Teixeira 2013

Regular (ICSI) versus ultra-high magnification (IMSI) sperm
selection for assisted reproduction (Review)
Teixeira DM, Barbosa MAP, Ferriani RA, Navarro PA, Raine-Fenning N, Nastri CO, Martins
WP
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 7
http://www.thecochranelibrary.com
Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 1.1. Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 1 Live birth per allocated
couple. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 1.2. Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 2 Clinical pregnancy per
allocated couple. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Analysis 1.3. Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 3 Miscarriage per clinical
pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Analysis 2.1. Comparison 2 IMSI versus ICSI: subgroup analysis by sperm quality, Outcome 1 Clinical pregnancy. . 35
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 40
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction (Review) i
[Intervention Review]
Regular (ICSI) versus ultra-high magnification (IMSI) sperm

selection for assisted reproduction
Danielle M Teixeira1 , Mariana AP Barbosa1 , Rui A Ferriani1 , Paula A Navarro1 , Nick Raine-Fenning2 , Carolina O Nastri1 , Wellington
P Martins1
1 Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil. 2 Division
of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, Nottingham, UK
Contact address: Wellington P Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of
Sao Paulo, Hospital das Clnicas da FMRP-USP, 8 andar, Campus Universitrio, Campus Universitario da USP, Ribeirao Preto, Sao
Paulo, 14048-900, Brazil. wpmartins@gmail.com.
Editorial group: Cochrane Menstrual Disorders and Subfertility Group.

Publication status and date: New, published in Issue 7, 2013.
Review content assessed as up-to-date: 8 May 2013.
Citation: Teixeira DM, Barbosa MAP, Ferriani RA, Navarro PA, Raine-Fenning N, Nastri CO, Martins WP. Regular (ICSI) versus
ultra-high magnification (IMSI) sperm selection for assisted reproduction. Cochrane Database of Systematic Reviews 2013, Issue 7. Art.
No.: CD010167. DOI: 10.1002/14651858.CD010167.pub2.
ABSTRACT
Background
Subfertility is a condition found in up to 15% of couples of reproductive age. Gamete micromanipulation, such as intracytoplasmic
sperm injection (ICSI), is very useful for treating couples with compromised sperm parameters. Recently a new method of sperm
selection named motile sperm organelle morphology examination (MSOME) has been described and the spermatozoa selected under
high magnification (over 6000x) used for ICSI. This new technique, named intracytoplasmic morphologically selected sperm injection
(IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing assisted reproduction techniques
(ART).
Objectives
To compare the effectiveness and safety of IMSI and ICSI in couples undergoing ART.
Search methods
We searched for randomised controlled trials (RCT) in electronic databases (Cochrane Menstrual Disorders and Subfertility Group
Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL,
LILACS), trials registers (ClinicalTrials.gov, Current Controlled Trials, World Health Organization International Clinical Trials Registry
Platform), conference abstracts (ISI Web of knowledge), and grey literature (OpenGrey); in addition, we handsearched the reference
lists of included studies and similar reviews. We performed the last electronic search on 8 May 2013.
Selection criteria
We considered only truly randomised controlled trials comparing ICSI and IMSI to be eligible; we did not include quasi or pseudo-
randomised trials. We included studies that permitted the inclusion of the same participant more than once (cross-over or per cycle
trials) only if data regarding the first treatment of each participant were available.
Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction (Review) 1
Data collection and analysis
Two review authors independently performed study selection, data extraction, and assessment of the risk of bias and we solved
disagreements by consulting a third review author. We corresponded with study investigators in order to resolve any queries, as required.
Main results
The search retrieved 294 records; from those, nine parallel design studies were included, comprising 2014 couples (IMSI = 1002; ICSI
= 1012). Live birth was evaluated by only one trial and there was no significant evidence of a difference between IMSI and ICSI (risk
ratio (RR) 1.14, 95% confidence interval (CI) 0.79 to 1.64, 1 RCT, 168 women, I2 = not applicable, low-quality evidence). IMSI was
associated with a significant improvement in clinical pregnancy rate (RR 1.29, 95% CI 1.07 to 1.56, 9 RCTs, 2014 women, I2 = 57%,
very-low-quality evidence). We downgraded the quality of this evidence because of imprecision, inconsistency, and strong indication
of publication bias. We found no significant difference in miscarriage rate between IMSI and ICSI (RR 0.82, 95% CI 0.59 to 1.14, 6
RCTs, 552 clinical pregnancies, I2 = 17%, very-low-quality evidence). None of the included studies reported congenital abnormalities.
Authors conclusions
Results from RCTs do not support the clinical use of IMSI. There is no evidence of effect on live birth or miscarriage and the evidence
that IMSI improves clinical pregnancy is of very low quality. There is no indication that IMSI increases congenital abnormalities.
Further trials are necessary to improve the evidence quality before recommending IMSI in clinical practice.
PLAIN LANGUAGE SUMMARY

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction
Background: sperm micromanipulation, such as intracytoplasmic sperm injection (ICSI), is very useful for treating couples in which
the male partner has a reduced sperm concentration or motility, or both. Recently, a new method of sperm selection named motile
sperm organelle morphology examination (MSOME) has been described, which analyses sperm under ultra-high powered (6000x)
magnification. Initial studies have shown that intracytoplasmic morphologically selected sperm injection (IMSI), using spermatozoa
selected under high magnification, is associated with higher pregnancy rates in couples with repeated implantation failures.
Search date: we searched the medical literature in May 2013 for studies that evaluated the effectiveness and safety of using ultra-high
magnification (over 6000x) for sperm selection prior to ICSI, compared with the use of a conventional ICSI procedure, with a 200-
400x magnification.
Study characteristics: we found nine randomised controlled trials, evaluating 2014 couples, that had compared regular ICSI with IMSI
for assisted reproduction. These studies were funded by fertility centres and universities.
Key results and quality of the evidence: for live birth, there was low-quality evidence compatible with either benefit or harm: for women
with a 38% chance of achieving live birth using regular ICSI, the chance of achieving live birth using ultra-high magnification (IMSI)
would be between 30% and 63%. For clinical pregnancy, there was very-low-quality evidence compatible with benefit: for women
with a 33% chance of achieving pregnancy using regular ICSI, the chance of achieving pregnancy using IMSI would be between 36%
and 52%; the quality of this evidence was downgraded because of imprecision, inconsistency of the observed effect across studies,
and high risk of publication bias. For miscarriage, there was very-low-quality evidence compatible with either benefit or harm: for
pregnant women with an 22% risk of miscarriage using regular ICSI, the risk using IMSI would be between 13% and 25%. There was
no evidence concerning congenital abnormalities. We concluded that the current evidence does not support using IMSI: there is no
evidence of benefit for live birth and miscarriage, we are very uncertain of the beneficial effect of IMSI in clinical pregnancy, and there
is no evidence of the effect of this intervention on congenital abnormalities. More studies to improve the evidence quality are necessary
before recommending IMSI in clinical practice.
Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Regular (ICSI) compared with ultra-high magnification (IMSI) for assisted reproduction
Patient or population: couples undergoing assisted reproduction techniques

Intervention: sperm selection under ultra-high magnification (IMSI)
Comparison: sperm selection under regular magnification (ICSI)
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
ICSI IMSI NNTB
Live birth per allocated 38 per 100 44 per 100 - RR 1.14 (0.79 to 1.64) 168
couple (30 to 63) (1 study) low1
Clinical pregnancy per 33 per 100 43 per 100 10 RR 1.29 (1.06 to 1.55) 2014
allocated couple (36 to 52) (5 to 33) (9 studies) very low2
Miscarriage per clinical 22 per 100 18 per 100 - RR 0.82 (0.59 to 1.14) 552
pregnancy (13 to 25) (6 studies) very low3
Congenital abnormali- No evidence.

