Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction

  • Review
  • Intervention

Authors

  • Danielle M Teixeira,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Mariana AP Barbosa,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Rui A Ferriani,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Paula A Navarro,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Nick Raine-Fenning,

    1. University of Nottingham, Division of Obstetrics and Gynaecology, School of Clinical Sciences, Nottingham, UK
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  • Carolina O Nastri,

    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
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  • Wellington P Martins

    Corresponding author
    1. University of Sao Paulo, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
    • Wellington P Martins, Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clínicas da FMRP-USP, 8 andar, Campus Universitário, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, 14048-900, Brazil. wpmartins@gmail.com.

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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.

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.

Résumé scientifique

Sélection normale de spermatozoïdes pour l'injection intracytoplasmique de spermatozoïdes (ICSI) par rapport à l'injection intracytoplasmique de spermatozoïdes choisis selon la morphologie (IMSI) par agrandissement ultra-grand pour la procréation assistée

Contexte

L'hypofertilité est un trouble qui touche les couples en âge de procréer dans une proportion atteignant 15 %. La micromanipulation des gamètes, comme l'injection intracytoplasmique de spermatozoïdes (ICSI), est très utile pour le traitement des couples dont les paramètres spermatiques sont affaiblis. Récemment, une nouvelle méthode de sélection des spermatozoïdes appelée 'examen morphologique des organites des spermatozoïdes motiles' (MSOME, motile sperm organelle morphology examination) a été décrite ainsi que les spermatozoïdes choisis par agrandissement ultra-grand (plus de 6000 fois) utilisés pour l'injection intracytoplasmique de spermatozoïdes (ICSI). Cette nouvelle technique, appelée injection intracytoplasmique de spermatozoïdes choisis selon la morphologie (IMSI), offre théoriquement le potentiel d'améliorer les critères de jugement pour la procréation chez les couples bénéficiant de techniques de procréation assistée (TPA).

Objectifs

Comparer l'efficacité et l'innocuité de la procédure IMSI et de la procédure ICSI chez les couples bénéficiant d'une TPA.

Stratégie de recherche documentaire

Nous avons recherché des essais contrôlés randomisés (ECR) dans les bases de données électroniques (le registre spécialisé du groupe Cochrane sur les troubles menstruels et de la fertilité, le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), les registres d'essais (ClinicalTrials.gov, Current Controlled Trials, le système d'enregistrement international des essais cliniques de l'Organisation Mondiale de la Santé), les actes de conférences (ISI Web of knowledge), et la littérature grise (OpenGrey) ; en outre, nous avons effectué des recherches manuelles dans les références bibliographiques des études incluses et des revues similaires. Nous avons consulté les bases de données électroniques pour la dernière fois le 8 mai 2013.

Critères de sélection

Nous avons considéré que seuls les véritables essais contrôlés randomisés comparant la procédure ICSI et la procédure IMSI étaient éligibles ; nous n'avons pas inclus d'essais quasi- ou pseudo-randomisés. Nous avons inclus les études qui ont permis l'inclusion du même participant plus d'une fois (essais croisés ou 'par cycle') uniquement si les données relatives au premier traitement de chaque participant étaient disponibles.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les études, extrait les données et évalué les risques de biais, et ont résolu tous les désaccords par la discussion avec un troisième auteur de la revue. Nous avons correspondu avec les chercheurs des études afin d'éliminer le moindre doute, en cas de besoin.

Résultats principaux

La recherche a permis de trouver 294 dossiers ; parmi ces derniers neuf études ayant un schéma parallèle ont été incluses, totalisant 2 014 couples (IMSI = 1002 ; ICSI = 1012). La naissance vivante a été évaluée dans un seul essai qui ne fournissait aucune preuve significative d'une différence entre la procédure IMSI et la procédure ICSI (risque relatif (RR) 1,14, intervalle de confiance (IC) à 95 % 0,79 à 1,64, 1 ECR, 168 femmes, I2 = non applicable, preuves de faible qualité). La procédure IMSI a été associée à une amélioration significative du taux de grossesses cliniques (RR 1,29, IC à 95 % 1,07 à 1,56, 9 ECR, 2 014 femmes, I2 = 57 %, preuves de très faible qualité). Nous avons rabaissé la qualité de ces preuves en raison de l'imprécision, de l'incohérence et de l'indication forte de biais de publication. Nous n'avons trouvé aucune différence significative au niveau du taux de fausses couches entre la procédure IMSI et la procédure ICSI (RR 0,82, IC à 95 % 0,59 à 1,14, 6 ECR, 552 grossesses cliniques, I2 = 17 %, preuves de très faible qualité). Aucune des études incluses n'a signalé des anomalies congénitales.

