D5 60.7% Blast rate: 55.2% ET policy: 2 embryos both groups #ET: D3 2.0 D5 1.96(2 patients D5 had 1 only due to lack of blasts) Pregnancy determination: HCG + US 7 weeks. Inclusion criteria: "Women <41, with <=2 prior fresh cycles with at least one embryo on day 3 GES R70 and sHLA‐G OD: 0.148–0.210"
Interventions	n/a
Outcomes	Pregnancy rate: 92% versus 50%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	High risk	Preliminary data
Other bias	Unclear risk	Not stated

Frattarelli 2003

Methods	Randomisation: computer generated randomisation table. Allocation concealed until intervention assigned. Randomisation day of OPU. Blinded: no Size: 57 separate women randomised, 8 withdrawals, 5 from day 3, and 3 from day 5 which were added to number of women randomised in order to achieve an ITT, including 4 who did not meet embryo criteria. Assumed no pregnancy for the withdrawals after randomisation. (D3 28 D5 29) Single centre: Army Medical Centre Hawaii Power calc: performed but not included ‐ needed 68 women per group
Participants	Criteria: <39y, 3 or less previous cycles, 4 or more 2PN on day 1 Age: D3 31±3 D5 32±4 Cause/duration: NS Previous treatment: D2 1.7±0.9 D5 2.0±1.0 ICSI: 67% both groups FSH:NS #eggs: D2 11.9±4.4 D5 12.0±4.9 Fert rate: D2 67.2% D5 67.5% Blast rate: 48.3% ET policy: D2 2‐3 depending on age and embryo quality D5 2 embryos #ET: D2 2.1±0.4 D5 1.9±0.3 Pregnancy determination: NS Criteria: 6 or more high grade embryos day3, less than 35y, FSH <12mIU/ml, >10 or more follicles day of HCG. Age D3 31.0 D5 30.2 Primary/Secondary: NS Cause/duration: NS Previous Treatment: 1st ICSI: 5x in each group #eggs:D3 17 D5 20 Blast rate: not calculated ET policy: D3 3‐4 embryos D5 2‐3 embryos # ET: D3 2.96(±0.5) D5 2.04(±0.2) Pregnancy determination: US 6 weeks, ongoing US 12 weeks
Interventions	Ov Stim: NS Luteal support: NS Media: sequential for both Culture method: NS AHA: NS
Outcomes	Primary a) LB per OPU/ET/woman D3 34.8% (8/23) D5 57.7% (15/26) b) preg OPU/ET/ woman D3 43.5% (10/23) D5 69.2% (18/26) c) multiple preg (initial): D3 70% (7/10) D5 27.7% (5/18) Secondary a) Imp: D3 26.1% (18/69) D5 43.4% (23/53) b) miscarriage D3 8.7% (2/23) D5 11.5% (3/26) c) embryo freeze: NS d) embryo utilisation: NS e) cancellation rate: D3 5/28 D5 3/29 (not due to lack of blastocysts) f) high order: D3 1/10 quad D5 0/18 number of triplets NS g) monozygotic twins: 1x D3
Notes	Prognosis: good 6 or greater high grade embryos D3, 1st cycle, young, high numbers of oocytes No dropouts due to lack of blasts High blast imp rate
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation table
Allocation concealment (selection bias)	Unclear risk	Allocation was concealed but method not given
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis was applied
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Gardner 1998

Methods	Randomisation: computer generated on day 8 prior to OPU Blinding: NS Inclusion decided on day of trigger Size: 92 separate women randomised no cancellations: day 3 47 cycles day 5 45 cycles excluded patients: NS single private clinic. USA. Time: 5 months 97/98 Power calculation: NS Intention to treat: needs clarification Therapeutic
Participants	Criteria: all ages and >10 follicles on day of trigger Age: D3 34.5 D5 33.6 Primary/secondary: NS Cause: no significant difference Previous treatment: D3 0.21 D5 0.62 cycles (significantly different) ICSI: D3 34%, D5 33% FSH: comparative details NS Criteria : >10 follicles on day of trigger # eggs retrieved: NS Fertilization rate: NS #PN embryos: D2 512.3, D5 522.0 Blast rate 46.5% (85% patients had 2+ blasts) ET policy: changed for day 5 mid study from 2‐3. day NS # ET: D3 3.7, D5 2.2 (4% had no ET) Pregnancy determination: NS
Interventions	Ov Stim: NS Luteal support: NS Media: sequential for both Culture method: NS AHA: NS AMS F10 15% FCS, D5 G1 /G2 Method: tubes in humidicrib AH for nearly all DOv Stim: Lupron D21. hMG dose? hCG 2 follicles >18mm OPU 35hrs trigger Luteal: steroids and tetracyclin for 4 days post OPU. Progesterone IM from 2 days post OPU Culture media: Sequential D3 H3 ‐ nil for D5
Outcomes	Primary a) live birth: NS b) preg/OPU: D3 31/47 66%, D5 32/45 71% b) preg/ET: D3 66% (31/47), D5 74% (32/43) c) mult preg: D3 ‐ NS D5 46% Secondary a)imp: D3 (64/174) 37%, D5 (53/95) 55.4% p<0.01 b) miscarriage: NS b) MZ twinning: NS c) embryo fz rate: D3 30% (14/47) patients, 3.0 embryos D5 64% (29/45) patients, 3.2 embryos d) embryo utilisation rate: NS e) embryo transfer rate: D3 ‐NS but must be (47/47) 100%, D5 (43/45) 95.5% f) high order: D3 NS, D5 15.5% g) monozygotic NS
Notes	Prognosis: good <1 previous cycle and >10 follicles Different media used for each arm of study Excluded patients not mentioned Number of ET policy change partway through ‐?unblinded interim analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random list
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Need more information
Selective reporting (reporting bias)	Low risk
Other bias	High risk	No age limit