ties per clinical preg-
nancy
The median control group risk across studies was used as the basis for the assumed risk. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the
comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ICSI: intracytoplasmic sperm injection; IMSI: intracytoplasmic morphologically selected sperm injection; NNTB: number needed to treat for an additional beneficial
outcome; RR: risk ratio.
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
3
Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction (Review)
1. The quality of the evidence was downgraded two levels due to very serious imprecision.
2. The quality of the evidence was downgraded one level due to the high risk of bias in the included studies; another level due to
inconsistency across studies; and one further level because publication bias was strongly suspected.
3. The quality of the evidence was downgraded two levels due to very serious imprecision; and another level due to the high risk of bias
in the included studies.
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4
Why it is important to do this review
BACKGROUND
Initial reports have shown that IMSI is associated with higher
pregnancy rates in couples with repeated implantation failures (
Bartoov 2002; Bartoov 2003). However, both the effectiveness
and safety of IMSI in clinical practice remain unclear. Since there
Description of the condition
are no large published studies, a systematic review of the best
Subfertility is a condition found in up to 15% of couples of re- available evidence is needed to facilitate a more robust conclusion.
productive age and until the late 1970s, there were few options Although a systematic review and meta-analysis on this issue has
for treating these couples. Since the first successful in vitro fer- been published (Setti 2010), the authors of that review evaluated a
tilisation (IVF) was described, the efficacy of subfertility treat- single database (MEDLINE) and supplemented the evidence from
ment has greatly improved. However, it was soon realised that the a single randomised controlled trial (RCT) with non-randomised
technique had great limitations in achieving pregnancy in couples studies to improve precision, which is poorly justifiable, as this
with compromised semen parameters. During the 1980s, some decision increases the risk of obtaining a biased estimate (Higgins
other assisted reproductive technology techniques (ART) were de- 2011). The present review aims to perform a wider and updated
veloped focusing on gamete micromanipulation. However, for all search, considering only the evidence from RCTs .
these techniques, spermatozoa had to be progressively motile and
needed to have the potential for an acrosome reaction, leaving in-
fertility due to severe male factors inadequately treated. Then, in
1992, the first successful intracytoplasmic sperm injection (ICSI) OBJECTIVES
was reported (Palermo 1992). For ICSI, after sperm preparation
an optical magnification of 200x to 400x is used to examine the To compare the effectiveness and safety of IMSI and ICSI in cou-
sample. The best normal looking motile spermatozoa are selected ples undergoing ART.
based on their major morphology and then injected into oocytes
retrieved after ovarian stimulation. With ICSI, even men with se-
vere male factor infertility could possibly achieve pregnancy. How- METHODS
ever, despite 20 years of technological improvements, both clini-
cal pregnancy and live birth rates remain relatively low at approx-
imately 35% and 25% per started cycle, respectively (Jungheim Criteria for considering studies for this review
2010).
Types of studies
We considered only RCTs for inclusion; we excluded quasi- or
Description of the intervention pseudo-randomised trials. We included studies that allowed the
inclusion of the same participant more than once (cross-over or
In the early 2000s, a new method of sperm selection named motile per cycle trials) only if we could obtain the data regarding the
sperm organelle morphology examination (MSOME) was de- first inclusion of each participant.
scribed (Bartoov 2002). This technique requires the analysis of
minor morphological criteria using ultra-high magnification (
6000x) microscopy. The ART using MSOME to select the sperm Types of participants
was named intracytoplasmic morphologically selected sperm in- Couples undergoing ART.
jection (IMSI) (Bartoov 2003). When using this technique, the
motile sperm fraction is examined based on six subcellular or- Types of interventions
ganelles: acrosome, postacrosomal lamina, neck, mitochondria,
Intracytoplasmic injection of sperm selected under high magnifi-
tail, and nucleus.
cation ( 6000x = IMSI) compared to intracytoplasmic injection
of sperm selected under regular magnification (200x to 400x =
ICSI).
How the intervention might work

Types of outcome measures
By using MSOME, some organelle malformations that are not
detectable using magnifications of 200x to 400x can be detected.
Sperm selection based on these small details is thought to improve Primary outcomes
reproductive outcomes (Berkovitz 2006). Effectiveness: live birth per allocated couple.
Secondary outcomes We searched for similar reviews in the Database of Abstracts of
Effectiveness: clinical pregnancy per allocated couple. Reviews of Effects (DARE) (Appendix 11).
Adverse events: miscarriage per clinical pregnancy; congenital ab-
normalities per live birth. Searching other resources
Although fertilisation and implantation rates were important out-
We handsearched the reference lists of included articles and related
comes for this review, we did not include them in the quantita-
reviews.
tive meta-analysis due to use of differing denominators (injected
oocytes for fertilisation rate and transferred embryos for implan-
tation rate). However, we included implantation and fertilisation
rates in the review for completeness, and describe them in the Data collection and analysis
Characteristics of included studies table. We conducted data collection and analyses in accordance with the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011).
Search methods for identification of studies
We developed the search strategy in consultation with the Men- Selection of studies
strual Disorders and Subfertility Group (MDSG) Trials Search Two review authors (DMT and MAPB) independently reviewed
Co-ordinator. We did not limit searches by language or publica- titles and abstracts, and checked for duplicates using the pre-es-
tion status. tablished criteria for inclusion. We resolved disagreements by con-
sulting a third review author (WPM). We retrieved the full-text
manuscripts of trials considered potentially eligible for inclusion
Electronic searches and two review authors (DMT and MAPB) independently evalu-
We performed the electronic searches on 31 August 2012 and ated eligibility of these trials. We resolved disagreements by con-
updated them on 8 May 2013. sulting a third review author (WPM). We corresponded with study
We searched for RCTs in the following electronic databases: investigators as required to clarify study eligibility. We placed no
MDSG Specialised Register (Appendix 1; inception to 8 limitations regarding language, publication date or publication
May 2013); status.
Cochrane Central Register of Controlled Trials
(CENTRAL) (Appendix 2; 2013, Issue 2);
Data extraction and management
MEDLINE (Appendix 3; 1946 to 8 May 2013), this search
was combined with the Cochrane highly sensitive search strategy We extracted data from eligible studies using a data extraction form
for identifying randomised trials (Higgins 2011); designed and pilot-tested by the review authors. Where studies
EMBASE (Appendix 4; 1980 to 8 May 2013), this search had multiple publications, we used the main trial report as the
was combined with trial filters developed by the Scottish reference and obtained additional details from secondary papers.
Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk); We contacted study authors in order to resolve any data queries, as
CINAHL (www.ebscohost.com/cinahl/) (Appendix 5; required. Two review authors (DMT and WPM) independently
inception to 7 May 2013); extracted the data and any disagreements between these review
LILACS (regional.bvsalud.org) (Appendix 6; inception to 7 authors were resolved by consulting a third review author (CON).
May 2013);
PsycINFO (Appendix 7; inception to 8 May 2013). Assessment of risk of bias in included studies
We searched for study protocols and ongoing trials in the following Two review authors (DMT and WPM) independently assessed
trials registers (Appendix 8): the risk of selection bias (random sequence generation and allo-
ClinicalTrials.gov (clinicaltrials.gov); cation concealment); performance bias (blinding of participants
Current Controlled Trials (www.controlled-trials.com); and personnel); detection bias (blinding of outcome assessors); at-
World Health Organization (WHO) International Clinical trition bias (incomplete outcome data); reporting bias (selective
Trials Registry Platform search portal (apps.who.int/trialsearch/ outcome reporting); and other potential sources of bias (e.g. a dif-
Default.aspx). ference in the number of embryos transferred, age of participants,
co-interventions). We resolved any disagreements by consulting a
We searched for conference abstracts in the Web of Knowledge third review author (CON). To judge the risk of bias, we used The
(http://wokinfo.com; Appendix 9). Cochrane Collaborations criteria for judging risk of bias (Higgins
We searched for grey literature in Open Grey (www.opengrey.eu/) 2011): we classified the trials as being at low, high, or unclear
(Appendix 10). risk of bias.
Measures of treatment effect Assessment of reporting biases
For dichotomous data (e.g. live birth rates), we used the numbers In view of the difficulty of detecting and correcting for publica-
of events in the control and intervention groups of each study to tion bias and other reporting biases, we aimed to minimise their
calculate the Mantel-Haenszel risk ratio (RR). We prefer to use potential impact by ensuring a comprehensive search for eligible
RR because odds ratio (OR) is harder to understand and apply studies and by being alert for duplication of data. Even though
in practice. Misinterpretation of the OR as if it equated to the only nine studies were included, a funnel plot was used to explore
RR will tend to overestimate the intervention effect, especially the possibility of small studies effect (a tendency for estimates of
when events are common, and there is concern that this occurs the intervention effect to be more beneficial in smaller studies) for
quite frequently in published reports of individual studies and clinical pregnancy.
systematic reviews (Higgins 2011). However, if we had observed a
zero cell count or prevalence less than 1%, the Peto fixed-effect OR
would have been used because this method is found to be the least Data synthesis
biased and most powerful, providing the best confidence interval We combined the data from primary studies to compare IMSI
(CI) coverage in these situations (Higgins 2011); in additional versus ICSI. An increased risk of a particular outcome associated
the OR value in such situations is very similar to RR, avoiding with IMSI, which may be beneficial (e.g. live birth) or detrimental
misinterpretations. We calculated the 95% CI to determine the (e.g. miscarriage), was displayed graphically in the meta-analysis
precision of the estimates. We considered the clinical relevance of to the right of the centre line and a decreased risk to the left of the
any statistically significant findings; in these situations, we also centre line.
determined the number needed to treat for an additional beneficial
outcome (NNTB) or an additional harmful outcome (NNTH).
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses if sub-
Unit of analysis issues stantial heterogeneity (I2 > 50%) was observed.
The primary analysis was per couple randomised. Exceptions were Sperm quality: studies including only couples where the
miscarriage, where we considered the number of clinical pregnan- male partner had poor sperm quality, or partners with good or
cies in each group as the denominator, because miscarriage is a unselected sperm quality.
harm that can only occur in pregnant women; and congenital ab- Sperm source: ejaculate or surgical.
normalities, which would be analysed per live birth (but this out- Previous unsuccessful embryo transfers: studies including
come was not reported by any study). We did not find any studies only women with repeated previous unsuccessful embryo
that permitted the participant to be included more than once, as transfers, or any women.
cross-over or per cycle trials. We counted the delivery of a mul-
However, we could only perform the first subgroup analysis as no
tiple pregnancy (e.g. twins or triplets) as one live birth event.
studies evaluated only sperm obtained from surgical procedures or
only women with repeated previous unsuccessful embryo transfers.
Dealing with missing data
We analysed the results on an intention-to-treat (ITT) basis, as far Sensitivity analysis
as possible, and we contacted most of the original investigators to We performed sensitivity analyses to verify whether the conclu-
obtain missing data. We planned that where these data were unob- sions about live birth and clinical pregnancy would differ if eligi-
tainable, clinical pregnancy (and subsequent live birth or miscar- bility was restricted to studies without high risk of bias.
riage) would be assumed not to have occurred in participants with
unreported outcomes. This was not necessary, because all studies
reported the occurrence of clinical pregnancy after embryo trans- Overall quality of the body of evidence: Summary of
fer for all participants. findings table
We generated a Summary of findings table using GRADEpro
software. This table evaluated the overall quality of the body of evi-
Assessment of heterogeneity dence for the main review outcomes, using the following GRADE
We assessed heterogeneity using the I2 statistic and addressed sub- criteria: study limitations (i.e. risk of bias), consistency of effect,
stantial heterogeneity (I2 > 50%) by: checking again that the data imprecision, indirectness, and publication bias. Judgements about
were correct; performing the planned subgroup analysis; excluding evidence quality (high, moderate, low, or very low) were justified,
studies with high risk of bias; and, if it could not be explained, we documented and incorporated into the reporting of results for
incorporated the heterogeneity by using a random-effects model. each outcome.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Results of the search