Conclusions des auteurs

Les résultats obtenus dans les ECR ne corroborent pas l'utilisation clinique de la procédure IMSI. Il n'existe aucune preuve de l'effet sur les naissances vivantes ou les fausses couches et les preuves indiquant que la procédure IMSI améliore les grossesses cliniques sont de très faible qualité. Il n'y a aucune indication que la procédure IMSI augmente les anomalies congénitales. D'autres essais sont nécessaires pour améliorer la qualité des preuves pour recommander la procédure IMSI dans la pratique clinique.

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.

Résumé simplifié

Sélection normale de spermatozoïdes pour l'injection intracytoplasmique de spermatozoïdes (ICSI) par rapport à l'injection intracytoplasmique de spermatozoïdes choisis selon la morphologie (IMSI) par agrandissement ultra-grand pour la procréation assistée

Contexte : La micromanipulation de spermatozoïdes, comme l'injection intracytoplasmique de spermatozoïdes (ICSI), est très utile pour le traitement des couples chez qui le partenaire masculin présente une baisse de la concentration ou motilité des spermatozoïdes, ou les deux. Récemment, une nouvelle méthode de sélection des spermatozoïdes appelée 'examen morphologique des organites des spermatozoïdes motiles' (MSOME, motile sperm organelle morphology examination) a été décrite, laquelle analyse le sperme par agrandissement à une puissance ultra-grande (6000 fois). Les études initiales ont montré que l'injection intracytoplasmique de spermatozoïdes choisis selon la morphologie (IMSI), en utilisant les spermatozoïdes choisis par agrandissement ultra-grand, est associée à des taux de grossesse plus élevés chez les couples ayant subi des échecs successifs d'implantation.

Date de la recherche : nous avons effectué une recherche dans la littérature médicale en mai 2013 pour trouver des études ayant évalué l'efficacité et l'innocuité de l'utilisation de l'agrandissement ultra-grand (plus de 6000 fois) pour la sélection des spermatozoïdes avant la procédure ICSI, comparée à l'utilisation d'une procédure ICSI conventionnelle, avec un agrandissement de 200 à 400 fois.

Caractéristiques des études : nous avons trouvé neuf essais contrôlés randomisés, ayant évalué 2 014 couples, qui avaient comparé une procédure ICSI conventionnelle à la technique IMSI pour la procréation assistée. Ces études ont été financées par des services de consultation externe de fertilité et des universités.

Principaux résultats et qualité des preuves : pour la naissance vivante, il y avait des preuves de faible qualité compatibles soit avec des bénéfices soit avec des risques : pour les femmes ayant 38 % de chances d'obtenir une naissance vivante en utilisant une injection intracytoplasmique de spermatozoïdes (ICSI) conventionnelle, les chances d'obtenir une naissance vivante avec une injection intracytoplasmique de spermatozoïdes choisis selon la morphologie par agrandissement ultra-grand (IMSI) seraient comprises entre 30 % et 63 %. Pour les grossesses cliniques, il y avait des preuves de très faible qualité compatibles avec des bénéfices : pour les femmes ayant 33 % de chances d'obtenir une grossesse en utilisant une injection intracytoplasmique de spermatozoïdes (ICSI) conventionnelle, les chances d'obtenir une grossesse avec une injection intracytoplasmique de spermatozoïdes choisis selon la morphologie (IMSI) seraient comprises entre 36 % et 52 % ; la qualité de ces preuves a été rabaissée en raison de l'imprécision, de l'incohérence de l'effet observé entre les études, et du risque élevé de biais de publication. Pour les fausses couches, il y avait des preuves de très faible qualité compatibles soit avec des bénéfices soit avec des risques : pour les femmes enceintes présentant un risque de 22 % de fausses couches en utilisant une ICSI conventionnelle, le risque avec la procédure IMSI serait compris entre 13 % et 25 %. Il n'existait aucune preuve concernant les anomalies congénitales. Nous en avons conclu que les preuves actuelles ne corroborent pas l'utilisation de la procédure IMSI : il n'y a aucune preuve en faveur des bénéfices pour les naissances vivantes et les fausses couches ; nous ne pouvons donc pas soutenir avec certitude l'effet bénéfique de la procédure IMSI dans les grossesses cliniques, et il n'existe aucune preuve de l'effet de cette intervention sur les anomalies congénitales. D'autres études sont nécessaires pour améliorer la qualité des preuves pour recommander la procédure IMSI dans la pratique clinique.

Notes de traduction

Traduit par: French Cochrane Centre 4th September, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. 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.