Hreinsson 2004

Methods	Randomisation: NS Allocation: sealed envelope on day prior to HCG Blinded: no Size: 144 separate women D2/3 80 day5/6 64 no dropouts Single centre: Sweden Power calc: Yes but not achieved Study stopped early due to change of national guidelines Therapeutic
Participants	Criteria: 6 follicles day prior to hCG Age: D3 33.1y D5 32.1y Cause/duration: similar Previous cycles: NS ICSI: D3 42 % D5 45% FSH: NS # eggs: D3 14.6 D5 14.9 Fert rate: D3 54% D5 61% Blast rate: 33% ET policy: 1‐2 at start of study but then only 1 at end of study #ET D3 1.8 D5 1.9 HCG: NS
Interventions	Ov Stim: long‐course GnRHa or short centrorelix hMG: rFSH, HCG 36hr Luteal supp: NS Media: Vitrolife mixture of IVF/CCM and G1/G2 sequential Culture method: microdrops 6% CO2 AHA: not done
Outcomes	Primary a) LB: NS b) preg/OPU D3 25/80 (31.3%) D5 22/64 (34.4%) b) preg/ET D3 25/77 (32.5%) D5 22/60 (36.7%) c)multiple rate: D3 4/25 (16%) D5 2/22 (9%) Secondary a) Imp: D3 29 /139 D5 24/114 (21.1%) b) miscarriage pre 12 weeks: D3 2/25 (8%) D5 3/22 (13.6%) c) embryo freeze: D3 34/80 (42.5%) D5 15/64 (23.4%) d) embryo utilisation: NS e) ET cancellation: D3 3/80 (4%) D5 4/64 (6%) f) high order rate: nil g) monozygotic twin: NS
Notes	Prognosis: good excluded poor responders. Mixture of media types and ET policy change over course of study Outcome no advantage of blast culture Letter sent and reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Low risk	Sealed envelope
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Karaki 2002

Methods	Randomisation: sealed envelope on D1 fert check Blinded: no Size: 162 separate women randomised and analysed D3 82 D5 80 Single centre: Uni affiliated. Jordan. Power calc: NS Therapeutic
Participants	Criteria: 5 or more zygotes Age: D3 29.2 D5 30.0 Primary /Secondary: NS Cause: No sig diff (Av: 51% Male factor, 9% tubal, 6% unexp) Duration: D3 6.7 D5 6.8 Previous treatment: D3 1.1 D5 0.9 ICSI: Yes but no effect found in outcome of imp or blast rate FSH: D3 7.5 D5 7.8 # eggs: D3 13.4 (±5.2) D5 13.0 (±3.2) Fert rate: D3 56.7% D5 63.8% Blast rate:33% day5/6 ET policy: 1‐2 embryos but if >35 and/or >2 previous cycles then up to 3 (same policy for both groups) # Et: D3 3.5±0.63 D5 2.0±1.0 Preg determination: HCG for preg rate US for viable preg rate
Interventions	Ov Stim: GnRH long and short + rFSH and HP FSH + 35hr trigger Luteal support: Prog V pessary Media: D3 Medicult, D5 G1/G2 Vitrolife Culture method: NS AHA: NS
Outcomes	Primary a)LB: NS b) preg/OPU/ET/woman (initial hCG): D3 29% (24/82) D5 35% (28/80) Viable: D3 26% (21/82) D5 29% (23/80) c) multiple rate: D3 47.6% (10/21) D5 39.1% (9/23) Secondary a) Imp: D3 13% (37/291) D5 26% (37/142) b)miscarriage: info only until 7 weeks D3 12.5% (3/24) D5 17.9% (5/28) c) embryo freeze: D3 42% (35/82) 1.74+/‐3.0 D5 28% (22/80) 0.65+/‐ 1.0 d) embryo utilisation: NS e) cancellation rate: D3 nil (0/82) D5 11% (9/80) due to lack of blasts f) high order rate: D3 19% (4/21) D5 4% (1/23) g) monozygotic twin: nil
Notes	Prognosis: moderate, young women, moderately high oocyte numbers. Large difference in embryo ET# between groups Sent letter
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Kolibianakis 2004