The search retrieved 270 records after removing duplicates. We
considered 28 to be potentially eligible and examined them for
eligibility. Nine trials (from 12 records) met our inclusion criteria,
and we excluded 11 studies (from 12 records). Three studies are
awaiting classification. The study flow diagram is shown in Figure
1.
Figure 1. Study flow diagram.
Interventions
Included studies
All studies compared regular (ICSI) versus ultra-high magnifica-
tion (IMSI).
Study design and setting
We included nine RCTs in the review. All were single-centre studies
conducted in academic centres from Italy (Antinori 2008), Turkey Outcomes
(Balaban 2011), Brazil (Figueira 2011; Setti 2011; Setti 2012a;
Setti 2012b), Slovenia (Knez 2011; Knez 2012), and Tunisia ( One study reported live birth.
Mahmoud 2011). Nine studies reported clinical pregnancy.
Six studies reported miscarriage.
No studies reported congenital abnormalities.
Participants
The studies included 1002 women in the intervention groups
(IMSI) and 1012 women in the control groups (ICSI). Five studies Excluded studies
included only couples in which the male partner had poor sperm
quality (Antinori 2008; Knez 2011; Knez 2012; Mahmoud 2011; We excluded 11 studies from the review, for the following reasons:
Setti 2011); three included women with advanced maternal age eight were not RCTs (observational studies);
(Figueira 2011; Setti 2012a; Setti 2012b); and one study included three randomly allocated the oocytes, not the couples.
couples who underwent ART without specifying further details
(Balaban 2011). One of the nine trials excluded couples with fe-
male factor infertility (Antinori 2008), and three excluded women
Risk of bias in included studies
with polycystic ovaries syndrome (PCOS) or endometriosis (Knez See table Characteristics of included studies; Figure 2; and Figure
2011; Knez 2012; Setti 2012b). 3 for detailed information.
Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
Allocation
studies might not be designed to evaluate these outcomes, as they
Five of the nine studies were at low risk of selection bias related take longer to be assessed.
to sequence generation, as they used computer randomisation or
a random numbers table. The other four studies did not describe
the method used and were at unclear risk of this bias. Two studies Other potential sources of bias
were at low risk of selection bias related to allocation concealment, We deemed four studies to be at high risk of other bias, because
as they used sealed opaque envelopes prepared by research nurses there were substantial differences regarding the mean number of
(Antinori 2008; Knez 2011). The other seven studies did not oocytes retrieved or embryos transferred between groups, or both
describe the method for allocation concealment and we classified (Figueira 2011; Setti 2011; Setti 2012a; Setti 2012b). We con-
them to be at unclear risk of bias. sidered three studies to be at unclear risk of bias, because there
was insufficient information to compare the number of oocytes
retrieved or embryos transferred, or both, per participant (Knez
Blinding 2011; Knez 2012; Mahmoud 2011). We judged two studies to
be at low risk of other potential sources of bias (Antinori 2008;
We did not consider that blinding of participants, personnel, and
Balaban 2011).
outcome assessors was likely to influence findings for any of the
outcomes evaluated by this review (live birth, pregnancy rates,
miscarriage and congenital malformations). We judged all studies Effects of interventions
to be at low risk of bias in this domain. See: Summary of findings for the main comparison
Incomplete outcome data 1. Ultra-high magnification (IMSI) versus regular

(ICSI) sperm selection for assisted reproduction
We considered all nine studies to be at low risk of bias in this
domain, as they stated that all allocated women were analysed.
Primary outcomes
Selective reporting
We considered all nine studies to be at low risk of selective report- 1. 1 Live birth (effectiveness)
ing bias, because clinical pregnancy was reported by all included No significant difference was observed between the IMSI and ICSI
studies. Although eight studies did not report live birth and nine groups (RR 1.14, 95% CI 0.79 to 1.64, 1 RCT, 168 women, I2 =
studies did not report congenital malformations, we believe these not applicable, low-quality evidence; Analysis 1.1, Figure 4 ).
Figure 4. Forest plot of comparison: 1 Ultra high (IMSI) versus regular magnification (ICSI), outcome: 1.1
Live birth per allocated couple.
1.2 Clinical pregnancy (effectiveness)

Secondary outcomes
IMSI was associated with a significantly higher rate of clinical
pregnancy than ICSI (RR 1.29, 95% CI 1.07 to 1.56, 9 RCTs,
2014 women, I2 = 57%, very-low-quality evidence, Figure 5). The
resulting NNTB was 10 (95% CI 5 to 33).
Figure 5. Forest plot of comparison: 1 Ultra high (IMSI) versus regular magnification (ICSI), outcome: 1.2
Clinical pregnancy per allocated couple.
Subgroup analysis (separating the studies by those that included

only couples with poor sperm quality and those that included cou-
ples with good or unselected sperm quality) did not reduce the ob-
served heterogeneity (Analysis 2.1). Sensitivity analysis restricting
the eligibility to studies without high risk of bias did not change
this estimate. We used a random-effects model to incorporate the
observed heterogeneity. The funnel plot suggested a small studies
effect (Figure 6), and therefore we strongly suspected publication
bias.
Figure 6. Funnel plot of comparison: 1 Ultra high (IMSI) versus regular magnification (ICSI), outcome: 1.2
Clinical pregnancy per allocated couple.
1.3 Miscarriage (adverse events)

Overall completeness and applicability of
No significant difference between the groups was observed in mis- evidence
carriage rates (RR 0.82, 95% CI 0.59 to 1.14, 6 RCTs, 552 women,
I2 = 17%, very-low-quality evidence; Analysis 1.3). The objectives of this review were addressed by the included stud-
ies. Five studies included only couples with poor sperm quality
and four included couples with good or unselected sperm quality;
1.4 Congenital abnormalities (adverse events) however, such subgroup analysis (Analysis 2.1) did not add to the
None of the included studies reported congenital abnormalities. global analysis. No study sorted the participants accordingly the
sperm source - ejaculate or surgical - or by previous unsuccess-
ful embryo transfers. However, the quality of the pooled evidence
does not allow robust conclusions and we are uncertain about the
DISCUSSION true effect of IMSI on the studied reproductive outcomes. In this
way, the review findings do not support the use of IMSI in clinical
Summary of main results practice.
There was no evidence of an effect on live birth (low-quality evi-

dence) or miscarriage (very-low-quality evidence). The use of IMSI
for sperm selection was associated with an improvement in the
Quality of the evidence
clinical pregnancy rate. However, we deemed this evidence to be We considered the pooled evidence to be very-low to low-quality
of very low quality, and therefore we are very uncertain about this (see Summary of findings for the main comparison). Issues such
estimate. No included studies reported congenital abnormalities. as risk of bias in the included studies, imprecision and strong
See Summary of findings for the main comparison for further de- suspicion of publication bias contributed to the downgrading of
tails. the evidence quality.
The evidence of effect on live birth was deemed low-quality be- supplemented evidence from a single RCT with non-RCT stud-
cause only one study reported this outcome, with very serious ies. In accordance to our review, they reported a significant im-
imprecision in the estimate (Balaban 2011). There were only 69 provement in clinical pregnancy rates. However, they observed a
events, and the 95% CI included appreciable harm, no effect, and beneficial effect of IMSI decreasing the risk of miscarriage while
appreciable benefit. we observed no evidence of such effect.
We considered the evidence of effect on clinical pregnancy to be
of very-low-quality. We considered four out of the nine included
studies to be at high risk of potential bias, regarding differences
in the mean number of oocytes retrieved or embryos transferred AUTHORS CONCLUSIONS
between groups, or both (see Assessment of risk of bias in included
studies; Figure 3). In addition, there was inconsistency across the Implications for practice
included studies; and publication bias was strongly suspected, as
funnel plot analysis (Figure 6) suggested a small studies effect. The current evidence from randomised controlled trials does not
Regarding miscarriage, we considered the evidence to be of very- support the clinical use of intracytoplasmic sperm injection (in-
low-quality. This occurred because the four out of six studies that tracytoplasmic morphologically selected sperm injection (IMSI)):
reported this outcome were considered to be at high risk of bias there is no evidence of effect on live birth or miscarriage and the
related to differences in the mean number of oocytes retrieved or evidence that IMSI improves clinical pregnancy is of very low qual-
embryos transferred between groups, and there was also very seri- ity. There is no evidence regarding the effect of this intervention
ous imprecision in the estimate. There were only 107 miscarriages on the risk of congenital abnormalities. Further trials are neces-
across both groups, and the 95% CI was compatible with both sary to improve the quality of the evidence before recommending
appreciable harm and no effect. IMSI in clinical practice.
There was no evidence from RCTs on the effect of IMSI on con-
genital abnormalities. Implications for research
More studies are needed to evaluate the effect of IMSI on live birth,
clinical pregnancy, miscarriage, and congenital abnormalities.
Potential biases in the review process
We did not identify potential biases in the review process.
ACKNOWLEDGEMENTS
We acknowledge the important help provided by Helen Nagels,
Agreements and disagreements with other Managing Editor from the Cochrane Menstrual Disorders and
studies or reviews Subfertility Group, and by Marian Showell, Trials Search Co-or-
Another review evaluated the effect of IMSI (Setti 2010). It in- dinator for the Cochrane Menstrual Disorders and Subfertility
cluded studies recovered from a single database (MEDLINE) and Group.
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[PUBMED: 18549694] FF, Iaconelli A, Borges E. The role of morphological