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)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk 
ICSIIMSI NNTB
Live birth per allocated couple 38 per 100 44 per 100
(30 to 63)
- RR 1.14 (0.79 to 1.64)168
(1 study)
⊕⊕⊝⊝
low 1
Clinical pregnancy per allocated couple 33 per 100 43 per 100
(36 to 52)

10

(5 to 33)

RR 1.29 (1.06 to 1.55)2014
(9 studies)
⊕⊝⊝⊝
very low 2
Miscarriage per clinical pregnancy 22 per 100 18 per 100
(13 to 25)
- RR 0.82 (0.59 to 1.14)552
(6 studies)
⊕⊝⊝⊝
very low 3
Congenital abnormalities per clinical pregnancyNo evidence.
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.

Background

Description of the condition

Subfertility is a condition found in up to 15% of couples of reproductive age and until the late 1970s, there were few options for treating these couples. Since the first successful in vitro fertilisation (IVF) was described, the efficacy of subfertility treatment has greatly improved. However, it was soon realised that the technique had great limitations in achieving pregnancy in couples with compromised semen parameters. During the 1980s, some other assisted reproductive technology techniques (ART) were developed focusing on gamete micromanipulation. However, for all these techniques, spermatozoa had to be progressively motile and needed to have the potential for an acrosome reaction, leaving infertility due to severe male factors inadequately treated. Then, in 1992, the first successful intracytoplasmic sperm injection (ICSI) was reported (Palermo 1992). For ICSI, after sperm preparation an optical magnification of 200x to 400x is used to examine the sample. The best 'normal looking' motile spermatozoa are selected based on their major morphology and then injected into oocytes retrieved after ovarian stimulation. With ICSI, even men with severe male factor infertility could possibly achieve pregnancy. However, despite 20 years of technological improvements, both clinical pregnancy and live birth rates remain relatively low at approximately 35% and 25% per started cycle, respectively (Jungheim 2010).

Description of the intervention

In the early 2000s, a new method of sperm selection named 'motile sperm organelle morphology examination' (MSOME) was described (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 was named intracytoplasmic morphologically selected sperm injection (IMSI) (Bartoov 2003). When using this technique, the motile sperm fraction is examined based on six subcellular organelles: acrosome, postacrosomal lamina, neck, mitochondria, tail, and nucleus.

How the intervention might work

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 reproductive outcomes (Berkovitz 2006).

Why it is important to do this review

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 are no large published studies, a systematic review of the best available evidence is needed to facilitate a more robust conclusion. Although a systematic review and meta-analysis on this issue has been published (Setti 2010), the authors of that review evaluated a single database (MEDLINE) and supplemented the evidence from a single randomised controlled trial (RCT) with non-randomised studies to improve precision, which is poorly justifiable, as this decision increases the risk of obtaining a biased estimate (Higgins 2011). The present review aims to perform a wider and updated search, considering only the evidence from RCTs .

Objectives

To compare the effectiveness and safety of IMSI and ICSI in couples undergoing ART.

Methods

Criteria for considering studies for this review

Types of studies

We considered only RCTs for inclusion; we excluded quasi- or pseudo-randomised trials. We included studies that allowed the inclusion of the same participant more than once (cross-over or 'per cycle' trials) only if we could obtain the data regarding the first inclusion of each participant.

Types of participants

Couples undergoing ART.

Types of interventions

Intracytoplasmic injection of sperm selected under high magnification (≥ 6000x = IMSI) compared to intracytoplasmic injection of sperm selected under regular magnification (200x to 400x = ICSI).

Types of outcome measures

Primary outcomes

Effectiveness: live birth per allocated couple.

Secondary outcomes

Effectiveness: clinical pregnancy per allocated couple.

Adverse events: miscarriage per clinical pregnancy; congenital abnormalities per live birth.

Although fertilisation and implantation rates were important outcomes for this review, we did not include them in the quantitative meta-analysis due to use of differing denominators (injected oocytes for fertilisation rate and transferred embryos for implantation rate). However, we included implantation and fertilisation rates in the review for completeness, and describe them in the Characteristics of included studies table.

Search methods for identification of studies

We developed the search strategy in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator. We did not limit searches by language or publication status.

Electronic searches

We performed the electronic searches on 31 August 2012 and updated them on 8 May 2013.

We searched for RCTs in the following electronic databases:

We searched for study protocols and ongoing trials in the following trials registers (Appendix 8):

We searched for conference abstracts in the Web of Knowledge (http://wokinfo.com; Appendix 9).

We searched for grey literature in Open Grey (www.opengrey.eu/) (Appendix 10).

We searched for similar reviews in the Database of Abstracts of Reviews of Effects (DARE) (Appendix 11).

Searching other resources

We handsearched the reference lists of included articles and related reviews.

