Abstract
Background
Starting over 40 years ago, in vitro fertilisation (IVF) has become the cornerstone for fertility treatment. Since then, in 1992, Palermo and colleagues successfully applied the technique intracytoplasmic sperm injection (ICSI) to benefit couples where conventional in vitro fertilisation (c‐IVF) and sub‐zonal insemination (SUZI) proved unsuccessful. After this case report, ICSI has become the treatment of choice for couples with severe male factor subfertility. Over time, ICSI has been used in the treatment of couples with mild male and even unexplained infertility. This review is an update of the review, first published in 1999, comparing ICSI with c‐IVF for couples with males presenting with normal total sperm count and motility.
Objectives
To evaluate the effectiveness and safety of ICSI relative to c‐IVF in couples with males presenting with normal total sperm count and motility.
Search methods
We searched the following databases and trial registers: Cochrane Central Register of Controlled Trials (CENTRAL), Embase (excerpta Medica Database), MEDLINE (Medical Literature Analysis and Retrieval System Online) and PsycINFO (Psychological literature database) for articles between January 2010 and 22 February 2023.
Selection criteria
We included randomised controlled trials (RCTs) that compared ICSI with c‐IVF in couples with males presenting with normal total sperm count and motility.
Data collection and analysis
We used standard methodical procedures recommended by Cochrane. The primary review outcomes were live birth and adverse events. Secondary outcomes included clinical pregnancy, viable intrauterine pregnancy and miscarriage.
Main results
The original review published in 2003 included one RCT. In this 2023 update, we identified an additional two RCTs totalling a cohort of 1539 couples, comparing ICSI with c‐IVF techniques. Two studies reported on live birth. Using the GRADE method, we assessed the certainty of evidence and reported evidence as low‐certainty for live birth.
We are uncertain of the effect of ICSI versus c‐IVF for live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI 0.94 to 1.30, I2 = 0%, 2 studies, n = 1124, low‐certainty evidence). The evidence suggests that if the chance of live birth following c‐IVF is assumed to be 32%, the chance of live birth with ICSI would be between 30% and 41%. For adverse events; multiple pregnancy, ectopic pregnancy, pre‐eclampsia and prematurity, there was probably little or no difference between the two techniques. No study reported the primary outcome stillbirth.
For secondary outcomes, we are uncertain of the effect of ICSI versus c‐IVF for clinical pregnancy rates (RR 1.00, 95% CI 0.88 to 1.13, I2 = 45%, 3 studies, n = 1539, low‐certainty evidence). Comparison of viable intrauterine pregnancy rates showed probably little or no difference between ICSI and c‐IVF (RR 1.00, 95% CI 0.86 to 1.16, I2=75%, 2 studies, n = 1479 couples, moderate‐certainty evidence). The high heterogeneity may have been caused by one older study conducted when protocols were less rigorous. The evidence suggests that if the chance of viable intrauterine pregnancy following c‐IVF is assumed to be 33%, the chance of viable intrauterine pregnancy with ICSI would be between 28% and 38%.
Miscarriage rates also showed probably little or no difference between the two techniques.
Authors' conclusions
The current available studies that compare ICSI and c‐IVF in couples with males presenting with normal total sperm count and motility, show neither method was superior to the other, in achieving live birth, adverse events (multiple pregnancy, ectopic pregnancy, pre‐eclampsia and prematurity), also alongside secondary outcomes, clinical pregnancy, viable intrauterine pregnancy or miscarriage.
Keywords: Female; Humans; Male; Pregnancy; Abortion, Spontaneous; Abortion, Spontaneous/epidemiology; Fertilization in Vitro; Fertilization in Vitro/methods; Live Birth; Live Birth/epidemiology; Pre-Eclampsia; Pregnancy Rate; Pregnancy, Ectopic; Sperm Count; Sperm Injections, Intracytoplasmic; Sperm Injections, Intracytoplasmic/methods
Plain language summary
Intracytoplasmic sperm injection versus conventional techniques for oocyte insemination during in vitro fertilisation in couples with non‐male subfertility
Title
Intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilisation (c‐IVF) for oocyte insemination during in vitro fertilisation (IVF) in couples with males presenting with normal total sperm count and motility.
Review question
Cochrane authors reviewed the evidence about the effect of ICSI versus c‐IVF in couples with males presenting with normal total sperm count and motility.
Background
Since starting over 40 years ago, IVF has become the cornerstone for fertility treatment. The process of IVF involves overstimulation of the ovaries to produce multiple eggs for collection. For c‐IVF, the eggs are incubated with sperm in the laboratory for the hope of fertilisation. Originally discovered in 1992, intracytoplasmic injection (ICSI) was introduced as a fertilisation technique to overcome low sperm counts. ICSI now is used also as an add‐on to IVF and is also utilised in cases with a history of low or total failure fertilisation with c‐IVF, and with mild male infertility or even unexplained infertility. We compare whether ICSI provides more favourable outcomes compared to c‐IVF.