Antinori S, Licata E, Dani G, Cerusico F, Versaci C, nuclear integrity of the sperm cells in preimplantation
Antinori M. A prospective randomized trial to verify the genetic aneuploidy screening cycles outcome. Journal fur
efficacy of IMSI procedure in daily IVF routine. Human Reproduktionsmedizin und Endokrinologie 2010;7:2501.
Reproduction 2008;23 Suppl 1:i165.
Figueira RDC, Braga DP, Setti AS, Iaconelli A Jr,
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A, Urman B. Clinical outcome of intracytoplasmic screening cycle outcomes. Fertility and Sterility 2011;95(3):
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Knez K, Zorn B, Tomazevic T, Vrtacnik-Bokal E, Virant- Berkovitz 2005 {published data only}
Klun I. The IMSI procedure improves poor embryo Berkovitz A, Eltes F, Yaari S, Katz N, Barr I, Fishman A,
development in the same infertile couples with poor et al.The morphological normalcy of the sperm nucleus
semen quality: a comparative prospective randomized and pregnancy rate of intracytoplasmic injection with
study. Reproductive Biology and Endocrinology 2011;9:123. morphologically selected sperm. Human Reproduction
[PUBMED: 21875440] 2005;20(1):18590. [PUBMED: 15471930]
Knez 2012 {published data only}
Berkovitz 2006 {published data only}
Knez K, Tomazevic T, Zorn B, Vrtacnik-Bokal E,
Berkovitz A, Eltes F, Lederman H, Peer S, Ellenbogen A,
Virant-Klun I. Intracytoplasmic morphologically selected
Feldberg B, et al.How to improve IVF-ICSI outcome by
sperm injection improves development and quality of
sperm selection. Reproductive Biomedicine Online 2006;12
preimplantation embryos in teratozoospermia patients.
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Reproductive Biomedicine Online 2012;25(2):16879.
[PUBMED: 22717245] Braga 2011 {published data only}
Mahmoud 2011 {published data only} Braga DPAF, Setti AS, Figueira RC, Nichi M, Martinhago
Mahmoud K, Triki-Hmam C, Terras K, Zhioua F, Hfaiedh CD, Iaconelli A Jr, et al.Sperm organelle morphologic
T, Ben Aribia MH. How and in which indication the IMSI abnormalities: contributing factors and effects on
could improve outcomes?. Human Reproduction 2011;26 intracytoplasmic sperm injection cycles outcomes. Urology
Suppl 1:i181. 2011;78(4):78691. [PUBMED: 21820702]
Setti 2011 {published data only} Cassuto 2011 {published data only}
Setti AS, Figueira Rde C, Braga DP, Iaconelli A Jr, Borges Cassuto NG, Hazout A, Benifla JL, Balet R, Larue L,
E Jr. Intracytoplasmic morphologically selected sperm Viot G. Decreasing birth defect in children by using high
injection benefits for patients with oligoasthenozoospermia magnification selected spermatozoon injection. Fertility and
according to the 2010 World Health Organization Sterility 2011;1:S85.
reference values. Fertility and Sterility 2011;95(8):27114.
De Vos 2013 {published data only}
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De Vos A, Van de Velde H, Bocken G, Eylenbosch G,
Setti 2012a {published data only} Franceus N, Meersdom G, et al.Does intracytoplasmic
Iaconelli JA, Figueira RCS, Setti AS, Braga DPAF, morphologically selected sperm injection improve embryo
Pasqualotto EE, Borges E Jr. Gender incidence on development? A randomized sibling-oocyte study. Human
intracytoplasmic morphologically selected sperm injection Reproduction 2013;28:61726.
approach: a prospective randomized study. Human
Reproduction 2011;26 Suppl 1:i71. Hazout 2005 {published data only}
Hazout A, Dumont-Hassan M, Junca AM, Cohen
Setti AS, Figueira RC, Braga DP, Iaconelli A Jr, Borges E
Jr. Gender incidence of intracytoplasmic morphologically Bacrie P, Tesarik J. High-magnification ICSI overcomes
selected sperm injection-derived embryos: a prospective paternal effect resistant to conventional ICSI. Reproductive
randomized study. Reproductive BioMedicine Online 2012; Biomedicine Online 2005;12(1):1924. [PUBMED:
24(4):4203. [PUBMED: 22377154] 16454928]
Setti 2012b {published data only} Mauri 2011 {published data only}
Setti AS, Figueira, RDC, de Almeida Ferreira Braga DP, Mauri AL, Petersen CG, Oliveira JB, Massaro FC, Baruffi
Iaconelli A, Borges E. IMSI is beneficial in cases of advanced RL, Franco JG Jr. Comparison of day 2 embryo quality after
maternal age: a prospective randomized study. Reproductive conventional ICSI versus intracytoplasmic morphologically
BioMedicine Online 2012;Withdrawn. [DOI: 10.1016/ selected sperm injection (IMSI) using sibling oocytes.
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Biology 2011;150(1):426. [PUBMED: 20171776]
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Oliveira 2011 {published data only}
Apryshko 2010 {published data only}
Oliveira JBA, Cavagna M, Petersen CG, Mauri
Apryshko VP, Yakovenko SA, Sivozhelezov VS, Yutkin EV, AL, Massaro FC, Silva LFI, et al.Pregnancy outcomes
Rutman BK, Troshina MN, et al.IMSI based on Hoffman in women with repeated implantation failures after
modulation contrast: 5 years experience. Reproductive intracytoplasmic morphologically selected sperm injection
BioMedicine Online 2010;20:S25. (IMSI). Reproductive Biology and Endocrinology 2011;9:99.
Bartoov 2003 {published data only} [PUBMED: 21781299]
Bartoov B, Berkovitz A, Eltes F, Kogosovsky A, Yagoda Oliveira JBA, Petersen CG, Mauri AL, Massaro FC, Baruffi
A, Lederman H, et al.Pregnancy rates are higher with RLR, Franco JG Jr. Clinical outcomes of IMSI in previous
intracytoplasmic morphologically selected sperm injection ICSI failures. Fertility and Sterility 2010;1:S55.
Wilding 2011 {published data only} Bartoov 2002
Wilding M, Coppola G, di Matteo L, Palagiano A, Fusco Bartoov B, Berkovitz A, Eltes F, Kogosowski A, Menezo
E, Dale B. Intracytoplasmic injection of morphologically Y, Barak Y. Real-time fine morphology of motile human
selected spermatozoa (IMSI) improves outcome after sperm cells is associated with IVF-ICSI outcome. Journal of
assisted reproduction by deselecting physiologically poor Andrology 2002;23(1):18. [PUBMED: 11780915]
quality spermatozoa. Journal of Assisted Reproduction and Higgins 2011
Genetics 2011;28(3):25362. [PUBMED: 21072684] Higgins JPT, Green S (editors). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
References to studies awaiting assessment [updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Check 2013 {published data only} Jungheim 2010
Check JH, Bollendorf A, Summers-Chase D, Yuan W, Jungheim ES, Ryan GL, Levens ED, Cunningham AF,
Horwath D. Isolating sperm by selecting those with normal Macones GA, Carson KR, et al.Embryo transfer practices
nuclear morphology prior to intracytoplasmic sperm in the United States: a survey of clinics registered with the
injection (ICSI) does not provide better pregnancy rates Society for Assisted Reproductive Technology. Fertility and
compared to conventional ICSI in women with repeated Sterility 2010;94(4):14326. [PUBMED: 19748089]
conception failure with in vitro fertilization. Clinical and Palermo 1992
Experimental Obstetrics & Gynecology 2013;40:157. Palermo G, Joris H, Devroey P, Van Steirteghem AC.
Pregnancies after intracytoplasmic injection of single
Parinaud 2013 {unpublished data only}
spermatozoon into an oocyte. Lancet 1992;340(8810):
Setti 2012c {published data only} 178. [PUBMED: 1351601]
Setti AS, Braga DPAF, Figueira RCS, Colturato SS, Setti 2010
Iaconelli A, Borges E. Intracytoplasmic morphologically Setti AS, Ferreira RC, Braga DPAF, Figueira RCS, Iaconelli
selected sperm injection (IMSI) benefits in the presence of A Jr, Borges E Jr. Intracytoplasmic sperm injection
unexplained infertility: a prospective randomized study. outcome versus intracytoplasmic morphologically selected
Fertility and Sterility 2012; Vol. 98 Suppl 1, issue 3:S80. sperm injection outcome: a meta-analysis. Reproductive
Biomedicine Online 2010;21(4):4505. [PUBMED:
Additional references 20800549]

Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Antinori 2008
Methods Randomised controlled trial conducted in a private assisted reproduction centre (Italy).
Period of enrolment not reported
Participants Inclusion criteria: at least 2 previous diagnoses of severe oligoasthenospermia; 3 years

of primary infertility; absence of female factor
Interventions Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnifica-
tion (IMSI): on the basis of MSOME criteria, the examination and spermatozoa selec-
tion for IMSI procedure was performed in real time using an inverted light microscope
equipped with high-power Nomarski optics, enhanced by digital imaging to achieve
a magnification up to 6300x, and the Eppendorf Micromanipulation System (Trans-
fer-Man NK2, Eppendorf, Germany). Only spermatozoa with normal head dimension
(length 4.75 0.28 m; width 3.28 0.20 m) and shape, with no or maximum 1 vac-
uole (0.78 0.18 m) were microinjected; spermatozoa with abnormal head size were
excluded (such spermatozoa were identified by superimposing a transparent celluloid
form representing the correct spermatozoon size on the examined gametes). 2 sperma-
tozoa for each oocyte were selected to be inseminated using the classical ICSI technique
Control: oocytes injected with spermatozoon selected under regular magnification
(ICSI): no further details
Outcomes Clinical pregnancy, miscarriage, and implantation rates.
Notes We considered 2 publications to be related to the same study although the numbers of
participants were not the same, because the only difference we observed was that the
newer publication had evaluated more participants; the authors did not answer our e-
mails to resolve these data queries
Live birth and congenital abnormalities not reported.
Implantation rate: 23.0% (IMSI) vs. 16.6% (ICSI); P value not reported.
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection Unclear risk Not reported.

bias)
Allocation concealment (selection bias) Low risk Sealed, opaque envelopes prepared by a re-
search nurse.
Blinding of participants and personnel Low risk Blinding of participants and personnel was
(performance bias) not considered as a potential source of bias
All outcomes
Antinori 2008 (Continued)
Blinding of outcome assessment (detection Low risk Blinding of outcome assessment was not
bias) considered as a potential source of bias
All outcomes
Incomplete outcome data (attrition bias) Low risk No loss to follow-up.

