Assisted hatching on assisted conception (IVF & ICSI)

Mourad MW Seif; Edmond CO Edi‐Osagie; Cindy M Farquhar; Lee Hooper; Debbie A Blake; Phil McGinlay

doi:10.1002/14651858.CD001894.pub2

Assisted hatching on assisted conception (IVF & ICSI)

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Referencias

References to studies included in this review

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Antinori S, Versaci C, Dani L, Barbaro E, Antinori M, Cerusico C, et al. Laser assisted hatching at the extremes of the IVF spectrum: first cycle and after 6 cycles. A randomized prospective trial [abstract]. Fertility and Sterility 1999;72(3, suppl 1):S111.

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Cohen J, Alikani M, Trowbridge J, Rosenwaks Z. Implantation enhancement by selective assisted hatching using zona drilling of human embryos with poor prognosis. Human Reproduction 1992;7(5):685‐91.

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Cohen J, Alikani M, Trowbridge J, Rosenwaks Z. Implantation enhancement by selective assisted hatching using zona drilling of human embryos with poor prognosis. Human Reproduction 1992;7:685‐91.

Liu H‐C, Alikani M, Cohen J, Rosenwaks Z. Assisted hatching facilitates earlier implantation after IVF‐ET. Fertility and Sterility Abstracts. 1992; Vol. 58:61 (O‐136).

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Petersen CG, Mauri AL, Baruffi RL, Oliveira JBA, Massaro FC, Elder K, et al. Implantation failures: Success of assisted hatching with quarter‐laser zona thinning. Reproductive Biomedicine Online 2005;10 Suppl 2:224‐9.

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References to studies excluded from this review

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References to ongoing studies

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estudios excluidos
otras referencias
otras versiones publicadas

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Additional references

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estudios excluidos
estudios en curso
otras versiones publicadas

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References to other published versions of this review

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estudios excluidos
estudios en curso
otras referencias

Edi Osagie E, Hooper L, Seif MW. The impact of assisted hatching on live birth rates and outcomes of assisted conception: a systematic review. Human Reproduction 2003;18(9):1828‐35.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos
estudios en curso

Antinori 1999A

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single/multi‐centre? Participants not blinded or unclear Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as abstract.
Participants	Women from Italy without previous IVF experience undergoing IVF. Mean age control 27.0, AH 27.5.
Interventions	AH (laser; complete zona breach; ? hours egg retrieval to AH;? hours AH to transfer) versus no AH AH: 96 women randomised, 221 embryos transferred (estimated) control: 103 women randomised, 247 embryos transferred (estimated)
Outcomes	clinical pregnancy, miscarriage, multiple pregnancy
Notes	No reply
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Antinori 1999B

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single/ multi‐centre? Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as abstract.
Participants	Women from Italy with >6 previous IVF failures undergoing IVF. Mean age control 36.0, AH 37.5.
Interventions	AH (laser; complete zona breach; ? hours egg retrieval to AH;? hours AH to transfer) versus no AH AH: 73 women randomised, 321 embryos transferred control: 69 women randomised, 307 embryos transferred
Outcomes	clinical pregnancy, miscarriage, multiple pregnancy
Notes	No reply
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Baruffi 2000

Methods	Randomised, method stated. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear. Published as full paper.
Participants	Women from Brazil aged 37 years or less, undergoing ICSI for the first time (mean zona thickness control 17.1 um (sd 1.7), AH 16.6 um (sd 2.2). Mean age control 31.4 (3.6), AH 31.8 (3.6).
Interventions	AH (laser; thinning partial; 48 hours egg retrieval to AH; 0 hours AH to transfer) versus no AH AH: 51 women randomised, 141 embryos transferred control: 52 women randomised, 149 embryos transferred
Outcomes	implantation, clinical pregnancy, miscarriage
Notes	No reply
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Cohen 1992A

Methods	Randomised, method stated. Allocation concealment inadequate. Single centre. Participants blinded. Assessor blinded. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from North America undergoing IVF, normal 3 day FSH levels (15IU/L or less). Mean age control 36.7 (3.7), AH 36.5 (3.3).
Interventions	AH by acid tyrodes (chemical; complete zona breach hole; 68‐72 hours egg retrieval to AH; 4‐8 hours AH to transfer) versus no AH AH: 69 women randomised, 239 embryos transferred control: 68 women randomised, 229 embryos transferred
Outcomes	implantation, clinical pregnancy, live births, multiple pregnancy
Notes	Attempted to contact author about this study. Reply received, but no additional information was offered.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Cohen 1992B

Methods	as for Cohen 1992A
Participants	Poor prognosis
Interventions
Outcomes
Notes	ttempted to contact author about this study. Reply received, but no additional information was offered.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Cohen 1992C

Methods	Randomised, method stated. Allocation concealment inadequate. Single centre. Participants blinded. Assessor blinded. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from North America undergoing IVF, high basal FSH ( >15IU/L). Mean age not stated.
Interventions	AH by acid tyrodes (chemical; complete zona breach; 68‐72 hours egg retrieval to AH; 4‐8 hours AH to transfer) versus no AH AH: 15 women randomised, 38 embryos transferred control: 15 women randomised, 41 embryos transferred
Outcomes	implantation, clinical pregnancy
Notes	Attempted to contact author about this study. Reply received, but no additional information was offered.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Hellebaut 1996

Methods	Randomised, method stated. Allocation concealment inadequate. Single centre. Participants not blinded Assessor not blinded. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from Belgium undergoing IVF or ICSI. Mean age control 30.8 (3.9), AH 30.9 (4.3).
Interventions	AH (mechanical; complete zona breach hole; 48 hours egg retrieval to AH; 0.2 hours AH to transfer) versus no AH AH: 60 women randomised, 168 embryos transferred control: 60 women randomised, 162 embryos transferred
Outcomes	implantation, clinical pregnancy, live births, miscarriage, ectopic pregnancy
Notes	Attempted to contact author about this study. A reply including much useful additional information was received.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Hurst 1998

Methods	Randomised, method stated. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from North America undergoing IVF either with no prior IVF (30 years or less, FSH<10IU/L, normal endometrium and sperm) or prior IVF (35 years or less, 6 embryos, 50% fertilisation, normal endometrium). Mean age control 30 (2.1), AH 30 (3.2).
Interventions	AH by acid tyrodes (chemical; complete zona breach hole; ? hours egg retrieval to AH; ? hours AH to transfer) versus no AH AH: 13 women randomised, 52 embryos transferred control: 7 women randomised, 28 embryos transferred
Outcomes	implatation, clinical pregnancy, live births
Notes	Attempted to contact author about this study. A reply including much useful additional information was received.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Isik 2000