Study characteristics
This review includes three randomised controlled trials (RCTs) comparing ICSI with c‐IVF in a total of 1539 couples undergoing fertility treatment. The evidence is current to February 2023.
Key results
The three well‐designed studies comparing ICSI and c‐IVF were included in the analysis. Two studies reported live birth, and we are uncertain of the effect of ICSI compared to c‐IVF for live birth rates. The evidence suggests that if the chance of live birth following c‐IVF is assumed to be 32%, the chance of live birth with ICSI would be between 30% and 41%. Adverse events including multiple pregnancy, ectopic pregnancy, pre‐eclampsia and prematurity showed probably little or no difference between the two techniques. No study reported on the primary outcome stillbirth.
Two studies report viable intrauterine pregnancy for ICSI and c‐IVF, suggesting that if the chance of viable intrauterine pregnancy following c‐IVF is assumed to be 33%, the chance of viable intrauterine pregnancy with ICSI would be between 28% and 38%. The results show that there is probably little or no difference for viable intrauterine pregnancy for ICSI compared to c‐IVF.
Clinical pregnancy and miscarriage rates also show probably little or no difference between the techniques.
Certainty of the evidence
There remains uncertainty about whether ICSI compared to c‐IVF increases live birth rate due to the lack of studies available. The certainty of evidence was assessed as low to moderate. The reason for this is that some the studies included in this review were not clear on the methodology including randomisation process. This means the results must be treated cautiously, and further studies are need to confirm the findings.
Summary of findings
Summary of findings 1. Summary of findings table ‐ ICSI compared to c‐IVF for males presenting with normal total sperm count and motility.
| ICSI compared to c‐IVF for males presenting with normal total sperm count and motility. | ||||||
| Patient or population: : Couples with males presenting normal total sperm count and motility were included in this review. Setting: IVF clinics Intervention: c‐IVF Comparison: ICSI | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with ICSI | Risk with c‐IVF | |||||
| Live Birth | 354 per 1000 | 393 per 1000 (333 to 460) | RR 1.11 (0.94 to 1.30) | 1124 (2 RCTs) | ⊕⊕⊝⊝ Lowa,b | |
| Multiple Pregnancy | 99 per 1000 | 89 per 1000 (66 to 119) | RR 0.89 (0.66 to 1.20) | 1479 (2 RCTs) | ⊕⊕⊕⊝ Moderateb | |
| Ectopic Pregnancy | 19 per 1000 | 19 per 1000 (8 to 45) | RR 1.00 (0.42 to 2.38) | 1064 (1 RCT) | ⊕⊕⊕⊝ Moderateb | |
| Pre‐Eclampsia | 2 per 1000 | 2 per 1000 (0 to 30) | RR 1.00 (0.06 to 15.95) | 1064 (1 RCT) | ⊕⊕⊕⊝ Moderateb | |
| Prematurity | 96 per 1000 | 72 per 1000 (51 to 102) | RR 0.75 (0.53 to 1.06) | 1064 (1 RCT) | ⊕⊕⊕⊝ Moderateb | |
| Clinical Pregnancy | 381 per 1000 | 381 per 1000 (335 to 430) | RR 1.00 (0.88 to 1.13) | 1539 (3 RCTs) | ⊕⊕⊝⊝ Lowa,b | |
| Viable intrauterine Pregnancy | 328 per 1000 | 328 per 1000 (282 to 381) | RR 1.00 (0.86 to 1.16) | 1479 (2 RCTs) | ⊕⊕⊕⊝ Moderateb | |
| Miscarriage | 51 per 1000 | 49 per 1000 (29 to 82) | RR 0.96 (0.58 to 1.61) | 1064 (1 RCT) | ⊕⊕⊕⊝ Moderateb | |
| *The risk in the intervention group (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; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426603407152284134. | ||||||
a Downgraded one level for risk of bias; unclear information on blinding b Decreased one level for Imprecision due to few events and confidence intervals include appreciable favour to either ICSI or c‐IVF
Background
Description of the condition
Since starting over 40 years ago, in vitro fertilisation (IVF) has been offered as a treatment for male factor subfertility. Male subfertility is associated with lower fertilisation and pregnancy rates than for other indications (Devroey 2004; Fishel 2000). Since the late 1980s, several assisted fertilisation techniques have emerged and have been rapidly developed to enhance results for couples with male factor subfertility, or to help couples with severe male factor for whom conventional IVF (c‐IVF) was not possible. Although such techniques do not address sperm defects such as low concentration, poor motility or poor morphology, neither solve the underlying male infertility condition. They allow such couples a chance to conceive, without having to resort to insemination with donor sperm, since a much smaller number of sperm is required. A second group of couples for whom such techniques are used are those with normal semen parameters but where c‐IVF has led to poor or failed fertilisation due to defective sperm‐oocyte interaction (Neri 2014). Intracytoplasmic sperm injection (ICSI) is such a technique. ICSI, originally introduced as an add‐on to IVF, has been used for couples with severe male infertility and currently is also used in cases with a history of low or total failure fertilisation with c‐IVF (Yuzpe 2000; Zhu 2011), with mild male infertility (Zheng 2020) or even unexplained infertility (Zheng 2020). We question whether ICSI might improve reproductive clinical outcomes in couples with males presenting with normal total sperm count and motility compared to c‐IVF.