All outcomes
Selective reporting (reporting bias) Low risk Not suspected.
Other bias Low risk None.
Balaban 2011
Methods Randomised controlled trial conducted in a private assisted reproduction centre (Turkey)
between February and July 2009
Participants Eligibility criteria: unselected women undergoing assisted reproduction treatment

tion (IMSI). The procedure was performed in real time using an inverted microscope
(Olympus IX-71; Japan) with actual digitally enhanced magnification, as determined by
a 0.01 mm Olympus objective micrometer, at 6300x. Normal-shaped nuclei were de-
fined as smooth, symmetric, having an oval configuration, with mean length and width
limits of 4.75 0.28 and 3.28 0.20 m, respectively, with a homogeneous nuclear
chromatin mass with no regional nuclear disorders and containing no more than one
small vacuole with a borderline diameter of 0.78 0.18 m. Mean time needed for
IMSI = 21 minutes
(ICSI): not specified; the mean time needed for regular ICSI = 14 minutes
Outcomes Duration of ICSI procedure; 2-pronuclei fertilisation rate; embryos with 4 blastomeres
on day 2 post fertilisation; embryos with 8 blastomeres on day 3 post fertilisation; grade 1
and 2 embryos on transfer day; clinical pregnancy; live birth; implantation; and multiple
pregnancy rate
Notes Miscarriage and congenital abnormalities not reported.

Implantation rate: 66/228 = 28.9% (IMSI) vs. 42/215 = 19.5% (ICSI); P value = 0.02
(however, study authors reported that P = NS [not significant])
Risk of bias
Random sequence generation (selection Low risk Computer-generated randomisation list.

bias)
Allocation concealment (selection bias) Unclear risk Not reported.
Balaban 2011 (Continued)
All outcomes
All outcomes

All outcomes
Other bias Low risk None.
Figueira 2011
Methods Randomised controlled trial conducted in a private assisted reproduction centre (Brazil)
between May and December 2009
Participants Eligibility criteria: women undergoing assisted reproduction treatment in conjunction

with pre-implantation genetic screening for aneuploidy, as a result of advanced maternal
age; sperm concentration > 1,000,000/mL and sperm motility > 20%; at least 6 oocytes
available on oocyte retrieval

Intervention: oocytes injected with spermatozoon selected under ultra-high magnifi-
cation (IMSI): sperm morphology selection was assessed using an inverted Nikon Di-
aphot microscope (Eclipse TE 300; Nikon, Tokyo) equipped with high-power DIC
(Nomarski). The total calculated magnification was 6600x. The sperm cells exhibiting
normally shaped nuclei (smooth, symmetric, and oval configuration) and normal nuclear
chromatin content (if it contained no more than 1 vacuole, which occupies < 4% of the
nuclear area) were selected for injection
(ICSI): sperm morphology selection was assessed using an inverted Nikon Diaphot mi-
croscope (Eclipse TE 300; Nikon, Tokyo) with a Hoffmann modulation contrast system
under 400x magnification
Outcomes Sperm nuclear morphology at high-magnification ICSI; incidence of aneuploidy in de-

rived embryos; clinical pregnancy rate
Notes All embryos were submitted to pre-implantation genetic diagnosis and aneuploidy screen-
ing. On the morning of day 3 of embryo development, 1 cell per embryo was biopsied
by laser zona drilling using a 1.48 mm infrared diode laser (Octax Laser Shot System,
MTG, Bruckberg, Germany). After the biopsies, the embryos were returned to the cul-
ture medium. The removed blastomere nuclei were spread using 0.1 N HCl and 0.01%
Tween 20 (Sigma, Dorset, UK). Briefly, the individual nuclei were placed on a slide in 1
drop of HCl-Tween spreading solution and observed until the cell had lysed. The slides
Figueira 2011 (Continued)
were then air dried and dehydrated before FISH analysis was performed. All embryos
were analysed for chromosomes X, Y, 13, 16, 18, 21, and 22. For the purpose of this
study, the blastomeres were classified as normal when 2 sexual and 2 of each tested auto-
somal chromosomes were present. Blastomeres with 2 or more chromosomal numerical
abnormalities were classified as chaotic. Embryos with abnormal findings in biopsied
nuclei were not submitted for re-analysis. Embryo transfer was performed on day 4 using
a soft catheter with transabdominal ultrasound guidance. Only the embryos found to
be chromosomally normal were considered for embryo transfer, and a maximum of 3
embryos were transferred. The cycle was cancelled if normal embryos were absent after
FISH
Implantation rate: 55.6% (IMSI) vs. 40.9% (ICSI); P value = 0.59.
Study authors were contacted to clarify information about the 4 different included
studies, from the same groups of authors (Figueira 2011; Setti 2011; Setti 2012a; Setti
2012b). All questions on methods of randomisation, patient overlapping, and data per
woman were clarified
Risk of bias
Random sequence generation (selection Low risk Computer-generated balanced table in sets
bias) of 10.
All outcomes
All outcomes

All outcomes
Other bias High risk The number of oocytes retrieved and em-
bryos transferred were significantly differ-
ent between groups (P value < 0.01). In the
article, study authors reported that differ-
ences were not significant (P value = 0.20
and P value = 0.17, oocytes retrieved and
embryos transferred, respectively)
Knez 2011
Methods Randomised controlled trial conducted in an academic setting (Slovenia) between Oc-
tober 2009 and June 2010
Participants Eligibility criteria: all embryos arrested after prolonged 5-day embryo culture to the
blastocyst stage in their previous conventional ICSI attempts; poor semen quality charac-
terised by the incidence of teratozoospermia by less than 14% of morphologically normal
sperm according to the Strict Kruger Criteria, oligozoospermia by a sperm concentration
of < 20 million/mL and asthenozoospermia by < 50% of motile sperm according the
WHO criteria; women without PCOS or endometriosis and age < 42 years

tion (IMSI): sperm were selected in dishes with a glass bottom (GWSt 1000; Will Co.,
Wells BV, Amsterdam, The Netherlands) and monitored under an inverted microscope
with a heated stage equipped with DIC (Nikon ECLIPSE TE2000-S, Japan). Approxi-
mately 5 elongated droplets of SpermSlow medium (Origio, Denmark) were placed on
the bottom of a glass dish to immobilise the sperm. A smaller droplet of prepared sperm
was placed near each SpermSlow droplet. Then the connections were made between
the sperm and the SpermSlow droplets for sperm to swim into the SpermSlow droplets
and to bind to the HA. All droplets were covered with paraffin oil (Origio, Denmark)
. For observation under 6000x magnification, a droplet of immersion oil was inserted
underneath the glass dish (under the SpermSlow droplet). One droplet of SpermSlow
with bound sperm was monitored by the immersion objective, DIC, and Nikon Digital
Sight DS-Ri1 camera. The single (mature) sperm that was bound to the HA and had
the best morphology was chosen, aspirated in the microinjection pipette, scored in 3-
dimensions, and evaluated according to the morphology and head vacuoles at 6000x
magnification
(ICSI): the sperm selection for microinjection was performed at a magnification of 200x
to 400x. Sperm with severe head-shape defects clearly seen under the magnification (pin,
amorphous, tapered, round, and multinucleated head) were excluded from microinjec-
tion into the oocyte
Outcomes Fertilisation, blastocyst, implantation, and pregnancy rates
Notes Live birth and congenital abnormalities not reported.