Methods	Randomised, method stated. Allocation not concealed Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from Turkey with >5 day‐3 cleavage stage embryos (FSH at day‐3 control 6.1 (3.0), AH 5.5 (1.4) IU/L, mean duration of infertility 6.7 years) undergoing ICSI. Mean age control 29.1 (3.6), AH 30.5 (5.2).
Interventions	AH enzymatic (chemical; complete and total zona breach; 120‐144 hours egg retrieval to AH; 0.5‐1 hours AH to transfer) versus no AH AH: 24 women randomised, 71 embryos transferred control: 22 women randomised, 63 embryos transferred
Outcomes	implantation
Notes	Author response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	C ‐ Inadequate

Isiklar 1999

Methods	Randomisation stated, but method unclear . Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as abstract.
Participants	Women from Turkey undergoing IVF. Mean age not stated.
Interventions	AH (mechanical; complete zona breach; ? hours egg retrieval to AH;? hours AH to transfer) versus no AH AH: 22 women randomised, 83 embryos transferred control: 22 women randomised, 78 embryos transferred
Outcomes	implantation, clinical pregnancy, multiple pregnancy
Notes	Attempted to contact author about this study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Jelinkova 2002

Methods	Randomisation stated, but method unclear. Allocation of concealment unclear. Single center. Participants not blinded or unclear. Published as a paper and an abstract
Participants	IVF patients only, at least 2 previous failures, mean age 32 in both groups. Germany.
Interventions	AH (chemical removal by acid, complete zona breech
Outcomes	Clinical pregnancy rate, implantation rate
Notes	Attempted to contact author about this study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Laffoon 1999

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as abstract.
Participants	Women from North America aged less than 40 years undergoing IVF. Mean age not stated.
Interventions	AH (mechanical; complete zona breach; ? hours egg retrieval to AH;? hours AH to transfer) versus no AH AH: 28 women randomised, embryos transferred not stated control: 28 women randomised, embryos transferred not stated
Outcomes	Clinical pregnancy
Notes	Attempted to contact author about this study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Lanzendorf 1998

Methods	Randomised, method stated. Allocation concealment unclear. Single centre. Participants blinded. Assessor blinded. Unclear if power calculation performed. ITT analysis performed. Published as full paper.
Participants	Women from North America aged at least 36 years (mean basal FSH control 7.6 IU/l (sd 2.0), AH 7.9 IU/l (sd 2.5)), undergoing IVF (some with ICSI), half had been previously treated with IVF. Mean age control 38.5 (1.8), AH 38.3 (2.0).
Interventions	AH by acid tyrodes (chemical; complete zona breach; 55 hours egg retrieval to AH;? hours AH to transfer) versus no AH AH: 42 women randomised, 180 embryos transferred control: 52 women randomised, 212 embryos transferred
Outcomes	implantation, clinical pregnancy, multiple pregnancy, live births
Notes	Attempted to contact author about this study. A reply including much useful additional information was received.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Nagy 1999

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as abstract.
Participants	Women from Italy with cryopreserved embryos undergoing IVF and ICSI. Mean age control 31.4 (3.7), AH 32.0 (4.0).
Interventions	AH (laser; complete zona breach; ? hours egg retreival to AH;? hours AH to transfer) with concomitant removal of damaged blastomeres versus no AH and no damaged blastomere removal AH: 20 women randomised, 65 embryos transferred control: 20 women randomised, 52 embryos transferred
Outcomes	clinical pregnancy
Notes	Attempted to contact author about this study. Reply received.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Ng 2005

Methods	Randomisation pm day of frozen embryo transfer, computer generated randomisation in sealed envelopes
Participants	Women from Hong Kong with frozen embryo transfer, mean age 34.0 years.
Interventions	Laser assisted thinning 1/4 with frozen embryos compared to frozen embryos
Outcomes	Clinical pregnancy, miscarriage and multiple pregnancy rates
Notes	No author contact as all details clearly stated in article
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Petersen 2005A

Methods	Random numbers table, unclear if allocation concealed, code id to mask identity of the patient
Participants	Women from Brazil, undergoing ART cycles. All patients had one failed treatment cycle. Mean age 34 years.
Interventions	ICSI cycles only. AH quarter‐laser thinning versus control
Outcomes	Live birth, clinical pregnancy, miscarriage and multiple pregnancy
Notes	Author response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Petersen 2005B

Methods	As for Petersen A
Participants	Women from Brazil, undergoing ART cycles, mean age 35 years. More than one failed cycle
Interventions	ICSI cycles only. AH quarter‐laser thinning versus control
Outcomes	Live birth, clinical pregnancy, miscarriage and multiple pregnancy
Notes	Author response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Rufas‐Sapir 2004

Methods	Unknown about randomization method and allocation of concealment
Participants	3 consecutive failed IVF cycles, all ages, undergoing IVF only
Interventions	Mechancial partial zonal dissection ‐complete breach technique versus control
Outcomes	Clinical pregnancy, miscarriage
Notes	Author response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Ryan 1997

Methods	Random numbers table, unclear if allocation concealed, or if blinding occured. SIngle center
Participants	Women from Sydney Australia undergoing ART cycles.
Interventions	AH ‐ tyrodes complete breach ‐ hole chemical means on both fresh and frozen‐thawed embryos
Outcomes	Clinical pregnancy,
Notes	Additional information was received from the 1st author regarding the definition of pregnancy. No further publication is planned.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Stein 1995

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from Israel with repeated implantation failure (>3 attempts) undergoing IVF. Mean age not stated.
Interventions	AH (mechanical; complete zona breach; ? hours egg retrieval to AH; 1.5 hours AH to transfer) versus no AH AH: 72 women randomised, 230 embryos transferred control: 82 women randomised, 295 embryos transferred
Outcomes	Clinical pregnancy, miscarriage
Notes	Attempted to contact author about this study, no reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Tucker 1993

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from North America undergoing IVF. (Mean basal FSH control 9.0 (5.3), AH 8.8 (3.7) IU/L). Mean age control 34.2 (4.1), AH 34.1 (4.8).
Interventions	AH with acid tyrodes thinning to 1/4; 72 hours egg retrieval to AH; 1‐3 hours AH to transfer) versus no AH AH: 110 women randomised, 333 embryos transferred control: 108 women randomised, 312 embryos transferred
Outcomes	Implantation, clinical pregnancy
Notes	Attempted to contact author about this study, no reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Tucker 1996

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as full paper.
Participants	Women from North America undergoing ICSI. Mean age control 33.5 (4.3), AH 35.3 (4.2).
Interventions	AH with acid tyrodes (chemical; complete zona breach; 72 hours egg retrieval to AH; 4 hours AH to transfer) versus no AH AH: 50 women randomised, 189 embryos transferred control: 50 women randomised, 184 embryos transferred
Outcomes	Implantation, clinical pregnancy
Notes	Attempted to contact author about this study, no reply received
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Utsunomiya 1998