Description of the intervention
For couples undergoing conventional IVF, the woman is overstimulated with hormonal injections to cause multiple follicles to grow. The growth of the follicle nurtures the oocytes (eggs) ready for aspiration. The oocytes are aspirated and placed in a petri dish where they are incubated with sperm in vitro with the hope for fertilisation. For c‐IVF, oocytes are inseminated with approximately 50,000 to 100,000 motile spermatozoa (Gangrade 2014). For males with severe infertility with low sperm concentrations, this fertilisation technique is not possible. ICSI was created to overcome this limitation.
During the ICSI procedure, a single spermatozoon (singular sperm) is injected centrally into the cytoplasm‐ a gel like substance within the inside of the oocyte, using a fine sharp tipped glass pipette (Zhou 2015). The procedure consists of two essential components that are completed within two to four minutes per oocyte. Firstly, a selected sperm is stunned by one of several commonly used techniques such as rubbing the tail with the injection pipette or abruptly aspirating the sperm into the pipette. The sperm tail is aspirated first into the injection pipette and positioned at three o'clock near the oocyte. A suction pipette stabilises the oocyte with the polar body at either the six o'clock or twelve o'clock position as the pipette is inserted. Secondly, the cytoplasm is drawn up into the pipette to ensure the cytoplasmic membrane is broken thus allowing successful insertion of the sperm. The pipette is subsequently withdrawn from the egg (Palermo 1992).
How the intervention might work
ICSI was originally introduced for couples with severe male infertility, however, this technique now represents the main type of assisted reproductive treatment (ART) worldwide (Esteves 2018; Haddad 2021). During the ICSI process, the pipette which is used to inseminate the oocyte breaks through the zona pellucida barrier. The zona pellucida barrier is a non‐cellular layer protecting the oocyte (Pierantoni 2002). The layer is made of carbohydrates and proteins. The process of ICSI is able to overcome the zona pellucida, as the sperm is manually injected into the cytoplasm of the oocyte. It is thought ICSI might improve the outcome in couples with non‐male factor subfertility due to spermatozoa not being able to successfully fertilise oocytes through this natural barrier.
Why it is important to do this review
For the couples undergoing assisted reproductive technologies (ARTs), the main goal is to have a healthy baby. ICSI has now been used for over 25 years and there are ongoing concerns about the use of this technique for effectiveness and long‐term outcomes of children born from it (Lu 2013/05).
The technique of ICSI is usually suggested to infertile males with low sperm count, poor sperm motility and poor sperm morphology. Importantly, one of the primary use of ICSI is for men with severe male factor infertility that require the use of surgically retrieve spermatozoa from either the epididymis or testicular tissue (Khera 2006). ICSI may also been used in cases of oocyte vitrification (ASRM 2013; Rienzi 2010). Despite ICSI being created to overcome poor fertilisation in males with severe infertility, this technique is now widely used worldwide. Indeed, some clinics have implemented an ICSI‐for‐all approach to reduce chances of failed fertilisation, aiming to increase embryo utilisation (Zheng 2020). Thus, ICSI has now been recorded to have a high incidence in couples with non‐male factor infertility (Hwang 2005; Johnson 2013), poor responders (Moreno 1998; Zheng 2020), unexplained infertility (Check 2011; Zheng 2020), and women of advanced age (Fishel 2000; Zheng 2020). The increase could be due to the availability of insurance coverage, perceived competition with other clinics in the country or laboratory efficiencies (Zheng 2020). Moreover, ICSI has also been reported to have higher fertilisation rates and decreased total fertilisation failure in unexplained infertility, causing the technique to be used more frequently (Johnson 2013), however, there is limited evidence to support this approach.
Importantly, there has been concerns about the effect of using an abnormal spermatozoon from males presenting with infertility. Some studies have suggested that underlying male subfertility may play a role in the risk of birth defects, but further research is required (Jwa 2019). Reviews investigating the birth outcomes of ICSI‐born children compared with c‐IVF born children, have also reported that there are no differences between the risks of birth defects between ICSI and c‐IVF conceived singletons (Banker 2019; Wen 2012; Zhu 2019). Moreover, a meta‐analysis reported an increase of birth defects in children born with ART compared to naturally conceived, but no difference between the use of ICSI to c‐IVF was found (Jia 2013). However, Luke and colleagues in 2021 reported an increase of 18% for non‐chromosomal defects in ART conceived singletons compared to naturally conceived singletons without the use of ICSI (Luke 2021). As a matter of concern, ART singletons conceived with ICSI in couples with male factor subfertility had an increase of 42% for non‐chromosomal defects. These findings align with Davies and colleagues in 2012, as they found there is an increased risk of birth defects with singletons born from ICSI (Davies 2012).