Methods	Randomisation: computer generated list. Sequence not concealed. Prior to stimulation Size: 460 different women D3 234 D5 226 Power Calc: 5% diff in preg rate, baseline preg rate 30% need 1416 women in each group ‐ unrealistic so aimed for estimate Single centre: Uni affiliated Belgium
Participants	Criteria: <43y, no PGD or azoospermia Age: D3 31.3y D5 31.5y Cause: Similar in both groups (av: 65% male, 10% tubal, 16% unexp) Duration: NS Previous Treatment: D3 0.7 D5 0.8 ICSI: 74% of all patients FSH: D3 10.4 D5 10.4 #eggs: D3 12.1 D5 12.0 Fert rate: D3 61.3% D5 63.4% Blast rate: 50.7%±2.4 ET policy:1‐2 embryos for both groups #ET: D3 1.9±0.1 D5 1.8±0.1 Pregnancy determination: ongoing pregnancy beyond 12 weeks
Interventions	Ov Stim: initially GnRHa long protocol with HMG, replaced by GnRH antagonist with rFSH hCG 36h Luteal support: vag micronised prog until 7 week of gestation Meida: Sequential G1/G2 Vitrolife Culture method: NS AHA: no
Outcomes	Primary a) LB: NS b) preg/randomised couple: D3 32.1% (75/234) D5 33.2% (75/226) preg/OPU: D3 33.1% (75/227) D5 33.2% (75/215) b) preg/ET D3 34.4% (75/218) D5 39.5% (75/190) c) multiple rate: D3 26.7% (20/75) D5 20% (15/75) Secondary a) imp: ongoing D3 24.5±2.5% (96/234) D5 26.6±2.7% (94/226) b) miscarriage: (first 12 weeks) D3 21.9% (21/96) D5 20.2% (19/94) c) embryo freeze: D3 61.5% (144/234) D5 50.4% (114/226) d) embryo utilisation: NS e) cancellation rate: D2 6.8% D5 15.9% (from randomisation to ET) day5 9.1% due to lack of blasts. f) high order rate: D3 nil D5 nil g) monozygotic twin: nil
Notes	Prognosis: mixed unselected
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated list
Allocation concealment (selection bias)	High risk	The sequence of randomisation was not concealed
Blinding (performance bias and detection bias) All outcomes	High risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Levitas 2004

Methods	Randomisation: computer generated random number table, blinded sealed envelopes prior to treatment. Size: 54 different women were randomised and analysed: D2/3 31 day5/6/7 23 Setting: single Uni clinic in Israel Time: NS Therapeutic
Participants	Criteria: min 3 failed IVF cycles, <37, adequate ovarian response Age: D2/3 31.2 day5 29.1 no stat diff Duration: D2/3 7.0y D5 7.1 y Previous cycles: D2/3 4.3 D5 4.9 Cause: D2/3 62% Male, 33% tubal D5 79% Male, 21% tubal ICSI: D2/3 62% D5 51% # eggs: D2/3 12.8+/‐5.3 D5 13.0+/‐5.1 Fert rate: D2/3 53.9% D5 66.1% Blast rate: 43% (65/151) ET policy: D2/3 was 3‐4 embryos D5 was 2‐3 embryos # embryo ET: D2/3 3.4±0.7 D5 1.9±0.4 Preg determination: hCG + US
Interventions	Ov Stim: GnRHa long and short +hMG doses adjusted daily, + hCG 36‐38hr Luteal: hCG x5, or Prog +less hCG Media: D2/3 P1 Irvine (23x) and Cook (8x) D5 Sequential G1/G2 Vitrolife Culture system: NS AHA: NS
Outcomes	Primary a) Live birth: D2/3 9.7% (3/31) D5 13.0% (3/23) b) preg/OPU: D2/3 12.9% (4/31), D5 21.7% (5/23) b) preg/ET: D2/3 13.8% (4/29), D5 29.4% (5/17) c) Multiple preg: D2/3 75% (3/4), D5 40% (2/5) Secondary a) Imp: D2/3 (6/100) 6.0% D5 (7/33) 21.2% b) miscarriage: D2/3 (1/4) D5 (2/5) c) embryo freeze rate: D3 22.6% (7/31) D5 13.0% (3/23) d) embryo utilisation: NS e) cancellation rate: D2 2/31 (6.4%), embryo arrest at 2PN D5 6/23 (26%) lack of blasts f) high order: D2/3 nil D5 1x trip (monozygotic twin) g) monozygotic twinning: 1 in D5
Notes	Prognosis: both good and poor Note: young women with large numbers of failed cycles Uneven number in each group Similar figures to the 2001 abstract letter sent and reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation list
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not clear which of participants or outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or exclusions
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Levron 2002