Methods	Randomisation stated, but method unclear or incorrect. Allocation concealment unclear. Single centre. Participants not blinded or unclear. Assessor not blinded or unclear. Unclear if power calculation performed. ITT analysis unclear Published as abstract only.
Participants	Women from Japan, undergoing either ICSI or IVF. No data provided on age.
Interventions	AH with acid (chemical). No other details about the day of treatment provided
Outcomes	Clinical pregnancy rate only (gestation sac on ultrasound)
Notes	No attempt to contact author
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

AH = assisted hatching
IVF = in‐vitro fertilisation, ICSI = intracytoplasmic sperm injection
Mean age given in years (standard deviation).
note: only arms where all or no embryos transfered were treated with AH were accepted for data extraction

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Abdelmassih 2002	Pooled oocytes and then randomised, No per woman data provided.
Antinori 1996a	Not an RCT. Mentions randomly selected not randomly allocated.
Antinori 1996b	No randomised comparison between control and assisted hatching groups.
Balaban 2002	Not randomised. No appropriate controls.
Bider 1997	Not randomised.
Blake 2001	Not randomised. No embryo transfer occurred, so no review outcomes could be measured.
Carter 2003a	No per woman data.
Chao 1997	Assessment of pregnancy was by HCG only 14 days after embryo transfer
Check 1996	Not randomised. Benefits of AH confounded by concurrent assessment of 2 different culture media.
Chen 1999	Not randomised. Benefits of assisted hatching confounded by concurrent assessment of two different culture media.
Cieslak 1999	Comparison of two types of assisted hatching, no 'no assisted hatching' control group was used. More than one cycle per woman.
Cohen 1990	Not randomised.
Demirol 2003	No pregnancy data provided.
Dirnfeld 2003	No hatching.
Dokras 1994	No appropriate outcome measure.
Domitrz 2000	Benefits of assisted hatching confounded by concurrent assessment of two different culture media.
Ebner 2002	No per woman data.
Edirisinghe 1999	Not randomised.
Gabrielsen 2004a	Pseudorandomized (alternate days).
Hershlag 1999	Not randomised. The control group were from the period 1990‐1993, while the assisted hatching group were from 1994‐1996 (historical controls).
Huttelova 1999	Not randomised. Benefits of AH confounded by concurrent assessment of 2 different culture media.
Komarovsky 2002	No per women data
Komarovsky 2003	No per women data
Lee 1999	Not randomised.
Levron 2003	No per women data
Magli 1998A	No per women data.
Magli 1998B	No per women data.
Magli 1998C	No per women data
Mahadevan 1998	Not randomised. No concurrent controls.
Mansour 2000	Randomisation by altenate days.
Meldrum 1998	Not randomised. No concurrent controls.
Montag 1999	Not randomised. No concurrent controls.
Nagy 2003	No per woman data.
Nakayama 1998	No appropriate outcome measure.
Nakayama 1999	No per woman data.
Obruca 1994	Not randomised. No concurrent controls.
Olivennes 1997	No per woman data.
Rienzi 2002	Assisted hatching was part of the ICSI method.
Ringler 1999	It was not clear how many women were included in the study, or for how many cycles (only cycles were mentioned), and a mixture of participants and donated eggs were used for the study.
Schoolcraft 1994	Not randomised. Control and intervention groups recruited at different times.
Shahin 2003	No per women data
Szell 1998	Not randomised. Benefits of assisted hatching confounded by concurrent assessment of two different culture media.
Tao 1997	Not randomised. Some of the women in the assisted hatching group were randomised, but most were allocated assisted hatching routinely, with no control option.
Tucker 1991	Not randomised.
Urman 2002	Alternate randomisation
Zech 1998	Numbers in tables do not add up correctly and the text and tables are contradictory on the age groups used in the prospective part of the study.

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

Germond 1998

Trial name or title
Methods
Participants	Group I, women who initiate their first transfer cycle of frozen‐thawed embryos. Group III, selected group of women with poor prognosis of conception following transfer of fresh embryos (basal FSH >10IU/L and/or age >37 years). Multi‐centre study across four European IVF centres, 600 women.
Interventions	Assisted hatching with a diode laser (use of immunosuppressive and antibiotic treatment will also be tested).
Outcomes	Clinical pregnancy.
Starting date	Underway in 1998.
Contact information	M. Germond, Reproductive Medicine Unit, Dept. of Obstetrics‐Gynaecology, CHUV, CH‐1011 Lausanne, Switzerland.
Notes