Considering the current state of knowledge, the effectiveness of ICSI is still questionable, therefore an update of evidence on ICSI outcomes in couples with non‐male subfertility is of importance. Thus, this review aimed to investigate whether, and to what extent, ICSI could improve reproductive outcomes compared to c‐IVF in couples with males presenting with normal total sperm count and motility.
Objectives
To evaluate the effectiveness and safety of Intracytoplasmic sperm injection (ICSI) relative to conventional in vitro fertilisation (c‐IVF) in couples with males presenting with normal total sperm count and motility.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) investigating Intracytoplasmic sperm injectio (ICSI) versus conventional in vitro fertilisation (c‐IVF) were included in this review. The unit of randomisation was couples. Sibling oocyte studies were excluded.
Types of participants
Couples with males presenting with normal total sperm count and motility were included in this review. Couples with severe male infertility were excluded.
Types of interventions
The comparison of ICSI versus c‐IVF was analysed.
Types of outcome measures
The following outcomes were stated, where possible.
Primary outcomes
1. Live birth rate (per couple)
Live birth is defined as delivery of a live fetus after 20 completed weeks' gestation
2. Adverse events (per couple)
-
Multiple pregnancy rate per couple
Multiple pregnancy defined as presence of more than one sac at early pregnancy ultrasound six to eight weeks gestation.
-
Ectopic pregnancy
A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualisation or histopathology.
-
Stillbirth
The death of a fetus prior to the complete expulsion or extraction from its mother after 20 completed weeks of gestational age. The death is determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation or definite movement of voluntary muscles.
Pre‐Eclampsia
Prematurity
Secondary outcomes
Secondary outcomes
-
Clinical pregnancy rate (per couple)
Clinical pregnancy defined as evidence of a gestational sac, confirmed by ultrasound.
-
Viable intrauterine pregnancy rate (per couple)
A pregnancy diagnosed by ultrasonographic examination of at least one fetus with a discernible heartbeat.
-
Miscarriage rate (per pregnancy)
Miscarriage rate defined as the spontaneous loss of an intrauterine pregnancy prior to 20 completed weeks of gestational age.
Fertilisation rate per oocyte inseminated, fertilisation rate per oocyte retrieved, fertilisation failure, implantation rate (defined by number of gestational sacs per number of embryos transferred with embryos as the denominator), embryo quality and blastocyst formation
Search methods for identification of studies
We searched for all reports, published and unpublished, that described RCTs investigating ICSI versus conventional techniques for oocyte insemination during IVF in couples with non‐male subfertility. We used both indexed and free‐text terms, and applied no language or date restrictions.
Electronic searches
The following electronic sources were searched in the update of this review (February 2023):
The Cochrane Gynaecology and Fertility specialised register (CGF), ProCite platform, searched from inception to 22 February 2023 (Appendix 1);
CENTRAL via the Cochrane Register Online (CRSO), Web platform, searched from inception to 22 Februrary 2023 (Appendix 2);
MEDLINE, Ovid platform, searched from 1946 to 22 February 2023 (Appendix 3);
Embase, Ovid platform, searched from 1980 to 22 February 2023 (Appendix 4);
PsycINFO, Ovid platform, searched from 1806 to 22 February 2023 (Appendix 5).
Searching other resources
We also searched:
International trial registers: the ClinicalTrials database, a service of the US National Institutes of Health (clinicaltrials.gov/ct2/home) and the World Health Organization International Trials Registry Platform search portal (www.who.int/trialsearch/Default.asp), Web platforms, searched from inception to 22 February 2023;
The reference lists of retrieved articles were handsearched and personal contact was made with experts in the field, for any additional trials.
Data collection and analysis
Selection of studies
Three review authors (EC, MR and FH) independently canned the titles and abstracts of the identified studies. Those that were clearly irrelevant were excluded. The full texts of potentially relevant articles were retrieved and independently assessed for inclusion by EC, MR and FH. Disagreement was resolved by consensus. We documented the selection process by a PRISMA flow chart Figure 1.
1.
Study flow diagram.
Data extraction and management
The review authors independently extracted data. Disagreements were resolved by consensus using the platform Covidence 2021. Where studies had multiple publications, the main trial was used as the reference and additional details were obtained from the supplementary references.
Assessment of risk of bias in included studies
The included studies were assessed for risk of bias using the Cochrane risk of bias assessment tool (Higgins 2017) to assess sequence generation, allocation concealment, blinding (participants, providers, outcome assessors), completeness of outcome data and selective reporting. Three review authors assessed these domains and disagreements were resolved by consensus.
Measures of treatment effect
For the included studies, we reported dichotomous data. We took the numbers of events in the c‐IVF and ICSI groups of each study to calculate relative risk ratio (RR). We presented 95% confidence intervals (CIs) for all outcomes. Where data to calculate risk ratios (RRs) were not available, we used the most detailed numerical data available. For example, if dichotomous data supplied percentages with sample numbers, we used these to calculate RRs. No continuous data were anticipated.