Data collection and analysis

We conducted data collection and analyses in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Selection of studies

Two review authors (DMT and MAPB) independently reviewed titles and abstracts, and checked for duplicates using the pre-established criteria for inclusion. We resolved disagreements by consulting a third review author (WPM). We retrieved the full-text manuscripts of trials considered potentially eligible for inclusion and two review authors (DMT and MAPB) independently evaluated eligibility of these trials. We resolved disagreements by consulting a third review author (WPM). We corresponded with study investigators as required to clarify study eligibility. We placed no limitations regarding language, publication date or publication status.

Data extraction and management

We extracted data from eligible studies using a data extraction form designed and pilot-tested by the review authors. Where studies had multiple publications, we used the main trial report as the reference and obtained additional details from secondary papers. We contacted study authors in order to resolve any data queries, as required. Two review authors (DMT and WPM) independently extracted the data and any disagreements between these review authors were resolved by consulting a third review author (CON).

Assessment of risk of bias in included studies

Two review authors (DMT and WPM) independently assessed the risk of selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective outcome reporting); and other potential sources of bias (e.g. a difference in the number of embryos transferred, age of participants, co-interventions). We resolved any disagreements by consulting a third review author (CON). To judge the risk of bias, we used The Cochrane Collaboration's criteria for judging risk of bias (Higgins 2011): we classified the trials as being at 'low', 'high', or 'unclear' risk of bias.

Measures of treatment effect

For dichotomous data (e.g. live birth rates), we used the numbers of events in the control and intervention groups of each study to calculate the Mantel-Haenszel risk ratio (RR). We prefer to use RR because odds ratio (OR) is harder to understand and apply in practice. Misinterpretation of the OR as if it equated to the RR will tend to overestimate the intervention effect, especially when events are common, and there is concern that this occurs quite frequently in published reports of individual studies and 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 biased and most powerful, providing the best confidence interval (CI) coverage in these situations (Higgins 2011); in additional the OR value in such situations is very similar to RR, avoiding misinterpretations. We calculated the 95% CI to determine the precision of the estimates. We considered the clinical relevance of any statistically significant findings; in these situations, we also determined the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH).

Unit of analysis issues

The primary analysis was per couple randomised. Exceptions were miscarriage, where we considered the number of clinical pregnancies in each group as the denominator, because miscarriage is a harm that can only occur in pregnant women; and congenital abnormalities, which would be analysed per live birth (but this outcome was not reported by any study). We did not find any studies that permitted the participant to be included more than once, as cross-over or 'per cycle' trials. We counted the delivery of a multiple pregnancy (e.g. twins or triplets) as one live birth event.

Dealing with missing data

We analysed the results on an intention-to-treat (ITT) basis, as far as possible, and we contacted most of the original investigators to obtain missing data. We planned that where these data were unobtainable, clinical pregnancy (and subsequent live birth or miscarriage) 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 transfer for all participants.

Assessment of heterogeneity

We assessed heterogeneity using the I2 statistic and addressed substantial heterogeneity (I2 > 50%) by: checking again that the data were correct; performing the planned subgroup analysis; excluding studies with high risk of bias; and, if it could not be explained, we incorporated the heterogeneity by using a random-effects model.

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. Even though only nine studies were included, a funnel plot was used to explore the possibility of small studies effect (a tendency for estimates of the intervention effect to be more beneficial in smaller studies) for clinical pregnancy.

Data synthesis

We combined the data from primary studies to compare IMSI versus ICSI. An increased risk of a particular outcome associated with IMSI, which may be beneficial (e.g. live birth) or detrimental (e.g. miscarriage), was displayed graphically in the meta-analysis to the right of the centre line and a decreased risk to the left of the centre line.

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses if substantial heterogeneity (I2 > 50%) was observed.

  • Sperm quality: studies including only couples where the male partner had poor sperm quality, or partners with good or unselected sperm quality.

  • Sperm source: ejaculate or surgical.

  • Previous unsuccessful embryo transfers: studies including only women with repeated previous unsuccessful embryo transfers, or any women.

However, we could only perform the first subgroup analysis as no studies evaluated only sperm obtained from surgical procedures or only women with repeated previous unsuccessful embryo transfers.

Sensitivity analysis

We performed sensitivity analyses to verify whether the conclusions about live birth and clinical pregnancy would differ if eligibility was restricted to studies without high risk of bias.

Overall quality of the body of evidence: 'Summary of findings' table

We generated a 'Summary of findings' table using GRADEpro software. This table evaluated the overall quality of the body of evidence for the main review outcomes, using the following GRADE criteria: study limitations (i.e. risk of bias), consistency of effect, imprecision, indirectness, and publication bias. Judgements about evidence quality (high, moderate, low, or very low) were justified, documented and incorporated into the reporting of results for 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.

Included studies

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 (Balaban 2011), Brazil (Figueira 2011; Setti 2011; Setti 2012a; Setti 2012b), Slovenia (Knez 2011; Knez 2012), and Tunisia (Mahmoud 2011).