Implantation rate: 6/35 = 17.1% (IMSI) vs. 3/44 = 6.8% (ICSI); P = 0.17.
Study author was contacted to clarify information about the 2 different included studies
(Knez 2011 and Knez 2012). All questions on methods of randomisation, patient over-
lapping, and data per woman were clarified
Risk of bias
Random sequence generation (selection Low risk Computer-generated random numbers

bias) (unrestricted randomisation list)
Knez 2011 (Continued)
Allocation concealment (selection bias) Low risk Sealed, opaque envelopes prepared by a re-
search nurse.
All outcomes
All outcomes

All outcomes
Other bias Unclear risk Study authors did not report the num-
ber of oocytes retrieved in the groups. The
number of transferred embryos per partici-
pant was not significantly different between
groups
Knez 2012
Methods Randomised controlled trial conducted in an academic setting (Slovenia) between Jan-
uary and October 2011
Participants Eligibility criteria: at least 6 mature oocytes available upon oocyte retrieval; isolated
teratozoospermia, which was determined as having < 14% of morphologically normal
spermatozoa according to the Kruger strict criteria, > 15 million spermatozoa per millilitre
and at least 40% motile spermatozoa; women without PCOS or endometriosis

tion (IMSI): a single spermatozoon bound to the HA and with the best morphology was
chosen, aspirated in the microinjection pipette, scored in 3-dimensions and evaluated
according to the morphology and head vacuoles at 6000x magnification
(ICSI): spermatozoa without severe head shape defects clearly seen under the microscope
(pin, amorphous, tapered, round, and multinucleated head) were selected at magnifica-
tion 200x to 400x
Outcomes Fertilisation, blastocyst, implantation, and pregnancy rates
Notes Live birth, miscarriage, and congenital abnormalities not reported

Implantation rate not reported.
Study author was contacted to clarify information about the 2 different included studies
(Knez 2011; Knez 2012). All questions on methods of randomisation, patient overlap-
Knez 2012 (Continued)
ping, and data per woman were clarified
Risk of bias

bias)
All outcomes
All outcomes

All outcomes
Other bias Unclear risk Study authors did not provide the number
of transferred embryos per participant nei-
ther the SD for the number of oocytes re-
trieved (mean 11.0 with IMSI vs. 9.8 with
ICSI)
Mahmoud 2011
Methods Randomised controlled trial conducted in a private assisted reproduction centre (Tunisia)
between April 2009 and November 2010
Participants Eligibility criteria: oligoasthenozoospermia based on WHO references values. Terato-

zoospermia evaluated by the strict criteria of Kruger sperm morphology; healthy woman
aged < 37 years

tion (IMSI): 6600x magnification, using Leica 6800 station
(ICSI)
Outcomes Fertilisation rate, percentage of good-quality embryos, and the rates of clinical pregnancy
and implantation
Mahmoud 2011 (Continued)
Notes Live birth, miscarriage, and congenital abnormalities not reported

Implantation rate: 19.2% (IMSI) vs. 17.2% (ICSI); P value = not significant.
Study authors were not contacted because we were unable to obtain their contact details
Risk of bias

bias)
All outcomes
All outcomes

All outcomes
Other bias Unclear risk Study authors did not report the number of
oocytes retrieved and embryos transferred
Setti 2011
. Period of enrolment not reported
Participants Eligibility criteria: first IVF treatment; abnormal semen parameters according to WHO,
except for azoospermia; use of fresh semen sample; absence of a known female factor
infertility; and at least 6 oocytes available on retrieval

tion (IMSI): sperm selection was examined at high magnification with an inverted mi-
croscope (Eclipse TE 300; Nikon, Tokyo, Japan) equipped with high-power DIC optics
(Nomarski). The total calculated magnification was 6600x
croscope (Eclipse TE 300; Nikon, Tokyo) with a Hoffmann modulation contrast system
under 400x magnification
Setti 2011 (Continued)
Outcomes Clinical pregnancy, implantation rate, and miscarriage.

Implantation rate: 158/664 = 23.8% (IMSI) vs. 28/156 = 25.4% (ICSI); P value = 0.
60
Risk of bias
Random sequence generation (selection Low risk Computer-generated randomisation list.

bias)
All outcomes
All outcomes

All outcomes
ent between groups (P value < 0.01 for
both). In the article, study authors re-
ported that differences were non-signifi-
cant (P value = 0.29 for oocytes retrieved
and P = 0.27 for embryos transferred)
Setti 2012a
between May 2009 and December 2010
Participants Eligibility criteria: women undergoing assisted reproduction treatment in conjunction

with pre-implantation genetic screening for aneuploidy, as a result of advanced maternal
age; no severe spermatogenic alteration; at least 6 oocytes available on oocyte retrieval
Setti 2012a (Continued)

Intervention: oocytes injected with spermatozoon selected under ultra-high magnifi-
cation (IMSI): sperm selection was examined at high magnification using a similar in-
verted microscope equipped with high-power DIC optics (Nomarski). The total cal-
culated magnification was 6600x. The sperm cells exhibiting normally shaped nuclei
(smooth, symmetric, and oval configuration) and normal nuclear chromatin content (if
it contained no more than 1 vacuole, which occupied < 4% of the nuclear area) were
selected for injection
croscope (Eclipse TE 300; Nikon, Tokyo, Japan) with a Hoffmann modulation contrast
system under 400x magnification
Outcomes Clinical pregnancy, implantation rate, miscarriage, and gender incidence
Notes All embryos were submitted to pre-implantation genetic diagnosis and aneuploidy screen-
ing. On the morning of day 3 of embryo development, 1 cell per embryo was biopsied
by laser zona drilling using a 1.48 mm infrared diode laser (Octax Laser Shot System,
MTG, Bruckberg, Germany). Following the biopsies, the embryos were returned to the
culture medium. The removed blastomere nuclei were spread using 0.1 mol/L HCl and
0.01% Tween 20 (Sigma, Dorset, UK). Briefly, the blastomeres were placed on a slide
in a drop of HCl-Tween spreading solution and observed until the cell had lysed. The
slides were then air-dried and dehydrated before FISH analysis was performed. All em-
bryos were analysed for chromosomes X, Y, 13, 16, 18, 21, and 22. For the purpose of
this study, the blastomeres were classified as normal when 2 sexual and 2 of each tested
autosomal chromosomes were present. Embryo transfer was performed on day 5 using a
soft catheter with transabdominal ultrasound guidance. Only the embryos found to be
chromosomally normal were considered for embryo transfer, and up to a maximum of
3 embryos were transferred
Implantation rate: 46.1% (IMSI) vs. 41.6% (ICSI); P value = 0.59.
Risk of bias

bias)
All outcomes
Setti 2012a (Continued)
All outcomes

All outcomes
ent between groups (P value = 0.01). In the
article, study authors reported these differ-
ences as not significant
Setti 2012b
Methods Prospective randomised clinical trial performed in a private fertility centre (Brazil). Period
of enrolment not reported
Participants Eligibility criteria: women of good physical and mental health; undergoing ICSI as a
result of advanced maternal age ( 37 years old); with regular menstrual cycles of 25-35
days; normal basal FSH and LH concentrations; body mass index < 30 kg/m2; presence
of both ovaries and intact uterus; absence of PCOS, endometriosis and gynaecological/
medical disorders; and a negative result in a screening for sexually transmitted diseases. All
male partners were normozoospermic, according to the WHO reference values (2010).
No woman had received any hormone therapy for at least 60 days preceding the study

Intervention: sperm selection in the IMSI group was analysed under high magnification
using an inverted Nikon Diaphot microscope equipped with high-power DIC optics.
The total calculated magnification was 6600x. An aliquot of the sperm cell suspension
was transferred to a microdroplet of modified human tubal fluid medium containing
8% polyvinyl pyrrolidone (Irvine Scientific, Santa Ana, CA, USA) in a sterile glass dish
(FluoroDish; World Precision Instrument, Sarasota, FL, USA). The dish was placed on
a microscope stage above an Uplan Apo 100 oil/1.35 objective lens previously covered
by a droplet of immersion oil. The sperm cells that were selected for injection exhibited
normally shaped nuclei (smooth, symmetric and oval configuration) and normal nuclear
chromatin content (if it contained no more than 1 vacuole that occupied < 4% of the
nuclear area)
Control: sperm selection in the ICSI group was analysed under 400x magnification
using an inverted Nikon Eclipse TE 300 microscope
Outcomes Fertilisation rate, high-quality embryo rate on day 3, blastocyst formation rate, number
of transferred embryos, implantation rate, miscarriage rate and pregnancy rate
Setti 2012b (Continued)

Implantation rate: 38.3% (IMSI) vs. 12.1% (ICSI). P value = 0.03.
This article has been withdrawn. Authors were contacted for more information regarding
the reasons why this happened. Authors had also been contacted to clarify information
about the 4 different included studies, from the same groups of authors (Figueira 2011;
Setti 2011; Setti 2012a; Setti 2012b). All questions on methods of randomisation, patient
overlapping and data per woman were clarified
Risk of bias
Random sequence generation (selection Low risk Computer-generated randomisation table.

bias)
All outcomes
All outcomes
Incomplete outcome data (attrition bias) Low risk No loss of follow-up.

All outcomes
Other bias High risk Although there was no significant differ-

ence in the number of oocytes retrieved,
and despite the total number of embryos
being higher in the ICSI group, more em-
bryos per woman were transferred in the
IMSI group
This article has been withdrawn.
DIC: differential interference contrast; FISH: fluorescent in situ hybridisation; FSH: follicle-stimulating hormone; HA: hyaluronate;
HCl: hydrochloric acid; ICSI: intracytoplasmic sperm injection; IMSI: intracytoplasmic morphologically selected sperm injection;
IVF: in vitro fertilisation; LH: luteinising hormone; MSOME: motile sperm organella morphology examination; PCOS: polycystic
ovaries syndrome; SD: standard deviation; WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Apryshko 2010 Not an RCT (observational study).
Bartoov 2003 Not an RCT (observational study).
Berkovitz 2005 Not an RCT (observational study).
Berkovitz 2006 Not an RCT (observational study).
Braga 2011 Oocytes (not participants) were allocated.
Cassuto 2011 Not an RCT (observational study).
De Vos 2013 Oocytes (not participants) were randomly allocated.
Hazout 2005 Not an RCT (observational study).
Mauri 2011 Oocytes (not participants) were randomly allocated.
Oliveira 2011 Not an RCT (observational study).
Wilding 2011 Not an RCT (observational study).
RCT: randomised controlled trial.
Characteristics of studies awaiting assessment [ordered by study ID]
Check 2013
Methods Prospective randomised clinical trial performed in a fertility centre (USA). Period of enrolment not reported
Participants Eligibility criteria: women aged 39, undergoing ART, with failure to have a successful conception after 3 consec-
utive embryo transfers and whose male partner had a DNA fragmentation index > 30%

Intervention: sperm selection in the ICSI group was analysed under high magnification
Control: sperm selection in the ICSI group was analysed under normal magnification
Outcomes Live birth and pregnancy rate.
Notes Authors were contacted for further information regarding period of enrolment, eligibility criteria and results
Parinaud 2013
Methods Randomised controlled trial conducted in 9 different assisted reproduction centres (France). Period of enrolment not
reported
Participants Eligibility criteria: couples undergoing ICSI due to male infertility, with < 1 million motile spermatozoa recovered
after gradient preparation and at least 3 million sperm cells in the ejaculate. Couples in which the female age was >
38 years or FSH level was > 9.0 mL/mlU were excluded from the study

Intervention: sperm selection in the ICSI group was analysed under 6000x magnification
Outcomes Number of deliveries and implantation rate.
Notes The study was registered at ClinicalTrials.gov and has already been completed. Authors were contacted for further
information, since study has not been published yet
Setti 2012c
Methods Prospective randomised clinical trial performed in a private fertility centre (Brazil). Period of enrolment not reported
Participants Eligibility criteria: women undergoing ICSI as a result of unexplained fertility.