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 woman randomised Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]
Open in figure viewer Analysis 1.1 Comparison 1 Live birth rate, Outcome 1 Live birth per woman randomised.
2 Live birth rate per women randomised: grouped by 1st attempt and repeat attempts Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]
Open in figure viewer Analysis 1.2 Comparison 1 Live birth rate, Outcome 2 Live birth rate per women randomised: grouped by 1st attempt and repeat attempts.
2.1 First attempt at IVF or ICSI	1	20	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 2.03]
2.2 Repeat attempt at IVF or ICSI	2	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.62, 3.14]
2.3 Unselected	3	346	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.78, 1.88]
3 Live birth rate per women randomised: grouped by ICSI cycles versus IVF cycles Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]
Open in figure viewer Analysis 1.3 Comparison 1 Live birth rate, Outcome 3 Live birth rate per women randomised: grouped by ICSI cycles versus IVF cycles.
3.1 ICSI only	2	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.62, 3.14]
3.2 IVF only	2	157	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.69, 2.47]
3.3 Mixed ICSI and IVF	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.56, 1.80]
4 Live birth rate per women randomised: grouped by method of assisted hatching used Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]
Open in figure viewer Analysis 1.4 Comparison 1 Live birth rate, Outcome 4 Live birth rate per women randomised: grouped by method of assisted hatching used.
4.1 Chemical	4	366	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.74, 1.74]
4.2 Laser	2	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.62, 3.14]
4.3 Mechanical	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Live birth rate: grouped by prognosis Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]
Open in figure viewer Analysis 1.5 Comparison 1 Live birth rate, Outcome 5 Live birth rate: grouped by prognosis.
5.1 Poor prognosis	4	376	Odds Ratio (M‐H, Fixed, 95% CI)	1.32 [0.84, 2.07]
5.2 Good prognosis	2	140	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.45, 1.83]
5.3 Not stated	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 2. Clinical pregnancy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical pregnancy rate per woman randomised Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
Open in figure viewer Analysis 2.1 Comparison 2 Clinical pregnancy, Outcome 1 Clinical pregnancy rate per woman randomised.
2 Clinical pregnancy rate per woman randomised: grouped by 1st attempt and repeat attempts Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
Open in figure viewer Analysis 2.2 Comparison 2 Clinical pregnancy, Outcome 2 Clinical pregnancy rate per woman randomised: grouped by 1st attempt and repeat attempts.
2.1 First attempt at IVF or ICSI	4	378	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.63, 1.49]
2.2 Repeat attempt at IVF or ICSI	7	963	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [1.08, 1.96]
2.3 Unselected or mixed	12	1345	Odds Ratio (M‐H, Fixed, 95% CI)	1.37 [1.09, 1.73]
3 Clinical pregnancy rate: grouped by ICSI versus IVF cycles Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
Open in figure viewer Analysis 2.3 Comparison 2 Clinical pregnancy, Outcome 3 Clinical pregnancy rate: grouped by ICSI versus IVF cycles.
3.1 ICSI only	5	399	Odds Ratio (M‐H, Fixed, 95% CI)	1.30 [0.85, 1.99]
3.2 IVF only	13	1785	Odds Ratio (M‐H, Fixed, 95% CI)	1.39 [1.13, 1.70]
3.3 Mixed ICSI and IVF	5	502	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.75, 1.68]
4 Clinical pregnancy rate: grouped by method of assisted hatching used Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
Open in figure viewer Analysis 2.4 Comparison 2 Clinical pregnancy, Outcome 4 Clinical pregnancy rate: grouped by method of assisted hatching used.
4.1 Chemical	12	1433	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [1.11, 1.73]
4.2 Laser	7	792	Odds Ratio (M‐H, Fixed, 95% CI)	1.36 [0.98, 1.88]
4.3 Mechanical	4	461	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.71, 1.66]
5 Clinical pregnancy rate: grouped by age >=35 years Show forest plot	6	697	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.81, 1.57]
Open in figure viewer Analysis 2.5 Comparison 2 Clinical pregnancy, Outcome 5 Clinical pregnancy rate: grouped by age >=35 years.
5.1 Age >= 35 years old	4	362	Odds Ratio (M‐H, Fixed, 95% CI)	1.54 [0.94, 2.51]
5.2 Age < 35 years old	4	335	Odds Ratio (M‐H, Fixed, 95% CI)	0.85 [0.53, 1.35]
6 Clinical pregnancy rate: grouped by prognosis Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]
Open in figure viewer Analysis 2.6 Comparison 2 Clinical pregnancy, Outcome 6 Clinical pregnancy rate: grouped by prognosis.
6.1 Poor prognosis	9	1082	Odds Ratio (M‐H, Fixed, 95% CI)	1.43 [1.09, 1.89]
6.2 Good prognosis	5	613	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.86, 1.67]
6.3 Unstated	9	991	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [1.00, 1.73]
7 Clinicial pregnancy rate per woman randomised: subgrouped extent of assisted hatching Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.13, 1.57]
Open in figure viewer Analysis 2.7 Comparison 2 Clinical pregnancy, Outcome 7 Clinicial pregnancy rate per woman randomised: subgrouped extent of assisted hatching.
7.1 Thinning only	6	686	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.85, 1.69]
7.2 Breach by hole only	15	1699	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [1.04, 1.58]
7.3 Complete removal of zona	2	301	Odds Ratio (M‐H, Fixed, 95% CI)	1.93 [1.21, 3.09]

Open in table viewer

Comparison 3. Miscarriage rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Miscarriage per woman randomised Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.73, 2.05]
Open in figure viewer Analysis 3.1 Comparison 3 Miscarriage rate, Outcome 1 Miscarriage per woman randomised.
2 Miscarriage rate per woman randomised: grouped by 1st or repeat attempt Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.73, 2.05]
Open in figure viewer Analysis 3.2 Comparison 3 Miscarriage rate, Outcome 2 Miscarriage rate per woman randomised: grouped by 1st or repeat attempt.
2.1 First attempt at IVF or ICSI	3	322	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.28, 2.44]
2.2 More than one previous IVF or ICSI cycle	5	606	Odds Ratio (M‐H, Fixed, 95% CI)	2.39 [0.78, 7.29]
2.3 Unselected couples	4	392	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.54, 2.20]
3 Miscarriage rate per woman randomised: grouped by ICSI or IVF Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.27 [0.76, 2.13]
Open in figure viewer Analysis 3.3 Comparison 3 Miscarriage rate, Outcome 3 Miscarriage rate per woman randomised: grouped by ICSI or IVF.
3.1 ICSI only	4	299	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.48, 3.05]
3.2 IVF only	6	812	Odds Ratio (M‐H, Fixed, 95% CI)	1.27 [0.62, 2.63]
3.3 Mixed ICSI and IVF	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.40, 4.75]
4 Miscarriage rate per woman randomised: grouped by method of assisted hatching used Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.73, 2.05]
Open in figure viewer Analysis 3.4 Comparison 3 Miscarriage rate, Outcome 4 Miscarriage rate per woman randomised: grouped by method of assisted hatching used.
4.1 Chemical	5	412	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.56, 2.21]
4.2 Laser	6	754	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [0.63, 3.17]
4.3 Mechanical	1	154	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.07, 18.58]
5 Miscarriage rate per woman: grouped by age>= 35 years Show forest plot	4	462	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.41, 2.71]
Open in figure viewer Analysis 3.5 Comparison 3 Miscarriage rate, Outcome 5 Miscarriage rate per woman: grouped by age>= 35 years.
5.1 Age >=35 years	2	243	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.28, 3.35]
5.2 Age < 35 years	2	219	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.28, 5.09]
6 Miscarriage rate per woman: grouped by prognosis Show forest plot	8	931	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.81, 3.49]
Open in figure viewer Analysis 3.6 Comparison 3 Miscarriage rate, Outcome 6 Miscarriage rate per woman: grouped by prognosis.
6.1 Poor prognosis	5	592	Odds Ratio (M‐H, Fixed, 95% CI)	1.86 [0.75, 4.64]
6.2 Good prognosis	3	339	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.40, 4.76]
8 Miscarriage per clinical pregnancy Show forest plot	11		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.8 Comparison 3 Miscarriage rate, Outcome 8 Miscarriage per clinical pregnancy.