Participants

The studies included 1002 women in the intervention groups (IMSI) and 1012 women in the control groups (ICSI). Five studies included only couples in which the male partner had poor sperm quality (Antinori 2008; Knez 2011; Knez 2012; Mahmoud 2011; Setti 2011); three included women with advanced maternal age (Figueira 2011; Setti 2012a; Setti 2012b); and one study included couples who underwent ART without specifying further details (Balaban 2011). One of the nine trials excluded couples with female factor infertility (Antinori 2008), and three excluded women with polycystic ovaries syndrome (PCOS) or endometriosis (Knez 2011; Knez 2012; Setti 2012b).

Interventions

All studies compared regular (ICSI) versus ultra-high magnification (IMSI).

Outcomes
  • One study reported live birth.

  • Nine studies reported clinical pregnancy.

  • Six studies reported miscarriage.

  • No studies reported congenital abnormalities.

Excluded studies

We excluded 11 studies from the review, for the following reasons:

  • eight were not RCTs (observational studies);

  • three randomly allocated the oocytes, not the couples.

Risk of bias in included studies

See table Characteristics of included studies; Figure 2; and Figure 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

Five of the nine studies were at low risk of selection bias related 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 were at low risk of selection bias related to allocation concealment, as they used sealed opaque envelopes prepared by research nurses (Antinori 2008; Knez 2011). The other seven studies did not describe the method for allocation concealment and we classified them to be at unclear risk of bias.

Blinding

We did not consider that blinding of participants, personnel, and 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 to be at low risk of bias in this domain.

Incomplete outcome data

We considered all nine studies to be at low risk of bias in this domain, as they stated that all allocated women were analysed.

Selective reporting

We considered all nine studies to be at low risk of selective reporting bias, because clinical pregnancy was reported by all included studies. Although eight studies did not report live birth and nine studies did not report congenital malformations, we believe these studies might not be designed to evaluate these outcomes, as they take longer to be assessed.

Other potential sources of bias

We deemed four studies to be at high risk of other bias, because there were substantial differences regarding the mean number of oocytes retrieved or embryos transferred between groups, or both (Figueira 2011; Setti 2011; Setti 2012a; Setti 2012b). We considered 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 2011; Knez 2012; Mahmoud 2011). We judged two studies to be at low risk of other potential sources of bias (Antinori 2008; Balaban 2011).

Effects of interventions

See: Summary of findings for the main comparison

1. Ultra-high magnification (IMSI) versus regular (ICSI) sperm selection for assisted reproduction

Primary outcomes
1. 1 Live birth (effectiveness)

No significant difference was observed between the IMSI and ICSI groups (RR 1.14, 95% CI 0.79 to 1.64, 1 RCT, 168 women, I2 = 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.

Secondary outcomes
1.2 Clinical pregnancy (effectiveness)

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 couples with good or unselected sperm quality) did not reduce the observed 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)

No significant difference between the groups was observed in miscarriage rates (RR 0.82, 95% CI 0.59 to 1.14, 6 RCTs, 552 women, I2 = 17%, very-low-quality evidence; Analysis 1.3).

1.4 Congenital abnormalities (adverse events)

None of the included studies reported congenital abnormalities.

Discussion

Summary of main results

There was no evidence of an effect on live birth (low-quality evidence) or miscarriage (very-low-quality evidence). The use of IMSI for sperm selection was associated with an improvement in the clinical pregnancy rate. However, we deemed this evidence to be of very low quality, and therefore we are very uncertain about this estimate. No included studies reported congenital abnormalities. See Summary of findings for the main comparison for further details.

Overall completeness and applicability of evidence

The objectives of this review were addressed by the included studies. Five studies included only couples with poor sperm quality and four included couples with good or unselected sperm quality; however, such subgroup analysis (Analysis 2.1) did not add to the global analysis. No study sorted the participants accordingly the sperm source - ejaculate or surgical - or by previous unsuccessful embryo transfers. However, the quality of the pooled evidence does not allow robust conclusions and we are uncertain about the true effect of IMSI on the studied reproductive outcomes. In this way, the review findings do not support the use of IMSI in clinical practice.

Quality of the evidence

We considered the pooled evidence to be very-low to low-quality (see Summary of findings for the main comparison). Issues such as risk of bias in the included studies, imprecision and strong suspicion of publication bias contributed to the downgrading of the evidence quality.

The evidence of effect on live birth was deemed low-quality because only one study reported this outcome, with very serious imprecision in the estimate (Balaban 2011). There were only 69 events, and the 95% CI included appreciable harm, no effect, and appreciable benefit.