Intervention: sperm selection in the ICSI group was analysed under 6000x magnification
Outcomes Fertilisation rate, high-quality embryo rate, number of transferred embryos, implantation rate and pregnancy rate
Notes Miscarriage, live birth and congenital abnormalities not reported

Implantation rate: 39.6% (IMSI) vs. 19.4% (ICSI). P value = 0.019.
Authors were contacted for further information regarding period of enrolment and eligibility criteria
ART: assisted reproduction technique; DNA: deoxyribonucleic acid; FSH: follicle-stimulating hormone; ICSI: intracytoplasmic sperm
injection; IMSI: intracytoplasmic morphologically selected sperm injection; IU: international units.
DATA AND ANALYSES
Comparison 1. Ultra high (IMSI) versus regular magnification (ICSI)
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Live birth per allocated couple 1 168 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.79, 1.64]
2 Clinical pregnancy per allocated 9 2014 Risk Ratio (M-H, Random, 95% CI) 1.29 [1.07, 1.56]
couple
3 Miscarriage per clinical 6 552 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.59, 1.14]
pregnancy
Comparison 2. IMSI versus ICSI: subgroup analysis by sperm quality
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Clinical pregnancy 9 2014 Risk Ratio (M-H, Random, 95% CI) 1.29 [1.07, 1.56]
1.1 Only poor sperm quality 5 1500 Risk Ratio (M-H, Random, 95% CI) 1.29 [0.98, 1.70]
1.2 Good or unselected sperm 4 514 Risk Ratio (M-H, Random, 95% CI) 1.33 [0.97, 1.82]
quality
Analysis 1.1. Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 1 Live birth per
allocated couple.
Review: Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction
Comparison: 1 Ultra high (IMSI) versus regular magnification (ICSI)
Outcome: 1 Live birth per allocated couple
Study or subgroup IMSI ICSI Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Balaban 2011 38/87 31/81 100.0 % 1.14 [ 0.79, 1.64 ]
Total (95% CI) 87 81 100.0 % 1.14 [ 0.79, 1.64 ]

Total events: 38 (IMSI), 31 (ICSI)
Heterogeneity: not applicable
Test for overall effect: Z = 0.71 (P = 0.48)
Test for subgroup differences: Not applicable
0.05 0.2 1 5 20
Favours ICSI Favours IMSI
Analysis 1.2. Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 2 Clinical
pregnancy per allocated couple.
Outcome: 2 Clinical pregnancy per allocated couple

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Antinori 2008 120/327 78/306 16.3 % 1.44 [ 1.13, 1.83 ]
Balaban 2011 47/87 36/81 13.8 % 1.22 [ 0.89, 1.66 ]
Figueira 2011 32/60 28/60 12.3 % 1.14 [ 0.80, 1.64 ]
Knez 2011 5/20 3/37 1.9 % 3.08 [ 0.82, 11.59 ]
Knez 2012 25/52 17/70 8.6 % 1.98 [ 1.20, 3.27 ]
Mahmoud 2011 41/93 42/95 13.5 % 1.00 [ 0.72, 1.38 ]
Setti 2011 93/250 92/250 16.7 % 1.01 [ 0.80, 1.27 ]
Setti 2012a 43/80 36/80 13.6 % 1.19 [ 0.87, 1.64 ]
Setti 2012b 18/33 4/33 3.2 % 4.50 [ 1.71, 11.87 ]
Total (95% CI) 1002 1012 100.0 % 1.29 [ 1.07, 1.56 ]

Heterogeneity: Tau2 = 0.04; Chi2 = 18.76, df = 8 (P = 0.02); I2 =57%
0.05 0.2 1 5 20
Analysis 1.3. Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 3 Miscarriage
per clinical pregnancy.
Outcome: 3 Miscarriage per clinical pregnancy

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Antinori 2008 20/120 18/78 36.9 % 0.72 [ 0.41, 1.28 ]
Figueira 2011 0/32 1/28 2.7 % 0.29 [ 0.01, 6.91 ]
Knez 2011 0/5 2/3 5.1 % 0.13 [ 0.01, 2.11 ]
Setti 2011 29/93 28/92 47.6 % 1.02 [ 0.67, 1.58 ]
Setti 2012a 0/43 3/36 6.4 % 0.12 [ 0.01, 2.25 ]
Setti 2012b 6/18 0/4 1.3 % 3.42 [ 0.23, 51.03 ]
Total (95% CI) 311 241 100.0 % 0.82 [ 0.59, 1.14 ]

Heterogeneity: Chi2 = 6.00, df = 5 (P = 0.31); I2 =17%
0.05 0.2 1 5 20
Favours IMSI Favours ICSI
Analysis 2.1. Comparison 2 IMSI versus ICSI: subgroup analysis by sperm quality, Outcome 1 Clinical
pregnancy.
Comparison: 2 IMSI versus ICSI: subgroup analysis by sperm quality
Outcome: 1 Clinical pregnancy

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Only poor sperm quality
Antinori 2008 120/327 78/306 16.3 % 1.44 [ 1.13, 1.83 ]
Knez 2011 5/20 3/37 1.9 % 3.08 [ 0.82, 11.59 ]
Knez 2012 25/52 17/70 8.6 % 1.98 [ 1.20, 3.27 ]
Mahmoud 2011 41/93 42/95 13.5 % 1.00 [ 0.72, 1.38 ]
Setti 2011 93/250 92/250 16.7 % 1.01 [ 0.80, 1.27 ]
Subtotal (95% CI) 742 758 57.0 % 1.29 [ 0.98, 1.70 ]

2 Good or unselected sperm quality
Balaban 2011 47/87 36/81 13.8 % 1.22 [ 0.89, 1.66 ]
Figueira 2011 32/60 28/60 12.3 % 1.14 [ 0.80, 1.64 ]
Setti 2012a 43/80 36/80 13.6 % 1.19 [ 0.87, 1.64 ]
Setti 2012b 18/33 4/33 3.2 % 4.50 [ 1.71, 11.87 ]
Subtotal (95% CI) 260 254 43.0 % 1.33 [ 0.97, 1.82 ]

Total (95% CI) 1002 1012 100.0 % 1.29 [ 1.07, 1.56 ]
Test for subgroup differences: Chi2 = 0.02, df = 1 (P = 0.90), I2 =0.0%
0.05 0.2 1 5 20
APPENDICES
Appendix 1. Menstrual Disorders and Subfertility Group search strategy

Search results for Menstrual Disorders and Subfertility Group (MDSG) database, 8 May 2013:
Keywords CONTAINS icsior ICSI failureor ICSI injection siteorintracytoplasmic sperm injectionorintracytoplasmic sperm
injection cycleor intracytoplasmic sperm injection techniquesor Title CONTAINS icsior ICSI failureor ICSI injection
siteorintracytoplasmic sperm injectionorintracytoplasmic sperm injection cycleor intracytoplasmic sperm injection techniques
AND
Keywords CONTAINS IMSI or intracytoplasmic morphologically selected sperm injection or Title CONTAINS IMSI or
intracytoplasmic morphologically selected sperm injection
22 records
Appendix 2. CENTRAL search strategy

Database: EBM Reviews - Cochrane Central Register of Controlled Trials, 2013, Issue 2
Search strategy:
--------------------------------------------------------------------------------
1 icsi.tw. (684)
2 intracytoplasmic sperm injection$.tw. (417)
3 exp Sperm Injections, Intracytoplasmic/ (334)
4 conventional intracytoplasmic injection$.tw. (1)
5 regular magnification.tw. (0)
6 or/1-5 (886)
7 intracytoplasmic morphologically selected sperm injection$.tw. (11)
8 IMSI.tw. (11)
9 MSOME.tw. (0)
10 motile sperm organelle morphology examination$.tw. (0)
11 high magnification.tw. (18)
12 or/7-11 (27)
13 6 and 12 (10)
Appendix 3. MEDLINE search strategy

Search results for Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R)
<1946 to Present>, 8 May 2013:
1 icsi.tw. (5253)
3 exp Sperm Injections, Intracytoplasmic/ (4426)
6 or/1-5 (7703)
8 IMSI.tw. (40)
9 MSOME.tw. (29)
12 or/7-11 (1101)
13 6 and 12 (62)
14 randomized controlled trial.pt. (348,486)
15 controlled clinical trial.pt. (85,883)
16 randomized.ab. (266,743)
17 placebo.tw. (147,938)
18 clinical trials as topic.sh. (164,266)
19 randomly.ab. (194,103)
20 trial.ti. (113,955)
21 (crossover or cross-over or cross over).tw. (56,715)
22 or/14-21 (857,284)
23 exp animals/ not humans.sh. (3,809,801)
24 22 not 23 (790,248)
25 13 and 24 (14)
Appendix 4. EMBASE search strategy