Methods	Randomisation: sealed envelope performed on day1 post OPU Blinded: Yes Size: 90 different women D3 44 D5 46 Single centre: Uni clinc Israel Power calc: No
Participants	Criteria: <38y, <5 prev IVF, >5 or more oocytes D1 Age: D3 31.5 D5 30.9 Primary/Secondary: NS Cause/Duration: NS Previous Treatment: <5 ICSI: D3 59.1% D5 51.2% FSH: NS # eggs: D3 16.3 D5 15.2 Fert rate: D3 60.1% D5 62.0% Blast rate: 34.2% (3 patients no blasts 6.5%) ET policy: max 3 for both D3 and D5 #ET: D3 3.1 (±0.6) D5 2.3 (±0.8) Pregnancy determination: NS
Interventions	Ov Stim: NS Luteal support: NS Media: sequential Cook Culture method: NS AHA: NS
Outcomes	Primary a) LB per woman: D3 34% (15/44) D5 17.4% (8/46) b) Preg/OPU/woman D3 45.5% (20/44) D5 17.4 (8/46) b) Preg/Et D3 45% (20/44) D5 18.6% (8/43) c) multiple preg D3 40% (8/20) D5 50% (4/8) Secondary a) Imp: D3 38.7 % (55/137) D5 20.2% (20/99) b) miscarriage: NS c) embryo freeze: D3 56.8% (25/44) D5 26.1% (12/46) d) cancellation rate D3 0% D5 6.5% (due to lack of blasts available) f) High order D3 3/20 pregs D5 1/8 pregs g) monozygotic twin: NS
Notes	Prognosis: moderate Young women Moderately high numbers of oocytes Clarification letter sent Same ET policy
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomisation unknown
Allocation concealment (selection bias)	Low risk	Sealed envelope
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Blinded, unclear who was blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	20 women were excluded post randomisation as they did not have a transfer, not clear from which group they came
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Livingstone 2002

Methods	Randomisation: sealed envelope
Participants	Size: 79 recruited 59 separate women analysed 20 failed criteria or various reasons ‐ outcomes given where possible D3 29 D5 30 Single Centre: Uni affiliated Australia Power Calc: Yes for reduction of twins Intention to treat: not done (those with no ET were excluded) Prognosis: moderate Young women Moderately high numbers of oocytes Clarification letter sent Criteria: <38y, 3 or less previous cycles Age: D3 31.6 D5 33.5 Primary/Secondary: NS Cause: Similar in both Duration: D3 3.8y D5 4.1y Previous treatment: NS ICSI: yes but no details FSH: NS ET policy: day2/3 2x embryos, day5 1x embryo #ET D3 2.0 D5 1.0 Preg determination: NS
Interventions	Ov Stim: GnRH long+ rFSH + hCG 36 hr trigger Luteal support: hCG x2 or prog pessaries Media: Syd IVF sequential Culture method: microdrops under oil in Minc incubator AHA: NS
Outcomes	Primary a) LB/woman: D3 37.9% (11/29) D5 46.7% (14/30) b) preg/woman D3 51.7% (15/29) D5 50% (15/30) c) multiple rate: D3 13.8% (4/15) D5 0% (0/15) Secondary a) Imp: D3 37.9% (22/58) D5 56.2% (18/32) b) miscarriage or ectopic: D3 20% (3/15) D5 7% (1/15) c) embryo freeze: performed but no details given d) embryo utilisation: NS e) cancellation rate: overall 26% (but not due lack of blasts ‐ other various reasons ‐ not included in stats) f) high order rate: Nil for both groups g) monozygotic twin: nil
Notes	Prognosis: high Data from Thesis 2002 and not abstract 2001 Low fert rate Aim to reduce twinning
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated
Allocation concealment (selection bias)	Low risk	Sealed envelope
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not possible to blind
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	20 recruited but not randomised
Selective reporting (reporting bias)	Low risk	Live birth and multiple pregnancy rate reported
Other bias	Unclear risk	Single blastocyst transfer (Day 5) but double embryo transfer (Day 3)

Motta 1998 A & B

Methods	Randomisation:"randomly assigned" Blinding: NS Size: 83 women in 116 cycles randomly assigned and analysed: D2 58 and D5 58 Setting: Uni clinic private in Brazil Time: NS Power analysis: NS Therapeutic
Participants	Criteria: unselected Age overall: 33.8± 6.6y ? All ICSI Baseline and population characteristics:NS #eggs: D3 12.9, D5 11.7 Fert rate: D3 7.8, D5 9.1 # PN embryos: D3 452, D5 528 Cycles with no fert: 2/116 Cycles with no blasts: 6 ET policy: D3 3‐5 embryos D5 1‐3 embryos #embryos ET: D3 4.6, D5 2.3 Preg determination: ultrasound
Interventions	Ov Stim: down reg with gonadotropin 150‐450 luteal: NS Media: sequential media P1/Irvines Blast Culture method: NS AH: NS
Outcomes	Primary a) Live birth: NS b) preg/ET: D3 (21/57) 36.8% D5 (21/52) 40.4% b) preg/OPU: D3 (21/58) 36.2% D5 (21/58) 36.2% c) Multi preg: D3 10/21 57%, D5 3/21 14% Secondary a) Imp: D3 (51/262) 19.4% D5 (36/120) 30.1%, P<0.01 b) miscarriage: NS c) emb Fz D3 5.1 /cycle 74%/pat (45/58) D5 1.4/cycle 26% pat (15/58) d) embryo utilisation rate: NS e) ET Rate: D2 (57/58) 98.3% D5 (52/58) 89.6% e) cancellation rate: D2 1.7% (1/58), D5 10.4% (6/58) f) high order: NS g) monozygotic: NS
Notes	Prognosis: moderate to good. No letter sent
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	Not stated
Other bias	Unclear risk	Not stated