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 between groups, or both (see Assessment of risk of bias in included studies; Figure 3). In addition, there was inconsistency across the included studies; and publication bias was strongly suspected, as funnel plot analysis (Figure 6) suggested a small studies effect.

Regarding miscarriage, we considered the evidence to be of very-low-quality. This occurred because the four out of six studies that reported this outcome were considered to be at high risk of bias related to differences in the mean number of oocytes retrieved or embryos transferred between groups, and there was also very serious imprecision in the estimate. There were only 107 miscarriages across both groups, and the 95% CI was compatible with both appreciable harm and no effect.

There was no evidence from RCTs on the effect of IMSI on congenital abnormalities.

Potential biases in the review process

We did not identify potential biases in the review process.

Agreements and disagreements with other studies or reviews

Another review evaluated the effect of IMSI (Setti 2010). It included studies recovered from a single database (MEDLINE) and supplemented evidence from a single RCT with non-RCT studies. In accordance to our review, they reported a significant improvement in clinical pregnancy rates. However, they observed a beneficial effect of IMSI decreasing the risk of miscarriage while we observed no evidence of such effect.

Authors' conclusions

Implications for practice

The current evidence from randomised controlled trials does not support the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (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 evidence regarding the effect of this intervention on the risk of congenital abnormalities. Further trials are necessary to improve the quality of the evidence before recommending IMSI in clinical practice.

Implications for research

More studies are needed to evaluate the effect of IMSI on live birth, clinical pregnancy, miscarriage, and congenital abnormalities.

Acknowledgements

We acknowledge the important help provided by Helen Nagels, Managing Editor from the Cochrane Menstrual Disorders and Subfertility Group, and by Marian Showell, Trials Search Co-ordinator for the Cochrane Menstrual Disorders and Subfertility Group.

Data and analyses

Download statistical data

Comparison 1. Ultra high (IMSI) versus regular magnification (ICSI)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Live birth per allocated couple1168Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.79, 1.64]
2 Clinical pregnancy per allocated couple92014Risk Ratio (M-H, Random, 95% CI)1.29 [1.07, 1.56]
3 Miscarriage per clinical pregnancy6552Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.59, 1.14]
Analysis 1.1.

Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 1 Live birth per allocated couple.

Analysis 1.2.

Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 2 Clinical pregnancy per allocated couple.

Analysis 1.3.

Comparison 1 Ultra high (IMSI) versus regular magnification (ICSI), Outcome 3 Miscarriage per clinical pregnancy.

Comparison 2. IMSI versus ICSI: subgroup analysis by sperm quality
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical pregnancy92014Risk Ratio (M-H, Random, 95% CI)1.29 [1.07, 1.56]
1.1 Only poor sperm quality51500Risk Ratio (M-H, Random, 95% CI)1.29 [0.98, 1.70]
1.2 Good or unselected sperm quality4514Risk Ratio (M-H, Random, 95% CI)1.33 [0.97, 1.82]
Analysis 2.1.

Comparison 2 IMSI versus ICSI: subgroup analysis by sperm quality, Outcome 1 Clinical pregnancy.

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 "icsi"or "ICSI failure"or "ICSI injection site"or"intracytoplasmic sperm injection"or"intracytoplasmic sperm injection cycle"or "intracytoplasmic sperm injection techniques"or Title CONTAINS "icsi"or "ICSI failure"or "ICSI injection site"or"intracytoplasmic sperm injection"or"intracytoplasmic sperm injection cycle"or "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)
2 intracytoplasmic sperm injection$.tw. (4724)
3 exp Sperm Injections, Intracytoplasmic/ (4426)
4 conventional intracytoplasmic injection$.tw. (1)
5 regular magnification.tw. (1)
6 or/1-5 (7703)
7 intracytoplasmic morphologically selected sperm injection$.tw. (36)
8 IMSI.tw. (40)
9 MSOME.tw. (29)
10 motile sperm organelle morphology examination$.tw. (22)
11 high magnification.tw. (1058)
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)
3 intracytoplasmic sperm injection$.tw. (5798)
4 conventional intracytoplasmic injection$.tw. (1)
5 regular magnification.tw. (2)
6 or/1-5 (13,225)
7 intracytoplasmic morphologically selected sperm injection$.tw. (75)
8 IMSI.tw. (111)
9 MSOME.tw. (59)
10 motile sperm organelle morphology examination$.tw. (41)
11 high magnification.tw. (1291)
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 Ciências da Saúde (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:
1 intracytoplasmic sperm injection$.tw. (33)
2 icsi.tw. (38)
3 conventional intracytoplasmic injection$.tw. (0)
4 regular magnification.tw. (0)
5 or/1-4 (50)
6 intracytoplasmic morphologically selected sperm injection$.tw. (0)
7 IMSI.tw. (1)
8 MSOME.tw. (0)
9 motile sperm organelle morphology examination$.tw. (0)
10 high magnification.tw. (20)
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 ((intracytoplasmic morphologically selected sperm injection*) OR (IMSI) OR (MSOME) OR (motile sperm organelle morphology 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 ((intracytoplasmic morphologically selected sperm injection*) OR (IMSI) OR (MSOME) OR (motile sperm organelle morphology 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

  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.