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 woman randomised Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]
Open in figure viewer Analysis 4.1 Comparison 4 Multiple pregnancy rate, Outcome 1 Multiple pregnancy rate per woman randomised.
2 Multiple pregnancy rate per woman: grouped by 1st attempt versus repeat attempts Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]
Open in figure viewer Analysis 4.2 Comparison 4 Multiple pregnancy rate, Outcome 2 Multiple pregnancy rate per woman: grouped by 1st attempt versus repeat attempts.
2.1 1st IVF attempt	1	136	Odds Ratio (M‐H, Fixed, 95% CI)	2.63 [0.11, 65.65]
2.2 More than one previous IVF attempt	2	359	Odds Ratio (M‐H, Fixed, 95% CI)	3.59 [0.97, 13.29]
2.3 Unselected couples	6	486	Odds Ratio (M‐H, Fixed, 95% CI)	1.64 [1.02, 2.63]
3 Multiple pregnancy rate per woman: grouped by ICSI or IVF Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]
Open in figure viewer Analysis 4.3 Comparison 4 Multiple pregnancy rate, Outcome 3 Multiple pregnancy rate per woman: grouped by ICSI or IVF.
3.1 ICSI only	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.07, 5.28]
3.2 IVF only	6	747	Odds Ratio (M‐H, Fixed, 95% CI)	2.38 [1.43, 3.94]
3.3 Mixed IVF or ICSI	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.28, 2.22]
4 Multiple pregnancy rate per woman: grouped by method of assisted hatching used Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]
Open in figure viewer Analysis 4.4 Comparison 4 Multiple pregnancy rate, Outcome 4 Multiple pregnancy rate per woman: grouped by method of assisted hatching used.
4.1 Chemical	5	442	Odds Ratio (M‐H, Fixed, 95% CI)	1.36 [0.82, 2.25]
4.2 Laser	3	495	Odds Ratio (M‐H, Fixed, 95% CI)	3.43 [1.02, 11.54]
4.3 mechanical	1	44	Odds Ratio (M‐H, Fixed, 95% CI)	8.33 [1.56, 44.64]
5 Multiple pregnancy rate per woman: grouped by age>=35 years old Show forest plot	2	74	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.34, 6.70]
Open in figure viewer Analysis 4.5 Comparison 4 Multiple pregnancy rate, Outcome 5 Multiple pregnancy rate per woman: grouped by age>=35 years old.
5.1 Age >= 35 years	1	44	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.12, 7.07]
5.2 Age < 35 years	1	30	Odds Ratio (M‐H, Fixed, 95% CI)	2.67 [0.26, 27.49]
6 Multiple pregnancy rate per woman: grouped by prognosis Show forest plot	4	544	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.53, 2.91]
Open in figure viewer Analysis 4.6 Comparison 4 Multiple pregnancy rate, Outcome 6 Multiple pregnancy rate per woman: grouped by prognosis.
6.1 Poor prognosis	2	225	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.29, 8.02]
6.2 Good prognosis	2	319	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.43, 3.11]
7 Multiple pregnancy rate per woman grouped by extent of assisted hatching Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]
Open in figure viewer Analysis 4.7 Comparison 4 Multiple pregnancy rate, Outcome 7 Multiple pregnancy rate per woman grouped by extent of assisted hatching.
7.1 Thinning only	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	3.16 [0.62, 16.17]
7.2 breach by hole	7	796	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [1.15, 2.92]
7.3 Complete removal of zona	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.07, 5.28]
8 Multiple pregnancy per pregnancy Show forest plot	9	394	Odds Ratio (M‐H, Fixed, 95% CI)	1.79 [1.11, 2.89]
Open in figure viewer Analysis 4.8 Comparison 4 Multiple pregnancy rate, Outcome 8 Multiple pregnancy per pregnancy.

Open in table viewer

Comparison 5. Monozygotic twinning rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Monozygotic twinning per woman randomised Show forest plot	4	524	Odds Ratio (M‐H, Fixed, 95% CI)	3.26 [0.14, 77.84]
Open in figure viewer Analysis 5.1 Comparison 5 Monozygotic twinning rate, Outcome 1 Monozygotic twinning per woman randomised.

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Comparison 7. Implantation rate (gestation sac/embryo transfer)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of gestation sacs per embryo transferred Show forest plot	12		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 7.1 Comparison 7 Implantation rate (gestation sac/embryo transfer), Outcome 1 Number of gestation sacs per embryo transferred.

Figure 1

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Analysis 1.1

Comparison 1 Live birth rate, Outcome 1 Live birth per woman randomised.

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Analysis 1.2

Comparison 1 Live birth rate, Outcome 2 Live birth rate per women randomised: grouped by 1st attempt and repeat attempts.

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Analysis 1.3

Comparison 1 Live birth rate, Outcome 3 Live birth rate per women randomised: grouped by ICSI cycles versus IVF cycles.

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Analysis 1.4

Comparison 1 Live birth rate, Outcome 4 Live birth rate per women randomised: grouped by method of assisted hatching used.

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Analysis 1.5

Comparison 1 Live birth rate, Outcome 5 Live birth rate: grouped by prognosis.

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Analysis 2.1

Comparison 2 Clinical pregnancy, Outcome 1 Clinical pregnancy rate per woman randomised.

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Analysis 2.2

Comparison 2 Clinical pregnancy, Outcome 2 Clinical pregnancy rate per woman randomised: grouped by 1st attempt and repeat attempts.

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Analysis 2.3

Comparison 2 Clinical pregnancy, Outcome 3 Clinical pregnancy rate: grouped by ICSI versus IVF cycles.

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Analysis 2.4

Comparison 2 Clinical pregnancy, Outcome 4 Clinical pregnancy rate: grouped by method of assisted hatching used.

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Analysis 2.5

Comparison 2 Clinical pregnancy, Outcome 5 Clinical pregnancy rate: grouped by age >=35 years.

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Analysis 2.6

Comparison 2 Clinical pregnancy, Outcome 6 Clinical pregnancy rate: grouped by prognosis.

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Analysis 2.7

Comparison 2 Clinical pregnancy, Outcome 7 Clinicial pregnancy rate per woman randomised: subgrouped extent of assisted hatching.

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Analysis 3.1

Comparison 3 Miscarriage rate, Outcome 1 Miscarriage per woman randomised.

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Analysis 3.2

Comparison 3 Miscarriage rate, Outcome 2 Miscarriage rate per woman randomised: grouped by 1st or repeat attempt.

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Analysis 3.3

Comparison 3 Miscarriage rate, Outcome 3 Miscarriage rate per woman randomised: grouped by ICSI or IVF.

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Analysis 3.4

Comparison 3 Miscarriage rate, Outcome 4 Miscarriage rate per woman randomised: grouped by method of assisted hatching used.

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Analysis 3.5

Comparison 3 Miscarriage rate, Outcome 5 Miscarriage rate per woman: grouped by age>= 35 years.

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Analysis 3.6

Comparison 3 Miscarriage rate, Outcome 6 Miscarriage rate per woman: grouped by prognosis.

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Analysis 3.8

Comparison 3 Miscarriage rate, Outcome 8 Miscarriage per clinical pregnancy.