Pantos 2004

Methods	Randomisation: not stated Allocation: not stated Blinded: no Size: 243, D2 81, D3 81, D5 81 No dropouts Single centre: Greece
Participants	<41 years olf. less than 4 previous unsuccessful ART attempts
Interventions	Ov Stim: long or short protocol, using GnRH agonist and recombinant FSH; Luteal support: NS Media: sequential media commercial AHA: N
Outcomes	Total: Pregnancy rate: D2 46.9%, D3: 48.1%, D5 37% Day 2 or 3: Pregnancy rate: 47.5%; Multiple PR: 29.9%; High Order Multiple PR: 3.9%; Miscarriage Rate: 11.7%; Embryo Freezing rate: 48.8% Day 5: Pregnancy rate: 37.0%; Multiple PR:33.3% ; High Order Multiple PR: 6.7% ; Miscarriage Rate: 33.3% ; Embryo Freezing rate: 19.8%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Papanikolaou 2005

Methods	Randomisation: computer generated list Randomised on day 3 following OPU Concealment? Blinded: no Size:164 separate patients D3 84 D5 80 Single centre Belgium Power calc: yes prospectively Interim analysis terminated at halfway point
Participants	Criteria: 4 good quality embryos on D3, <38y, <4 cycles FSH <12 D3 Age: D3 29.6 D5 29.9 Cause: no difference Duration: D3 2.7y D5 2.9y Prev treatment: D3 1.3 D5 1.4 ICSI:D3 66.7% D5 67.5% FSH: NS # eggs: D3 13.9 D5 15.1 Fert rate: D3 65% D5 65% Blast rate: NS ET policy: 2 embryos # embryos transferred: D3 2.0 D5 1.97 (4 women D5 had 1 embryo transferred due to lack of availability) Pregnancy determinant: HCG + US 7 weeks
Interventions	Ov Stim: 2 types a) GnRH agonist b) GnRH antagonist rFSH/HCG Luteal support: prog vaginal Media: G1/G2 Vitrolife Culture method: NS AHA: no
Outcomes	Primary a) LB/woman, OPU and ET D3 27.4% (23/84) D5 47.5% (38/80) b) Preg/woman, OPU, ET D3 32.1% (27/84) D5 52% (42/80) c) Multiple rate: D3 29.6% (8/27) D5 42.9% (18/42) Secondary: a) Imp: D3 20.6% (35/170) D5 37.3% (59/158) b) miscarriage from positive hCG: D3 34.3% (12/35) D5 28.3% (15/53) c) embryo freeze: D3 36.3% 3.3±0.5 D5 23.5% 2.3±0.3 d) embryo utilisation D3 58% (5.3/9.1) D5 43.6% (4.27/9.8) e) ET rate: 100% both groups f) High order rate: nil g) monozygotic twin rate: NS
Notes	Prognosis: high, 4 high qual embryos D3, young women Letter sent regarding concealment 100% ET rate
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Computer generated list
Allocation concealment (selection bias)	High risk	No concealment
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Papanikolaou 2006

Methods	Randomisation: computer generated list Randomised prior to start of cycle Concealment: no but used group A or B Blinded: no Size:351 separate patients D3 176 D5 175 To OPU D3 166 D5 163 To ET D3 156 D5 149 Single centre Belgium Power calc: yes prospectively Interim analysis: Yes ‐ study terminated at halfway point. Intention to treat: yes
Participants	Criteria: single embryo transfer, <36y, <3 cycles FSH ≤12 on D3 Age: D3 30.4 D5 30.5 Cause: no difference Duration: D3 3.5y D5 3.7y Prev treatment: D3 7.4% D5 9.1% ICSI:D3 63.2% D5 64.5% FSH: NS # eggs: D3 12.5 D5 13.9 Fert rate: D3 60% D5 58% Blast rate: NS ET policy: 1 embryo # embryos transferred: D3 1.0 D5 1.0 (Number patients where no embryos were available for ET: D3 8 D5 11 Pregnancy determinant: HCG + US 7 weeks
Interventions	Ov Stim: GnRH antagonist rFSH/HCG Luteal support: prog vaginal Media: NS Culture method: NS AHA: no
Outcomes	Primary a) LB/woman D3 21.6% (38/176) D5 32.0% (56/175) b) Preg/woman D3 23.3% (41/176) D5 33.1% (58/175) c) Multiple rate: D3 5% (2/176) D5 0% (0/175) Secondary: a) imp: D3 24.2% (38/156) D5 38.9% (58/149) b) miscarriage from positive hCG: D3 35.6% (21/59) D5 23.3% (17/73) c) embryo freeze: D3 ?% 4.2±4.1 D5 ?% 2.2±2.7 d) embryo utilisation D3 65% (5.2/8.0) D5 42.6%(3.2/7.5) e) cancellation rate (from those those that had OPU: D3 5.3% D5 8.6% f) High order rate: nil g) monozygotic twin rate (clinical preg): D3 2/41 D5 0
Notes	Prognosis: high, young women Letter sent regarding concealment, media and freezing
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generation list
Allocation concealment (selection bias)	High risk	Not concealed
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis was applied
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Rienzi 2002