    Scholarship

  • Hospital das Clínicas FMRP-USP, Brazil.

    Salary

  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.

    Scholarship

  • Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil.

    Scholarship

External sources

  • No sources of support supplied

Differences between protocol and review

None.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Antinori 2008

MethodsRandomised 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 magnification (IMSI): on the basis of MSOME criteria, the examination and spermatozoa selection 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 (Transfer-Man NK2, Eppendorf, Germany). Only spermatozoa with normal head dimension (length 4.75 ± 0.28 μm; width 3.28 ± 0.20 μm) and shape, with no or maximum 1 vacuole (0.78 ± 0.18 μm) 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 spermatozoa 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.

OutcomesClinical 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Low riskSealed, opaque envelopes prepared by a research nurse.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasLow riskNone.

Balaban 2011

MethodsRandomised controlled trial conducted in a private assisted reproduction centre (Turkey) between February and July 2009.
Participants Eligibility criteria: unselected women undergoing assisted reproduction treatment.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (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 defined as smooth, symmetric, having an oval configuration, with mean length and width limits of 4.75 ± 0.28 and 3.28 ± 0.20 μm, 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 μm. Mean time needed for IMSI = 21 minutes.

Control: oocytes injected with spermatozoon selected under regular magnification (ICSI): not specified; the mean time needed for regular ICSI = 14 minutes.

OutcomesDuration 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation list.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasLow riskNone.

Figueira 2011

MethodsRandomised 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.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (IMSI): sperm morphology selection was assessed using an inverted Nikon Diaphot 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.

Control: oocytes injected with spermatozoon selected under regular magnification (ICSI): sperm morphology selection was assessed using an inverted Nikon Diaphot microscope (Eclipse TE 300; Nikon, Tokyo) with a Hoffmann modulation contrast system under 400x magnification.

OutcomesSperm nuclear morphology at high-magnification ICSI; incidence of aneuploidy in derived embryos; clinical pregnancy rate.
Notes

All embryos were submitted to pre-implantation genetic diagnosis and aneuploidy screening. 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 culture 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 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 autosomal 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.

Live birth and congenital abnormalities not reported.

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated balanced table in sets of 10.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasHigh riskThe number of oocytes retrieved and embryos transferred were significantly different between groups (P value < 0.01). In the article, study authors reported that differences were not significant (P value = 0.20 and P value = 0.17, oocytes retrieved and embryos transferred, respectively).

Knez 2011

MethodsRandomised controlled trial conducted in an academic setting (Slovenia) between October 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 characterised 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.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (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). Approximately 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.

Control: oocytes injected with spermatozoon selected under regular 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 microinjection into the oocyte.

OutcomesFertilisation, 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 overlapping, and data "per woman" were clarified.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers (unrestricted randomisation list).
Allocation concealment (selection bias)Low riskSealed, opaque envelopes prepared by a research nurse.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasUnclear riskStudy authors did not report the number of oocytes retrieved in the groups. The number of transferred embryos per participant was not significantly different between groups.

Knez 2012

MethodsRandomised controlled trial conducted in an academic setting (Slovenia) between January 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.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (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.

Control: oocytes injected with spermatozoon selected under regular magnification (ICSI): spermatozoa without severe head shape defects clearly seen under the microscope (pin, amorphous, tapered, round, and multinucleated head) were selected at magnification 200x to 400x.

OutcomesFertilisation, 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 overlapping, and data "per woman" were clarified.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasUnclear riskStudy authors did not provide the number of transferred embryos per participant neither the SD for the number of oocytes retrieved (mean 11.0 with IMSI vs. 9.8 with ICSI).

Mahmoud 2011

MethodsRandomised 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. Teratozoospermia evaluated by the strict criteria of Kruger sperm morphology; healthy woman aged < 37 years.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (IMSI): 6600x magnification, using Leica 6800 station.

Control: oocytes injected with spermatozoon selected under regular magnification (ICSI).

OutcomesFertilisation rate, percentage of good-quality embryos, and the rates of clinical pregnancy and implantation.
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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasUnclear riskStudy authors did not report the number of oocytes retrieved and embryos transferred.

Setti 2011

MethodsRandomised controlled trial conducted in a private assisted reproduction centre (Brazil). 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.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (IMSI): sperm selection was examined at high magnification with an inverted microscope (Eclipse TE 300; Nikon, Tokyo, Japan) equipped with high-power DIC optics (Nomarski). The total calculated magnification was 6600x.