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Analysis 4.1

Comparison 4 Multiple pregnancy rate, Outcome 1 Multiple pregnancy rate per woman randomised.

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Analysis 4.2

Comparison 4 Multiple pregnancy rate, Outcome 2 Multiple pregnancy rate per woman: grouped by 1st attempt versus repeat attempts.

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Analysis 4.3

Comparison 4 Multiple pregnancy rate, Outcome 3 Multiple pregnancy rate per woman: grouped by ICSI or IVF.

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Analysis 4.4

Comparison 4 Multiple pregnancy rate, Outcome 4 Multiple pregnancy rate per woman: grouped by method of assisted hatching used.

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Analysis 4.5

Comparison 4 Multiple pregnancy rate, Outcome 5 Multiple pregnancy rate per woman: grouped by age>=35 years old.

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Analysis 4.6

Comparison 4 Multiple pregnancy rate, Outcome 6 Multiple pregnancy rate per woman: grouped by prognosis.

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Analysis 4.7

Comparison 4 Multiple pregnancy rate, Outcome 7 Multiple pregnancy rate per woman grouped by extent of assisted hatching.

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Analysis 4.8

Comparison 4 Multiple pregnancy rate, Outcome 8 Multiple pregnancy per pregnancy.

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Analysis 5.1

Comparison 5 Monozygotic twinning rate, Outcome 1 Monozygotic twinning per woman randomised.

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Analysis 7.1

Comparison 7 Implantation rate (gestation sac/embryo transfer), Outcome 1 Number of gestation sacs per embryo transferred.

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Table 1. Quality of Included studies

Study ID	Allocation concealed	Randomisation method	Blinding	Follow up complete	No. embryos transfer	Day of randomisat
Antinori 1999A	Unclear	Unclear	Unclear	Unknown	AH 4.3 Control 4.4	Not stated
Antinori 1999B	Unclear	Unclear	No	Unknown	AH 2.3, control 2.4	Not stated
Baruffi 2000	no	Randomisation table	No	Unknown	AH 2.76, Control 2.87	Not stated
Chao 1997	Unclear	Unclear	No	Unknown	AH 5.8, control 5.7	Not stated
Cohen 1992A	No	Preprinted randomisation list	Yes ‐ double	Unknown	AH 3.4, control 3.5	Not stated
Cohen 1992B	No	Preprinted randomisation list	Yes ‐ double	Unknown	AH 3.4, Control 3.5	Not stated
Cohen 1992C	No	Preprinted randomisation list	Yes ‐ double	Unknown	No data	Not stated
Hellebaut 1996	Unclear	Computer randomised	No	Unknown	AH 4.0, Control 4.0	Day of embryo transfer
Hurst 1999	Unclear	Computer randomised	No	Unknown	AH 4.0, Control 4.0	Not stated
Isik 2000	Unclear	Random numbers table	No	Unknown	Blastocyst transfer AH 2.86, Control 2.95	Randomised on day 3
Isiklar 1999	Unclear	Unclear	No	Unknown	AH 3.7, Control 3.5 NB Blastocyst transfer	Randomised on day 3
Jelinkova 2002	Unclear	Unclear	Unclear	Yes	AH 2.2, Control 2.2	Not stated
Laffoon 1999	Unclear	Unclear	No	Unknown	Not stated	Day of Hcg administration
Lanzendorf 1998	Sealed envelope	Unclear	Yes ‐ double	Yes	AH 4.4, Control 4.4	Day of aspiration
Mansour 2000B	Unclear	Unclear 3:4 ratio	No	Unknown	AH 3.9, Control 3.8	Day of embryo transfer
Nagy 1999	Unclear	Unclear	No	Unknown	Not stated	Not stated
Ng 2005	Sealed envelopes	Computer generated	Yes ‐ double until completion of the whole study	Yes	AH ‐ transfered 2 in 52% and 3 in 41%, control transfered 2 in 36% and 3 in 61%.	Day of frozen embryo transfer
Petersen 2005A	Unclear	Random numbers table to be allocated into experimental or control	Code numbers used to identify patients but no true blinding	yes	yes ‐ mean of 2.7	Not stated
Petersen 2005B	Unclear	Random numbers table to be allocated into experimental or control	Code numbers used to identify patients but no true blinding	yes	yes ‐ mean of 30	Not stated
Rufas‐Sapir 2004	Unclear	Unclear	Unclear	yes	AH 3.4 ETs, control 3.7	Day of embryo transfer
Ryan 1996	Unclear	Random numbers table	Unclear	yes	mean 2.17	Not stated
Stein 1995	Unclear	Unclear	No	yes	Not stated	Not stated
Tucker 1993	Unclear	Unclear	Unclear	yes	AH 2.9, control 3.0	Not stated
Tucker 1996	Unclear	Unclear	Unclear	yes	AH 3.4, control 3.6	Not stated
Utsinomiya 1998	Unclear	Unclear	Unclear	yes	Not stated	Not stated

Table 1. Quality of Included studies

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Table 2. Mean age of participants in assisted hatching and control groups

Study	n, mean age (sd) AH	n, mean age (sd) con	WMD (95% CI)	OR for clinical preg
Baruffi 2000	51, 31.80 (3.60)	52, 31.40 (3.60)	0.40 (‐0.99 to 1.79)	0.74 (0.33‐1.65)
Cohen 1992A	39, 36.50 (3.30)	68, 36.70 (3.70)	‐0.20 (‐1.37 to 0.97)	1.30 (0.66‐2.55)
Hellebaut 1996	60, 30.90 (4.30)	60, 30.80 (3.90)	0.10 (‐1.37 to 1.57)	1.15 (0.55‐2.43)
Hurst 1998	13, 30.00 (0.90)	7, 30.00 (0.80)	0.00 (‐0.77 to 0.77)	0.40 (0.06‐2.89)
Isik 2000	24, 30.50 (5.20)	22, 29.10 (3.60)	1.40 (‐1.17 to 3.97)	2.0 (0.62‐6.49)
Jelinkova	128, 32.3 (4.24)	127, 32.1 (3.16)	0.20 (‐0.72‐1.12)	1.86 (1.12‐3.10)
Lanzendorf 1998	41, 38.30 (0.31)	48, 38.50 (0.26)	‐0.20 (‐0.32 to ‐0.08)	0.90 (0.38‐2.10)
Mansour 2000B	30, 37.30 (5.60)	41, 36.30 (5.20)	1.00 (‐1.56 to 3.56)	3.86 (0.91‐16.41)
Nagy 1999	20, 32.00 (4.00)	20, 31.40 (3.70)	0.60 (‐1.79 to 2.99)	8.0 (1.44‐44.3)
Ng 2005	80, 34 (25‐40) (range)	80, 34 (24‐40)	0.00 (‐1.57 ‐ 1.57) needs checking about the SD from a range	0.81 (0.33‐2.00)
Petersen 2005A	35, 34.6 (4.6)	35, 34.1 (5.3)	0.50 (‐1.82, 2.82)	1.15 (0.41‐3.19)
Petersen 2005B	40, 35.7 (3.8)	40, 35.3 (5.1)	0.40 (‐1.57‐2.37)	4.11 (1.04‐16.29)