Methods	Randomisation: computer generated randomised list. Randomised on day 1 following OPU Blinded: No Size: 98 separate women randomised and analysed no dropouts D3 48 D5 50 Single centre Italy Power calc: No Therapeutic
Participants	Criteria: <38y, ICSI only, 8 or more zygotes Age: D3 31.6±3.1 D5 32.2±2.5 Primary/Secondary: NS Cause/Duration: NS Previous Treatment: NS ICSI: 100% both groups FSH: NS # eggs: D3 12.7±7.1 D5 13.1±5.2 Fert rate: D3 71.2% D5 71.8% Blast rate: 44.8% (211/470) ET policy: Max 2 for both groups #ET: D2 2.0 D5 2.0 Preg determination hCG + US 8 weeks LBR:yes Cumulative including freezing: yes
Interventions	Ov Stim: down reg with rFSH + hCG trigger 36h Luteal support: NS Media: G1/G2 Vitrolife both groups Culture method: NS AHA: NS
Outcomes	Primary Fresh transfer cycles only a) LB/woman: D3 50% (24/48) D5 48% (24/50) b) preg/OPU/ET: (clinical) D3 56% (27/48) D5 58% (29/50) c) multiple rate/preg: D3 25.9% (7/27) D5 31.0 (9/29) from personal communication Secondary a) imp: D3 35% (34/96) D5 38% (38/100) b)miscarriage: D3 6.3% (3/48) D5 10% (5/50) c) embryo freeze: D3 87.5% (42/48) D5 36% (18/50) d) embryo utilisation: cumulative LBR results including fresh and thawed: D3 77% (37births/48 OPUs) D5 52% (26births/50 OPUs) e) ET rate f) high order rate D3 nil D5 nil g) monozygotic twin: NS
Notes	Prognosis: Good >8 zygotes Conclude that embryo/PN score system as good as blast culture Cumulative fresh thawed results Letter sent and reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated list
Allocation concealment (selection bias)	Unclear risk	Method of allocation not stated
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Schillaci 2002

Methods	Randomisation: method NS "randomly allocated" on day1 fert check Size 120 separate patients randomised and analysed no dropouts D3 60 D5 60 Single centre Italy Power calc: NS Therapeutic
Participants	Criteria: 8 or more MII oocytes and 3 zygotes Age: NS Primary/Secondary: NS Cause/Duration: NS Previous Treatment: NS ICSI: yes but no details FSH: NS #eggs D3 9.0 D5 8.9 Fert rate: no diff Blast rate: 60.3% ET policy: 2‐3 embryos for both groups except only 2 if expanded blasts for D5 #ET: D3 2.8±0.2 D5 1.8±0.4 Preg determination: NS
Interventions	Ov Stim: NS Luteal support: NS Media: D3 IVF‐20 D5 G1/G2 both Vitrolife Culture method: NS AHA: NS
Outcomes	Primary a) LB: NS b) preg/OPU/ET/woman: D3 38.3% (23/60) D5 40.0%(24/60) c) multiple rate: NS Secondary a) imp: D3 13.7% (23/168) D5 23.6% (26/110) b)miscarriage: NS c) embryo freeze: NS d) embryo utilisation e) ET rate: nil cancellations f) high order rate: NS g) monozygotic twin: NS
Notes	Prognosis: ? unclear ? moderate #eggs Abstract only ?Error in No. of patients 51 or 60?
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No dropouts or exclusions
Selective reporting (reporting bias)	Unclear risk	Not stated
Other bias	Unclear risk	Not stated

Ten 2011

Methods	Randomisation: method NS "distributed randomly" on day 3 fert check 55 separate patients randomised and analysed no drop outs D3 27 D5 28 Single centre Spain Power calc: NS
Participants	Criteria: at least one embryo type A and 2 type B Age: NS first or second cycle Cause/Duration: NS IVf and ICSI
Interventions	day 3 versus day 5
Outcomes	clinical pregnancy rate but cumulative pregnancy rate later number of frozen embryos
Notes	abstract only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Distributed randomly
Allocation concealment (selection bias)	Unclear risk	Distributed randomly
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Low risk
Other bias	Unclear risk	It is an abstract