Unit of analysis issues
The primary analysis was per couple randomised. Per cycle data were not reported. We counted multiple births as one live birth event.
Dealing with missing data
We analysed data using an intention‐to‐treat basis as far as possible. We attempted to obtain missing data from the original trialists.
Assessment of heterogeneity
We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity by the measure of the I2 statistic (Higgins 2022). When heterogeneity exceeded 50%, a sensitivity analysis was conducted in an attempt to explain the data. Where heterogeneity could not be adequately explained, we decided the data would not be pooled in a meta‐analysis.
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. We planned to produce a funnel plot where there were more than 10 studies in an analysis.
Data synthesis
If the studies were sufficiently similar, we combined the data using a fixed‐effect model comparing c‐IVF with ICSI. We planned to pool the data for the included studies through the use of RevMan Web 2020.
Subgroup analysis and investigation of heterogeneity
There were no pre‐specified subgroups in this review.
Sensitivity analysis
Sensitivity analysis was conducted on all outcomes to determine whether the conclusions were robust. When heterogeneity exceeded 50%,then we conducted a sensitivity analysis was conducted based on the quality components of the risk of bias.
Summary of findings and assessment of the certainty of the evidence
We prepared a summary of findings table using GRADEpro and Cochrane methods (Schünemann 2021; GRADEpro GDT). This table evaluates the overall quality certainty of the body of evidence for the main review outcomes (live birth, multiple pregnancy, ectopic pregnancy, clinical pregnancy, viable intrauterine pregnancy and miscarriage) for the main review comparison (ICSI versus c‐IVF). As per agreement with the editorial base, the primary safety outcomes have been expanded to include pre‐eclampsia and prematurity.
We assessed the certainty of the evidence using GRADE criteria; risk of bias, consistency of effect, imprecision, indirectness and publication bias. Judgements about evidence certainty (high, moderate, low or very low) were made by at least two review authors (EC, MR and FH) working independently, and disagreements were resolved by discussion. All judgements are justified, documented and incorporated into the results of each outcome.
Results
Description of studies
Results of the search
The original review identified 15 controlled trials that evaluated the use of ICSI in comparison with an alternative method, with one study meeting the inclusion criteria.
For this update, the search retrieved 36 studies that evaluated the use of ICSI in comparison with c‐IVF. Two studies met our inclusion criteria. In the update of this review, 28 studies were excluded, and three studies are noted as ongoing. See Characteristics of included studies and Characteristics of excluded studies.
Included studies
See Characteristics of included studies
Study design and setting
Three RCTs (Bhattacharya 2001; Dang 2021;Foong 2006) met the inclusion criteria and were included in this review. Two studies were multicenter studies conducted in fertility clinics in theUK and Vietnam. One study was a single‐centre study completed in Canada.
Participants
The three studies n the current version of the review included i1539 couples undergoing fertility treatment with males presenting with normal total sperm count and motility. The mean age ranged from 30 to 36 years across the three studies.
Interventions
All three included studies compared ICSI with c‐IVF in couples with males presenting with normal total sperm count and motility.
Outcomes
Two studies (Dang 2021 and Foong 2006) reported live birth rate. Only one study (Dang 2021) reported miscarriage rate and ectopic pregnancy rate.
All three studies reported clinical pregnancy. Only Bhattacharya 2001 and Dang 2021 reported multiple pregnancy rate, implantation rate and fertilisation rates (oocyte inseminated, oocyte retrieved and total failed fertilisation). Foong 2006 also reported implantation rate and fertilisation rates, but the data were not available for analysis. Stillbirth was not reported by any study.
In the original review an attempt was made to obtain live birth rates, but unfortunately live birth was not recorded. For this reason live birth was only analysed for the two ew additional studies as the data were available.
In the previous published version of this review the outcome was ‘pregnancy’ rather than ‘viable intrauterine pregnancy’. After correspondence with the authors of Bhattacharya 2001 and the original review team, it was confirmed that pregnancy was defined as 'ongoing pregnancy' defined as a pregnancy reaching >20 weeks gestation.
Excluded studies
See Characteristics of excluded studies
In the previous version of this review (van Rumste 2003), eight studies were excluded because they randomised oocytes instead of couples (Aboulghar 1995; Aboulghar 1996; Calderon 1995; Catt 1995; Kastrop 1999; Payne 1997; Staessen 1998; Yang 1996).
Three studies were excluded because they used non‐random methods (for example, alternation) to allocate participants to either treatment group (Aboulghar 1996b; Bukulmez 2000; Ruiz 1997). One study (Moreno 1998) was excluded as it was not clear if it was a randomised study and the numbers of participants were not stated. Clasen 1996 was excluded because the study was a pilot study with fertilisation as the endpoint. This study was never continued. Levran 1995, which was included in the previous review, compared ICSI with SUZI and not IVF and was therefore excluded.