Tucker 1993	110, 34.10 (4.80)	108, 34.20 (4.10)	‐0.10 (‐1.28 to 1.08)	1.37 (0.79‐2.35)
Tucker 1996	50, 35.30 (4.20)	50, 33.50 (4.30)	1.80 (0.13 to 3.47)	0.74 (0.35‐1.59)

Table 2. Mean age of participants in assisted hatching and control groups

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Table 3. Meta‐analysis, subgrouping and sensitivity analysis results

Outcome	Analysis type	Description	No. of studies	OR (fixed effects)	95% CI	heterogeneity p
Live births, per woman randomised	Overall meta‐analysis		6	1.19	0.81 to 1.73	0.27
Live births, per woman randomised	Sensitivity analysis	Allocation concealment	1	0.91	0.37 to 2.26	‐
Live births, per woman randomised	Sensitivity analysis	Method of randomisation	5	1.04	0.66 to 1.65	0.26
Live births, per woman randomised	Sensitivity analysis	Balanced reporting of age	5	1.25	0.83 to 1.90	0.19
Clinical pregnancy, per woman randomised	Overall meta‐analysis		23	1.33	1.12 to 1.57	0.20
Clinical pregnancy, per woman randomised	Sensitivity analysis	Allocation concealment	2	0.85	0.49 to 1.59	0.87
Clinical pregnancy, per woman randomised	Sensitivity analysis	Method of randomisation	9	1.15	0.88 to 1.50	0.38
Clinical pregnancy, per woman randomised	Sensitivity analysis	Balanced reporting of age	12	1.49	1.21 to 1.85	0.18

Table 3. Meta‐analysis, subgrouping and sensitivity analysis results

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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 woman randomised Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]

2 Live birth rate per women randomised: grouped by 1st attempt and repeat attempts Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]

2.1 First attempt at IVF or ICSI	1	20	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 2.03]
2.2 Repeat attempt at IVF or ICSI	2	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.62, 3.14]
2.3 Unselected	3	346	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.78, 1.88]
3 Live birth rate per women randomised: grouped by ICSI cycles versus IVF cycles Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]

3.1 ICSI only	2	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.62, 3.14]
3.2 IVF only	2	157	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.69, 2.47]
3.3 Mixed ICSI and IVF	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.56, 1.80]
4 Live birth rate per women randomised: grouped by method of assisted hatching used Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]

4.1 Chemical	4	366	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.74, 1.74]
4.2 Laser	2	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.62, 3.14]
4.3 Mechanical	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Live birth rate: grouped by prognosis Show forest plot	6	516	Odds Ratio (M‐H, Fixed, 95% CI)	1.19 [0.81, 1.73]

5.1 Poor prognosis	4	376	Odds Ratio (M‐H, Fixed, 95% CI)	1.32 [0.84, 2.07]
5.2 Good prognosis	2	140	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.45, 1.83]
5.3 Not stated	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Live birth rate

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Comparison 2. Clinical pregnancy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical pregnancy rate per woman randomised Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]

2 Clinical pregnancy rate per woman randomised: grouped by 1st attempt and repeat attempts Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]

2.1 First attempt at IVF or ICSI	4	378	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.63, 1.49]
2.2 Repeat attempt at IVF or ICSI	7	963	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [1.08, 1.96]
2.3 Unselected or mixed	12	1345	Odds Ratio (M‐H, Fixed, 95% CI)	1.37 [1.09, 1.73]
3 Clinical pregnancy rate: grouped by ICSI versus IVF cycles Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]

3.1 ICSI only	5	399	Odds Ratio (M‐H, Fixed, 95% CI)	1.30 [0.85, 1.99]
3.2 IVF only	13	1785	Odds Ratio (M‐H, Fixed, 95% CI)	1.39 [1.13, 1.70]
3.3 Mixed ICSI and IVF	5	502	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.75, 1.68]
4 Clinical pregnancy rate: grouped by method of assisted hatching used Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]

4.1 Chemical	12	1433	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [1.11, 1.73]
4.2 Laser	7	792	Odds Ratio (M‐H, Fixed, 95% CI)	1.36 [0.98, 1.88]
4.3 Mechanical	4	461	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.71, 1.66]
5 Clinical pregnancy rate: grouped by age >=35 years Show forest plot	6	697	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.81, 1.57]

5.1 Age >= 35 years old	4	362	Odds Ratio (M‐H, Fixed, 95% CI)	1.54 [0.94, 2.51]
5.2 Age < 35 years old	4	335	Odds Ratio (M‐H, Fixed, 95% CI)	0.85 [0.53, 1.35]
6 Clinical pregnancy rate: grouped by prognosis Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.12, 1.57]

6.1 Poor prognosis	9	1082	Odds Ratio (M‐H, Fixed, 95% CI)	1.43 [1.09, 1.89]
6.2 Good prognosis	5	613	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.86, 1.67]
6.3 Unstated	9	991	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [1.00, 1.73]
7 Clinicial pregnancy rate per woman randomised: subgrouped extent of assisted hatching Show forest plot	23	2686	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [1.13, 1.57]

7.1 Thinning only	6	686	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.85, 1.69]
7.2 Breach by hole only	15	1699	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [1.04, 1.58]
7.3 Complete removal of zona	2	301	Odds Ratio (M‐H, Fixed, 95% CI)	1.93 [1.21, 3.09]

Comparison 2. Clinical pregnancy

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Comparison 3. Miscarriage rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Miscarriage per woman randomised Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.73, 2.05]

2 Miscarriage rate per woman randomised: grouped by 1st or repeat attempt Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.73, 2.05]

2.1 First attempt at IVF or ICSI	3	322	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.28, 2.44]
2.2 More than one previous IVF or ICSI cycle	5	606	Odds Ratio (M‐H, Fixed, 95% CI)	2.39 [0.78, 7.29]
2.3 Unselected couples	4	392	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.54, 2.20]
3 Miscarriage rate per woman randomised: grouped by ICSI or IVF Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.27 [0.76, 2.13]

3.1 ICSI only	4	299	Odds Ratio (M‐H, Fixed, 95% CI)	1.21 [0.48, 3.05]
3.2 IVF only	6	812	Odds Ratio (M‐H, Fixed, 95% CI)	1.27 [0.62, 2.63]
3.3 Mixed ICSI and IVF	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.40, 4.75]
4 Miscarriage rate per woman randomised: grouped by method of assisted hatching used Show forest plot	12	1320	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [0.73, 2.05]