Van der Auwera 2002

Methods	Randomisation: blind randomisation with sealed envelope at start of hormone stimulation Size: 136 separate patients randomised and 129 were analysed due to 7 dropouts (3x D2 and 4xD5) D2 63 D5 66 Single centre Belgium Power calc: performed but abandoned due to high multiple rate, difficulty in recruitment and high cancellation rate in D5 Therapeutic
Participants	Criteria: unselected Age: D2 31.7±3.3 D5 31.5±3.5 Primary/Secondary: no diff between groups Duration: D2 3.3±2.0 D5 3.4±1.5 Cause: no diff (approx 50% male <10% tubal, slightly more unexp in D5) Previous treatment: D2 1.7 D5 1.7 ICSI: D2 19/63 D5 25/66 FSH: NS #eggs: D2 10.7±5.4 D5 11.5±5.1 Fert rate: D2 51.4% D5 55.7% Blast rate: 44.7% ET policy: max of two for both groups. NOTE that D2 group had only 5x PN cultured on for transfer with remaining frozen. While all D5 group were cultured to ET. #ET: D2 1.86±0.28 D5 1.87±0.22 Pregnancy determination: +ve HCG also clinical pregnancy (definition NS)
Interventions	Ov Stim: NS Luteal support: NS Media: D3 IVF‐20 D5 G1/G2 both Vitrolife Culture method: NS AHA: NS Ov Stim: GnRH down reg+Humegon+HCG trigger 36h Luteal support: HCG every 3 days or prog pessaries Media: either Cook sequential or Vitrolife G1/G2 simultaneous trial Culture method NS but used low O2 AHA: NS
Outcomes	Primary a) LB/OPU/woman: D2 27% (17/63) D536% (24/66) LB/ET D2 30% (17/57) D5 50% (24/48) b) preg/OPU/woman: (clinical only) D2 32% (20/63) D5 44% (29/66) b) preg/ET D3 35% (20/57) D5 60% (2948) c) multiple rate: D2 45% (9/20) D5 31% (9/29) Secondary a) imp: D2 27.4% (31/106) D5 51.1% (41/90) b) miscarriage: per randomised: D2 3/66 D5 5/70 D2 15% (3/20) D5 17.2% (5/29) c) embryo freeze: D2 56% (but many 2PN) D5 39% d) embryo utilisation: D2 73.3% (252/344) D5 42.1% (178/423) e) cancellation rate: D2 10% (6/63) D5 27% (18/66) lack of blasts on day6 f) high order rate: Nil g) monozygotic twin: NS
Notes	Prognosis: mixed ‐ unselected Aim to reach highest cryoaugmented preg rate Smaller cohort of embryos to choose from in D2 group due to freezing on day1. New policy patients with >5 zygotes go to D5 transfer with 79% preg rate
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Not stated
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

ET ‐ embryo transfer
Blast ‐ blastocyst
Fert ‐ fertilization
OPU ‐ oocyte pick up
AH ‐ assisted hatching
# ‐ number
NS ‐ not stated
US ‐ ultrasound
Fz ‐ freeze
D3 ‐ embryo transfer on day 3 post OPU (i.e early cleavage stage)
D5 ‐ embryo transfer on day 5 post OPU (i.e. blastocyst stage)
Imp ‐ implantation
Clin preg ‐ clinical pregnancy
IM ‐ intramuscular injection
Ov Stim ‐ ovarian stimulation regimen
FCS ‐ fetal chord serum
G1/G2 sequential media from Vitrolife
emb ‐ embryo
trans ‐ transfer
years ‐ years
Unex ‐ unexplained
morula‐ embryonic stage prior to blastocysts (usually embryos with delayed development on day5)
rFSH ‐ recombinant follicle stimulating hormone (fertility ovarian stimulation drug)
IU ‐ international unit of drug administration
hCG ‐ human chorionic gonadotropin (trigger injection that initiates ovulation and maturation of oocytes)
Blastocyte rate ‐ number of blastocysts developed divided by number of 2PN embryos available

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Bungum 2002	Used co‐culture
Guerin 1991	Used co‐culture
Levitas 2001	Duplicate of Levitas 2004
Levron 2001	Quasi Randomised
Loup 2009	Included transfer of embryos on two separate days within the same cycle
Menezo 1992	Used co‐culture
Papanikolaou 2005a	Duplicate data
Papanikolaou 2005b	Duplicate data
Utsonomiya 2004a	non‐randomised study (sequentially numbered)
Vanderzwalmen 2006	non‐randomised study ‐ according to even or odd year of birth
Zech 2007	non‐randomised study ‐ according to even or odd year of birth

Data and analyses

Open in table viewer

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]
Open in figure viewer Analysis 1.1 Comparison 1 Live birth rate, Outcome 1 Live birth per couple.
2 Live birth per couple: grouped by number of embryos transferred Show forest plot	12		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.2 Comparison 1 Live birth rate, Outcome 2 Live birth per couple: grouped by number of embryos transferred.
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]
Open in figure viewer Analysis 1.3 Comparison 1 Live birth rate, Outcome 3 Live birth rate per couple: grouped by prognosis.
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]
Open in figure viewer Analysis 1.4 Comparison 1 Live birth rate, Outcome 4 Live birth rate: grouped by day of randomisation.
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]

Open in table viewer

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]
Open in figure viewer Analysis 2.1 Comparison 2 Clinical pregnancy rate, Outcome 1 clinical pregnancy rate per couple.
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
Open in figure viewer Analysis 2.2 Comparison 2 Clinical pregnancy rate, Outcome 2 clinical pregnancy rate per couple: grouped by number of embryos transferred.
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]
Open in figure viewer Analysis 2.3 Comparison 2 Clinical pregnancy rate, Outcome 3 clinical pregnancy rate per couple: grouped by prognosis.
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]
Open in figure viewer Analysis 2.4 Comparison 2 Clinical pregnancy rate, Outcome 4 clinical pregnancy rate per couple: grouped by day of randomisation.
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]

Open in table viewer

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]
Open in figure viewer Analysis 3.1 Comparison 3 Cumulative pregnancy rate, Outcome 1 cumulative pregnancy rate from fresh and frozen transfers.