In the 2023 update, 17 studies were excluded because they randomised sibling oocytes instead of couples (Chamayou 2022; Chatterjee 2021; Chi 2012; ChungCHS 2018; DeMunck 2020; Elizur 2004; Isikoglu 2021; Khamsi 2001; Liu 2011; Makwana 2022; Mateizel 2020; Ombelet 2022;Rakic 2011; Thondehal 2020;Urfan 2017; vanderWesterlaken 2006; Youssef 2009).
One study was excluded because they used non‐random methods (for example alternation) to allocate participants to either treatment group (Eftekhar 2012). Ten studies were excluded as they were not an RCTs (Bhattacharya 2018; Chargui 2018; Drakopoulos 2019; Johnson 2013; Kim 2007;Lattes 2019; Micara 2000; Poehl 1998; Tannus 2017; Wu 2023). Two studies (Mortier 2000; Plachot 2002) were excluded because they were not non‐male factor. Wyns 2004 was excluded because the comparison was c‐IVF versus IVF‐ICSI split. Berntsen 2021; Fancsovits 2020; Zheng 2019 were classified as ongoing.
Risk of bias in included studies
Two of the review authors (FH and EC) independently assessed the included studies for risk of bias using the Cochrane risk of bias assessment tool to assess: selection, performance, detection, attrition, reporting and other bias. Judgements were assigned as recommended in the Cochrane Handbook Chapter 8 (Higgins 2017). Disagreements were resolved by discussion or consultation with a third review author (MVR). All judgements and conclusions are presented in the risk of bias table and incorporated into the interpretation of the review findings by means of sensitivity analyses. As displayed in Figure 2 and Figure 3, risk of bias was considered low in Dang 2021 due to their methods for selection, performance (blinding), detection and reporting. For Bhattacharya 2001, risk of bias was considered low, however there was high risk bias for methods due to lack of blinding. For Foong 2006, risk of bias was considered high as there was a lack of information for the methods of the study. There was no information on blinding and the results for the study were only presented as percentage values rather than whole numbers.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
A summary can also be referred to in the risk of bias table (Characteristics of included studies). The main source of bias was the unclear blinding in the methods for two studies. Other sources of bias for the review include one study reporting both groups reported an average infertility time of three years, whereas the other reported an infertility time of 4.5 years. The longer time of infertility could impact the results as the cohort may have had more failures in comparison. However, the difference between groups (ICSI or c‐IVF patients) is quite minor.
Allocation
The allocation method was clear in two included studies (Bhattacharya 2001 and Dang 2021). In the Bhattacharya study, couples were randomised by means of a centralised telephone system. Stratification was performed by centre and there was minimisation of key prognostic variables including age, parity and previous treatment with IVF.
In the Dang 2021 study, a telephone‐based central randomisation method was used for allocation. Allocation was a computer‐generated random list performed by an independent statistician who had no other involvement in the study, using the ‘blockrand’ package in R statistical program, version 4·0 (R Core Team, 2020).
Foong 2006 did not provide information in regard to allocation concealment, and we rated these as at unclear risk of bias for this domain.
Blinding
Bhattacharya 2001 did not state any details on blinding or detection in the manuscript, however upon contacting the primary author, it was confirmed no blinding took place.
In the case of Dang 2021, the study stated “embryologists and couples were not blinded, but clinicians performing embryo transfer (ET) were unaware of study group allocation”. Dang 2021 study elaborated laboratory staffs were advised to “strictly adhered to standard operation procedures and similar management in both groups”. Although there was only blinding to clinicians, low bias still persists for performance, as randomisation was performed through a telephone‐based central randomisation system.
For detection bias, in Dang 2021, the assessors were not blinded, however the outcome measurement (live birth) could not be affected by the influence of lack of blinding. The funding role also had no part in analysing in the study data.
It is unlikely that the influence of blinding of participants or embryologist would affect the primary outcome (live birth).
Foong 2006 did not provide information in regard to the blinding of participants or assessors, therefore we rated these as at unclear risk of bias for this domain.
Incomplete outcome data
For all studies, all the women were randomised. Two studies were judged to be low risk of attrition bias.
Data was originally presented as per cycle (Bhattacharya 2001) and attrition (per cycle) was documented throughout the trial. The original review authors were able to obtain per couple data from the original author.
All outcomes were reported for Dang 2021. However, the numerical values for fertilisation per oocyte retrieved, per oocyte inseminated and fertilisation failure was attained, alongside pre‐eclampsia rates for data analysis. For Dang 2021 the results have been analysed based on intention‐to‐treat. It must be noted that within the original groups, 41 patients who were randomised to c‐IVF chose ICSI and two randomised to ICSI chose c‐IVF. It must be noted that the results reported within this review are based on the groups at randomisation.
Foong 2006 did not report the whole numbers for the outcomes, only percentages. Significance values (P value) was only provided when the outcome was significant. Risk ratio (RR) and odds ratios (OR) were also not reported.