Control: oocytes injected with spermatozoon selected under regular magnification (ICSI): sperm morphology selection was assessed using an inverted Nikon Diaphot microscope (Eclipse TE 300; Nikon, Tokyo) with a Hoffmann modulation contrast system under 400x magnification.

OutcomesClinical pregnancy, implantation rate, and miscarriage.
Notes

Live birth and congenital abnormalities not reported.

Implantation rate: 158/664 = 23.8% (IMSI) vs. 28/156 = 25.4% (ICSI); P value = 0.60.

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation list.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasHigh riskThe number of oocytes retrieved and embryos transferred were significantly different between groups (P value < 0.01 for both). In the article, study authors reported that differences were non-significant (P value = 0.29 for oocytes retrieved and P = 0.27 for embryos transferred).

Setti 2012a

MethodsRandomised controlled trial conducted in a private assisted reproduction centre (Brazil) 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.
Interventions

Couples were randomised into 2 groups:

Intervention: oocytes injected with spermatozoon selected under ultra-high magnification (IMSI): sperm selection was examined at high magnification using a similar inverted microscope equipped with high-power DIC optics (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 occupied < 4% of the nuclear area) were selected for injection.

Control: oocytes injected with spermatozoon selected under regular magnification (ICSI): sperm morphology selection was assessed using an inverted Nikon Diaphot microscope (Eclipse TE 300; Nikon, Tokyo, Japan) with a Hoffmann modulation contrast system under 400x magnification.

OutcomesClinical pregnancy, implantation rate, miscarriage, and gender incidence.
Notes

All embryos were submitted to pre-implantation genetic diagnosis and aneuploidy screening. 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 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 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.

Live birth and congenital abnormalities not reported.

Implantation rate: 46.1% (IMSI) vs. 41.6% (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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasHigh riskThe number of oocytes retrieved and embryos transferred were significantly different between groups (P value = 0.01). In the article, study authors reported these differences as not significant.

Setti 2012b

  1. a

    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.

MethodsProspective 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.
Interventions

Couples were randomised into 2 groups:

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.

OutcomesFertilisation rate, high-quality embryo rate on day 3, blastocyst formation rate, number of transferred embryos, implantation rate, miscarriage rate and pregnancy rate.
Notes

Live birth and congenital abnormalities not reported.

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation table.
Allocation concealment (selection bias)Unclear riskNot reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding of participants and personnel was not considered as a potential source of bias.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessment was not considered as a potential source of bias.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss of follow-up.
Selective reporting (reporting bias)Low riskNot suspected.
Other biasHigh risk

Although there was no significant difference in the number of oocytes retrieved, and despite the total number of embryos being higher in the ICSI group, more embryos per woman were transferred in the IMSI group.

This article has been withdrawn.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial.

Apryshko 2010Not an RCT (observational study).
Bartoov 2003Not an RCT (observational study).
Berkovitz 2005Not an RCT (observational study).
Berkovitz 2006Not an RCT (observational study).
Braga 2011Oocytes (not participants) were allocated.
Cassuto 2011Not an RCT (observational study).
De Vos 2013Oocytes (not participants) were randomly allocated.
Hazout 2005Not an RCT (observational study).
Mauri 2011Oocytes (not participants) were randomly allocated.
Oliveira 2011Not an RCT (observational study).
Wilding 2011Not an RCT (observational study).

Characteristics of studies awaiting assessment [ordered by study ID]

Check 2013

MethodsProspective 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 consecutive embryo transfers and whose male partner had a DNA fragmentation index > 30%.
Interventions

Couples were randomised into 2 groups:

Intervention: sperm selection in the ICSI group was analysed under high magnification.

Control: sperm selection in the ICSI group was analysed under normal magnification.

OutcomesLive birth and pregnancy rate.
NotesAuthors were contacted for further information regarding period of enrolment, eligibility criteria and results.

Parinaud 2013

MethodsRandomised 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.
Interventions

Couples were randomised into 2 groups:

Intervention: sperm selection in the ICSI group was analysed under 6000x magnification.

Control: sperm selection in the ICSI group was analysed under 400x magnification.

OutcomesNumber of deliveries and implantation rate.
NotesThe 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

  1. a

    ART: assisted reproduction technique; DNA: deoxyribonucleic acid; FSH: follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; IMSI: intracytoplasmic morphologically selected sperm injection; IU: international units.

MethodsProspective 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.
Interventions

Couples were randomised into 2 groups:

Intervention: sperm selection in the ICSI group was analysed under 6000x magnification.

Control: sperm selection in the ICSI group was analysed under 400x magnification.

OutcomesFertilisation 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.

Ancillary