Open in table viewer

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]
Open in figure viewer Analysis 4.1 Comparison 4 Multiple‐pregnancy rate, Outcome 1 multiple‐pregnancy rate per couple.
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
Open in figure viewer Analysis 4.2 Comparison 4 Multiple‐pregnancy rate, Outcome 2 multiple‐pregnancy rate per couple: grouped by number of embryo transfer.
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]
Open in figure viewer Analysis 4.3 Comparison 4 Multiple‐pregnancy rate, Outcome 3 multiple‐pregnancy rate per couple: grouped by prognosis.
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]
Open in figure viewer Analysis 4.4 Comparison 4 Multiple‐pregnancy rate, Outcome 4 high order pregnancies (more than 2 gestational sacs) per couple.
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]
Open in figure viewer Analysis 4.5 Comparison 4 Multiple‐pregnancy rate, Outcome 5 high order pregnancy: grouped by number of embryos transferred.
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]
Open in figure viewer Analysis 4.6 Comparison 4 Multiple‐pregnancy rate, Outcome 6 high order pregnancies: grouped by prognosis.
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
Open in figure viewer Analysis 4.7 Comparison 4 Multiple‐pregnancy rate, Outcome 7 multiple‐pregnancy rate per pregnancy.
8 high order pregnancies per total pregnancies Show forest plot	12		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.8 Comparison 4 Multiple‐pregnancy rate, Outcome 8 high order pregnancies per total pregnancies.

Open in table viewer

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]
Open in figure viewer Analysis 5.1 Comparison 5 Miscarriage rate, Outcome 1 miscarriage rate per couple.
2 miscarriage rate per pregnancy Show forest plot	14		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.2 Comparison 5 Miscarriage rate, Outcome 2 miscarriage rate per pregnancy.

Open in table viewer

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]
Open in figure viewer Analysis 6.1 Comparison 6 Embryo freezing rate, Outcome 1 embryo freezing per couple.
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]
Open in figure viewer Analysis 6.2 Comparison 6 Embryo freezing rate, Outcome 2 Embyro freezing per couple: grouped by number of embryos transferred.
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]
Open in figure viewer Analysis 6.3 Comparison 6 Embryo freezing rate, Outcome 3 Embryo freezing per couple: grouped by prognostic factors.
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]

Open in table viewer

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]
Open in figure viewer Analysis 7.1 Comparison 7 Failure to transfer embryos rate per couple, Outcome 1 Failure to transfer any embryos per couple.
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]
Open in figure viewer 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.
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
Open in figure viewer 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.
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]

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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Referencias

References to studies included in this review

Brugnon 2010 {published data only}

Bungum 2003 {published data only}

Coskun 2000 {published data only}

Devreker 2000 {published data only}

Elgindy 2011 {published data only}

Emiliani 2003 {published data only}

Fisch 2007 {published data only}

Frattarelli 2003 {published data only}

Gardner 1998 {published data only}

Hreinsson 2004 {published data only}

Karaki 2002 {published data only}

Kolibianakis 2004 {published data only}

Levitas 2004 {published data only}

Levron 2002 {published data only}

Livingstone 2002 {published and unpublished data}

Motta 1998 A & B {published data only}

Pantos 2004 {published data only}

Papanikolaou 2005 {published data only}

Papanikolaou 2006 {published data only}

Rienzi 2002 {published data only}

Schillaci 2002 {published data only}

Ten 2011 {published data only}

Van der Auwera 2002 {published data only}

References to studies excluded from this review

Bungum 2002 {published data only}

Guerin 1991 {published data only}

Levitas 2001 {published data only}

Levron 2001 {published data only}

Loup 2009 {published data only}

Menezo 1992 {published data only}

Papanikolaou 2005a {published data only}

Papanikolaou 2005b {published data only}

Utsonomiya 2004a {published data only}

Vanderzwalmen 2006 {published data only}

Zech 2007 {published data only}

Additional references

Begg 1996

Behr 2000

Borg 2000

Braude 1998

Bukulmez 2007

Cohen 1990

Croxatto 1972

De Felici 1982

De Placido 2002

Edgar 2012

Edwards 1983

Edwards 1995

Fanchin 2001

Gardner 1996

Gardner 1998b

Gardner 2003a

Gardner 2003b

Gardner 2004

Hamberger 2005

Higgins 2011

Iwayama 2011

Jain 2004

Jones 1999

Jones 2008

Laverge 2001

Luna 2007

Magli 1998

Magli 2000

Marek 1999

Marston 1977

Menezo 1990

Menezo 1999

Milki 1999

Milki 2004

Moayeri 2007

Nel‐Themaat 2011

Palmstierna 1998

Plachot 1999

Puissant 1987

Racowsky 2000