Selective reporting
All outcomes specified within the protocols for the studies were reported for Bhattacharya 2001 and Dang 2021. Therefore, we rated them as low risk of selective bias.
The protocol for Foong 2006 was not available, therefore it was reported as unclear risk of bias.
Other potential sources of bias
The baseline characteristics for all studies were similar in relation to age. However, for Dang 2021, both groups reported an average infertility time of 3three years, whereas Bhattacharya 2001 reported an infertility time of 4.5 years. Foong 2006 also reported a larger time of infertility compared to Dang 2021. The longer time of infertility could impact the results as the cohort may have had more failures compared to the Dang 2021 cohort.
Effects of interventions
See: Table 1
We included three studies involving 1539 couples in this review. See: Table 1
Comparison of Intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilisation (c‐IVF)
1.1 Live birth rate per couple
This analysis was based on two studies (Dang 2021; Foong 2006). We are uncertain of the effect of ICSI versus c‐IVF for live birth rates (RR 1.11, 95% CI 0.94 to 1.30, I2=0%, 2 studies, n =1124, low‐certainty evidence;Analysis 1.1; Figure 4). The evidence suggests that if the chance of live birth following c‐IVF is assumed to be 32%, the chance of live birth with ICSI would be between 30% and 41%.
1.1. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 1: Live birth
4.
Forest Plot for live birth rate. Each marker represents the estimate summary risk ratio for each comparison; each horizontal line represents confidence interval for each comparison; black vertical line represents line of no effect (risk ratio =1). Risk ratio greater than 1 favours the ICSI; risk ratio less than 1 favours c‐IVF
1.2 Adverse events
1.2.1 Multiple pregnancy per couple
The primary analysis was based on two studies (Dang 2021; Foong 2006). The analysis showed that there is probably little or no difference between ICSI and c‐IVF for multiple pregnancy (RR 0.89, 95% CI 0.66 to 1.20, I2 = 0%, 2 studies, n=1479 couples, moderate‐certainty evidence;Analysis 1.2;Figure 5). This suggests that if the chance of multiple pregnancy following c‐IVF is assumed to be 11%, the chance of multiple pregnancy with ICSI would be between 7% and 13%.
1.2. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 2: Multiple pregnancy
5.
Forest Plot for multiple pregnancy rate. Each marker represents the estimate summary risk ratio for each comparison; each horizontal line represents confidence interval for each comparison; black vertical line represents line of no effect (risk ratio =1). Risk ratio greater than 1 favours the ICSI; risk ratio less than 1 favours c‐IVF
1.2.2 Other adverse events
These analyses were based on one study (Dang 2021), as only one study reported on incidence of ectopic pregnancy, pre‐eclampsia and prematurity. All three adverse events reported showed there is probably little or no difference between the two techniques. Ectopic pregnancy (RR 1.00, 95% CI 0.42 to 2.38, 1 study, 1064 couples; moderate‐certainty evidence; Analysis 1.3); pre‐eclampsia (RR 1.00, 95% CI 0.06 to 15.95, 1 study, 1064 couples; moderate‐certainty evidence; Analysis 1.4); prematurity (RR 0.75, 95% CI 0.53 to 1.06, 1 study, 1064 couples; moderate‐certainty evidence; Analysis 1.5).
1.3. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 3: Ectopic pregnancy
1.4. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 4: Pre‐eclampsia
1.5. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 5: Prematurity
No study reported our primary adverse event stillbirth.
1.3 Clinical pregnancy rate per couple
This analysis was based on three studies. We are uncertain of the effect of ICSI versus c‐IVF for clinical pregnancy (RR 1.00, 95% CI 0.88 to 1.13, I2= 45%, 3 studies, n=1539, low‐certainty evidence, Analysis 1.6). The evidence suggests that if the chance of clinical pregnancy following c‐IVF is assumed to be 39%, the chance of clinical pregnancy with ICSI would be between 34% and 44%. A Forest plot for clinical pregnancy is presented in Figure 6.
1.6. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 6: Clinical pregnancy
6.
Forest Plot for clinical pregnancy rates. Each marker represents the estimate summary risk ratio for each comparison; each horizontal line represents confidence interval for each comparison; black vertical line represents line of no effect (risk ratio =1). Risk ratio greater than 1 favours the ICSI; risk ratio less than 1 favours c‐IVF
1.4 Viable intrauterine pregnancy per couple
The primary analysis was based on the two studies. The analysis showed that there is probably little or no difference between ICSI and c‐IVF for viable intrauterine pregnancy (RR 1.00, 95% CI 0.86 to 1.16, I2=75%, 2 studies, n =1479 couples, moderate‐certainty evidence; Analysis 1.7; Figure 7). This suggests that if the chance of a viable intrauterine pregnancy following c‐IVF is assumed to be 33%, the chance of viable intrauterine pregnancy with ICSI would be between 28% and 38%.
1.7. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 7: Viable intrauterine pregnancy
7.