4.1 Chemical	5	412	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.56, 2.21]
4.2 Laser	6	754	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [0.63, 3.17]
4.3 Mechanical	1	154	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.07, 18.58]
5 Miscarriage rate per woman: grouped by age>= 35 years Show forest plot	4	462	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.41, 2.71]

5.1 Age >=35 years	2	243	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.28, 3.35]
5.2 Age < 35 years	2	219	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.28, 5.09]
6 Miscarriage rate per woman: grouped by prognosis Show forest plot	8	931	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.81, 3.49]

6.1 Poor prognosis	5	592	Odds Ratio (M‐H, Fixed, 95% CI)	1.86 [0.75, 4.64]
6.2 Good prognosis	3	339	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.40, 4.76]
8 Miscarriage per clinical pregnancy Show forest plot	11		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 3. Miscarriage 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 woman randomised Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]

2 Multiple pregnancy rate per woman: grouped by 1st attempt versus repeat attempts Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]

2.1 1st IVF attempt	1	136	Odds Ratio (M‐H, Fixed, 95% CI)	2.63 [0.11, 65.65]
2.2 More than one previous IVF attempt	2	359	Odds Ratio (M‐H, Fixed, 95% CI)	3.59 [0.97, 13.29]
2.3 Unselected couples	6	486	Odds Ratio (M‐H, Fixed, 95% CI)	1.64 [1.02, 2.63]
3 Multiple pregnancy rate per woman: grouped by ICSI or IVF Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]

3.1 ICSI only	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.07, 5.28]
3.2 IVF only	6	747	Odds Ratio (M‐H, Fixed, 95% CI)	2.38 [1.43, 3.94]
3.3 Mixed IVF or ICSI	2	209	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.28, 2.22]
4 Multiple pregnancy rate per woman: grouped by method of assisted hatching used Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]

4.1 Chemical	5	442	Odds Ratio (M‐H, Fixed, 95% CI)	1.36 [0.82, 2.25]
4.2 Laser	3	495	Odds Ratio (M‐H, Fixed, 95% CI)	3.43 [1.02, 11.54]
4.3 mechanical	1	44	Odds Ratio (M‐H, Fixed, 95% CI)	8.33 [1.56, 44.64]
5 Multiple pregnancy rate per woman: grouped by age>=35 years old Show forest plot	2	74	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.34, 6.70]

5.1 Age >= 35 years	1	44	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.12, 7.07]
5.2 Age < 35 years	1	30	Odds Ratio (M‐H, Fixed, 95% CI)	2.67 [0.26, 27.49]
6 Multiple pregnancy rate per woman: grouped by prognosis Show forest plot	4	544	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.53, 2.91]

6.1 Poor prognosis	2	225	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.29, 8.02]
6.2 Good prognosis	2	319	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.43, 3.11]
7 Multiple pregnancy rate per woman grouped by extent of assisted hatching Show forest plot	9	981	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.19, 2.83]

7.1 Thinning only	1	160	Odds Ratio (M‐H, Fixed, 95% CI)	3.16 [0.62, 16.17]
7.2 breach by hole	7	796	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [1.15, 2.92]
7.3 Complete removal of zona	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.07, 5.28]
8 Multiple pregnancy per pregnancy Show forest plot	9	394	Odds Ratio (M‐H, Fixed, 95% CI)	1.79 [1.11, 2.89]

Comparison 4. Multiple pregnancy rate

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Comparison 5. Monozygotic twinning rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Monozygotic twinning per woman randomised Show forest plot	4	524	Odds Ratio (M‐H, Fixed, 95% CI)	3.26 [0.14, 77.84]

Comparison 5. Monozygotic twinning rate

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Comparison 7. Implantation rate (gestation sac/embryo transfer)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of gestation sacs per embryo transferred Show forest plot	12		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 7. Implantation rate (gestation sac/embryo transfer)

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Referencias

References to studies included in this review

Antinori 1999A {published data only}

Antinori 1999B {published data only}

Baruffi 2000 {published data only}

Cohen 1992A {published data only}

Cohen 1992B {published data only}

Cohen 1992C {published data only}

Hellebaut 1996 {published and unpublished data}

Hurst 1998 {published and unpublished data}

Isik 2000 {published data only}

Isiklar 1999 {published data only}

Jelinkova 2002 {published data only}

Laffoon 1999 {published data only}

Lanzendorf 1998 {published and unpublished data}

Nagy 1999 {published data only}

Ng 2005 {published data only}

Petersen 2005A {published data only}

Petersen 2005B {published data only}

Rufas‐Sapir 2004 {published data only}

Ryan 1997 {published data only}

Stein 1995 {published data only}

Tucker 1993 {published data only}

Tucker 1996 {published data only}

Utsunomiya 1998 {published data only}

References to studies excluded from this review

Abdelmassih 2002 {published data only}

Antinori 1996a {published data only}

Antinori 1996b {published data only}

Balaban 2002 {published data only}

Bider 1997 {published data only}

Blake 2001 {published data only}

Carter 2003a {published data only}

Chao 1997 {published data only}

Check 1996 {published data only}

Chen 1999 {published data only}

Cieslak 1999 {published data only}

Cohen 1990 {published data only}

Demirol 2003 {published data only}

Dirnfeld 2003 {published data only}

Dokras 1994 {published data only}

Domitrz 2000 {published data only}

Ebner 2002 {published data only}

Edirisinghe 1999 {published data only}

Gabrielsen 2004a {published data only}

Hershlag 1999 {published data only}

Huttelova 1999 {published data only}

Komarovsky 2002 {published data only}

Komarovsky 2003 {published data only}

Lee 1999 {published data only}

Levron 2003 {published data only}

Magli 1998A {published and unpublished data}

Magli 1998B {published and unpublished data}

Magli 1998C {published and unpublished data}

Mahadevan 1998 {published data only}

Mansour 2000 {published data only}

Meldrum 1998 {published data only}

Montag 1999 {published data only}

Nagy 2003 {published data only}

Nakayama 1998 {published data only}

Nakayama 1999 {published data only}

Obruca 1994 {published data only}

Olivennes 1997 {published data only}

Rienzi 2002 {published data only}

Ringler 1999 {published data only}

Schoolcraft 1994 {published data only}

Shahin 2003 {published data only}

Szell 1998 {published data only}

Tao 1997 {published data only}

Tucker 1991 {published data only}

Urman 2002 {published data only}

Zech 1998 {published data only}

References to ongoing studies

Germond 1998 {published data only}

Additional references

Al‐Nuaim 2002

Bleil 1980

Bronson 1970