Database: EMBASE <1980 to 8 May 2013>
Search strategy:
--------------------------------------------------------------------------------
1 exp intracytoplasmic sperm injection/ (11,216)
2 icsi.tw. (8334)
6 or/1-5 (13,225)
8 IMSI.tw. (111)
9 MSOME.tw. (59)
12 or/7-11 (1374)
13 6 and 12 (142)
14 Clinical Trial/ (877227)
15 Randomized Controlled Trial/ (341,619)
16 exp randomization/ (61290)
17 Single Blind Procedure/ (17,333)
18 Double Blind Procedure/ (114,409)
19 Crossover Procedure/ (36,788)
20 Placebo/ (217,264)
21 Randomi?ed controlled trial$.tw. (86,231)
22 Rct.tw. (11,331)
23 random allocation.tw. (1232)
24 randomly allocated.tw. (18,653)
25 allocated randomly.tw. (1878)
26 (allocated adj2 random).tw. (718)
27 Single blind$.tw. (13,248)
28 Double blind$.tw. (135,874)
29 ((treble or triple) adj blind$).tw. (312)
30 placebo$.tw. (187828)
31 prospective study/ (231,998)
32 or/14-31 (1,324,701)
33 case study/ (19,500)
34 case report.tw. (242,862)
35 abstract report/ or letter/ (866,817)
36 or/33-35 (1,124,107)
37 32 not 36 (1,288,419)
38 13 and 37 (34)
Appendix 5. CINAHL search strategy

Search results for Cumulative Index to Nursing and Allied Health Literature (CINAHL), 7 May 2013:
((intracytoplasmic sperm injection*) OR (icsi) OR (conventional intracytoplasmic injection*) OR (regular magnification)) AND
((intracytoplasmic morphologically selected sperm injection*) OR (IMSI) OR (MSOME) OR (motile sperm organelle morphology
examination*) OR (high magnification))
0 records
Appendix 6. LILACS search strategy

Search results for Literatura Latino-Americana e do Caribe em Cincias da Sade (LILACS), 7 May 2013:
((intracytoplasmic sperm injection$) OR (icsi) OR (conventional intracytoplasmic injection$) OR (regular magnification)) AND
((intracytoplasmic morphologically selected sperm injection$) OR (IMSI) OR (MSOME) OR (motile sperm organelle morphology
examination$) OR (high magnification))
1 record
Appendix 7. PsycINFO search strategy

Search results for PsycINFO, 8 May 2013:
2 icsi.tw. (38)
5 or/1-4 (50)
7 IMSI.tw. (1)
8 MSOME.tw. (0)
11 or/6-10 (21)
12 5 and 11 (0)
Appendix 8. Trials registers search strategy

Search results for ClinicalTrial.gov, 7 May 2013:
(imsi) OR (msome) OR (motile sperm organelle morphology examination) OR ((high magnification) AND (sperm))
6 records
Search results for Current Controlled Trials, 7 May 2013:
(imsi) OR (msome) OR (motile sperm organelle morphology examination) OR ((high magnification) AND (sperm))
0 records
Search results for World Health Organization International Clinical Trials Registry Platform, 7 May 2013:
IMSI OR MSOME
6 records
Appendix 9. Web of Knowledge search strategy
Search results for Web of Knowledge, 7 May 2013:
(((intracytoplasmic sperm injection*) OR (icsi) OR (conventional intracytoplasmic injection*) OR (regular magnification)) AND
examination*) OR (high magnification)))
240 records
Appendix 10. OpenGrey search strategy

Search results for OpenGrey, 7 May 2013:
((intracytoplasmic sperm injection*) OR (icsi) OR (conventional intracytoplasmic injection*) OR (regular magnification)) AND
examination*) OR (high magnification))
0 records
Appendix 11. DARE search strategy

Search results for Database of Abstracts of Reviews of Effects (DARE), 7 May 2013:
((intracytoplasmic sperm injection$) OR (icsi) OR (conventional intracytoplasmic injection$) OR (regular magnification)) AND
((intracytoplasmic morphologically selected sperm injection$) OR (IMSI) OR (MSOME) OR (motile sperm organelle morphology
examination$) OR (high magnification))
5 records
CONTRIBUTIONS OF AUTHORS
Drafting the protocol: Danielle M Teixeira, Mariana AP Barbosa, Rui A Ferriani, Paula A Navarro, Nick Raine-Fenning, Carolina O
Nastri, Wellington P Martins.
Development of search strategy: Danielle M Teixeira, Wellington P Martins.
Search for trials: Danielle M Teixeira, Mariana AP Barbosa, Wellington P Martins.
Obtaining copies of trials: Danielle M Teixeira, Wellington P Martins.
Selection of which trials to include: Danielle M Teixeira, Mariana AP Barbosa, Wellington P Martins.
Extraction of data from trials: Danielle M Teixeira, Mariana AP Barbosa, Wellington P Martins.
Assessment of risk of bias in included studies: Danielle M Teixeira, Mariana AP Barbosa, Carolina O Nastri.
Entry of data into RevMan: Danielle M Teixeira, Carolina O Nastri, Wellington P Martins.
Drafting the review: Danielle M Teixeira, Mariana AP Barbosa, Rui A Ferriani, Paula A Navarro, Nick Raine-Fenning, Carolina O
Nastri, Wellington P Martins.
DECLARATIONS OF INTEREST
The authors declare no conflicts of interest.
SOURCES OF SUPPORT
Internal sources
Coordenao de Aperfeioamento de Pessoal de Nvel Superior (CAPES), Brazil.
Scholarship
Hospital das Clnicas FMRP-USP, Brazil.
Salary
Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico (CNPq), Brazil.
Scholarship
Fundao de Amparo Pesquisa do Estado de So Paulo (FAPESP), Brazil.
Scholarship
External sources
No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

None.
INDEX TERMS
Medical Subject Headings (MeSH)
Infertility, Male; Pregnancy Rate; Sperm Retrieval; Abortion, Spontaneous [epidemiology]; Live Birth [ epidemiology]; Microma-
nipulation [methods]; Organelle Shape; Randomized Controlled Trials as Topic; Sperm Injections, Intracytoplasmic [ methods]
MeSH check words

Female; Humans; Male; Pregnancy

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Regular (ICSI) versus ultra-high magnification (IMSI) sperm

selection for assisted reproduction (Review)

Regular (ICSI) versus ultra-high magnification (IMSI) sperm

of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, Nottingham, UK

Editorial group: Cochrane Menstrual Disorders and Subfertility Group.

PLAIN LANGUAGE SUMMARY

Patient or population: couples undergoing assisted reproduction techniques

Assumed risk Corresponding risk

ICSI IMSI NNTB

Congenital abnormali- No evidence.

GRADE Working Group grades of evidence

How the intervention might work

Results of the search

Incomplete outcome data 1. Ultra-high magnification (IMSI) versus regular

1.2 Clinical pregnancy (effectiveness)

Subgroup analysis (separating the studies by those that included

1.3 Miscarriage (adverse events)

There was no evidence of an effect on live birth (low-quality evi-

Characteristics of included studies [ordered by study ID]

Participants Inclusion criteria: at least 2 previous diagnoses of severe oligoasthenospermia; 3 years

Interventions Couples were randomised into 2 groups:

Outcomes Clinical pregnancy, miscarriage, and implantation rates.

Bias Authors judgement Support for judgement

Random sequence generation (selection Unclear risk Not reported.

Incomplete outcome data (attrition bias) Low risk No loss to follow-up.

Selective reporting (reporting bias) Low risk Not suspected.

Other bias Low risk None.

Participants Eligibility criteria: unselected women undergoing assisted reproduction treatment

Interventions Couples were randomised into 2 groups:

Notes Miscarriage and congenital abnormalities not reported.

Bias Authors judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated randomisation list.

Allocation concealment (selection bias) Unclear risk Not reported.

Incomplete outcome data (attrition bias) Low risk No loss to follow-up.

Selective reporting (reporting bias) Low risk Not suspected.

Other bias Low risk None.

Participants Eligibility criteria: women undergoing assisted reproduction treatment in conjunction

Interventions Couples were randomised into 2 groups:

Outcomes Sperm nuclear morphology at high-magnification ICSI; incidence of aneuploidy in de-

Bias Authors judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Not reported.

Incomplete outcome data (attrition bias) Low risk No loss to follow-up.

Selective reporting (reporting bias) Low risk Not suspected.

Interventions Couples were randomised into 2 groups:

Outcomes Fertilisation, blastocyst, implantation, and pregnancy rates

Notes Live birth and congenital abnormalities not reported.

Bias Authors judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random numbers

Incomplete outcome data (attrition bias) Low risk No loss to follow-up.

Selective reporting (reporting bias) Low risk Not suspected.

Interventions Couples were randomised into 2 groups:

Outcomes Fertilisation, blastocyst, implantation, and pregnancy rates

Notes Live birth, miscarriage, and congenital abnormalities not reported

ping, and data per woman were clarified

Bias Authors judgement Support for judgement

Random sequence generation (selection Unclear risk Not reported.

Allocation concealment (selection bias) Unclear risk Not reported.

Incomplete outcome data (attrition bias) Low risk No loss to follow-up.

Selective reporting (reporting bias) Low risk Not suspected.

Participants Eligibility criteria: oligoasthenozoospermia based on WHO references values. Terato-

Interventions Couples were randomised into 2 groups:

Notes Live birth, miscarriage, and congenital abnormalities not reported

Bias Authors judgement Support for judgement

Random sequence generation (selection Unclear risk Not reported.