Forest Plot for viable intrauterine pregnancy rate. Each marker represents the estimate summary risk ratio for each comparison; each horizontal line represents confidence interval for each comparison; black vertical line represents line of no effect (risk ratio =1). Risk ratio greater than 1 favours the ICSI; risk ratio less than 1 favours c‐IVF
We note heterogeneity of 75%. The two studies in Analysis 1.7 had differing directions of effect. This could be due to Bhattacharya 2001 transferring two embryos and sometimes three embryos at embryo transfer, stating the analysis was not quote: "adjusted for the correlated outcomes resulting from the clustering of embryos transferred to each woman". Therefore, it may be possible that more embryos were transferred in the c‐IVF group causing the increase of pregnancy.
1.5 Miscarriage rate per pregnancy
This analysis was based on one study (Dang 2021), as only one study reported on miscarriage rate. There is probably little or no difference for miscarriage rate when comparing ICSI with c‐IVF (RR 0.96, 95% CI 0.58 to 1.61, 1 study, 1064 couples; moderate‐certainty evidence; Analysis 1.8). The evidence suggests that if the chance of miscarriage following c‐IVF is assumed to be 5%, the chance of miscarriage with ICSI would be between 3% and 9%.
1.8. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 8: Miscarriage
1.6 Fertilisation rate per oocyte inseminated
This analysis was based on two studies (Bhattacharya 2001; Dang 2021). The analysis showed there was probably slight improvement in fertilisation for ICSI compared to c‐IVF (RR 1.12, 95% CI 1.09 to 1.15, I2=0%, 2 studies, n=1479 couples, moderate‐certainty evidence; Analysis 1.9). Although ICSI provides higher fertilisation rates, this may be due to the ICSI technique being used only on mature oocytes (immature oocytes discarded), whereas the c‐IVF technique is used on all oocytes retrieved regardless their maturation status.
1.9. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 9: Fertilisation per oocyte inseminated
1.7 Fertilisation rate per oocyte retrieved
This analysis was based on two studies (Bhattacharya 2001; Dang 2021). The analysis showed probably little or no difference between ICSI and c‐IVF in regard to fertilisation rate per oocyte retrieved (RR 1.00, 95% CI 0.97 to 1.02, I2 = 99%, 2 studies, n = 1479 couples, moderate‐certainty evidence; Analysis 1.10). The high heterogeneity score is due to the studies having differing directions of effect, this may have been caused by one older study being conducted when protocols were less rigorous.
1.10. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 10: Fertilisation per oocyte retrieved
1.8 Fertilisation failure
This analysis was based on one study (Dang 2021), as only one study reported on fertilisation failure. The analysis showed probably little or no difference between the two techniques (RR 0.85, 95% CI 0.53 to 1.38, 1 study, 1064 couples; moderate‐certainty evidence; Analysis 1.11).
1.11. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 11: Fertilisation failure
1.9 Implantation rate
This analysis was based on two studies (Bhattacharya 2001; Dang 2021). The analysis showed probably little or no difference between ICSI and c‐IVF for implantation rates (RR 0.94, 95% CI 0.83 to 1.06, I2=74%, 2 studies, n = 1479 couples, moderate‐certainty evidence; Analysis 1.12). The high heterogeneity score is due to the studies having differing directions of effect, this may have been caused by one older study being conducted when protocols were less rigorous.
1.12. Analysis.
Comparison 1: ICSI vs. c‐IVF, Outcome 12: Implantation rate
Discussion
Summary of main results
Our findings suggest that Intracytoplasmic sperm injection (ICSI) compared to c‐IVF results in similar clinical pregnancy rates, viable intrauterine pregnancy rates, miscarriage rates, multiple pregnancy rates, implantation rates and similar results for adverse events. In terms of live birth rates, the current evidence indicates neither method is superior to the other, however, due to only one study (Dang 2021) reporting this evidence, further investigation on live birth rates for ICSI compared to c‐IVF is required.
Importantly, two studies reported fertilisation rates. Bhattacharya 2001 reported a higher fertilisation rate per oocyte retrieved for c‐IVF, however the fertilisation rate per oocyte inseminated was higher in ICSI. Similarly, Dang 2021 reported fertilisation per oocyte inseminated being higher in the ICSI technique compared to the c‐IVF fertilisation method, but contrary to Bhattacharya 2001, fertilisation per oocyte retrieved for Dang 2021, presented no difference between the two techniques. The higher value of fertilisation per oocyte inseminated for the ICSI group may be due to the ICSI technique being only used on mature oocytes (immature oocytes discarded), whereas the c‐IVF technique is used on all oocytes retrieved regardless their maturation status. However, as both studies present contradictory findings for fertilisation rate per oocyte retrieved, further research is required to investigate this hypothesis.
Significantly, fertilisation failure presented probably little or no differences between ICSI and c‐IVF in both studies, indicating that ICSI does not provide improved total fertilisation failure results over c‐IVF.
As a significant remark, it is important to recognise that both studies included couples with males presenting with poor sperm morphology even though they had normal total sperm count and motility. This could potentially play a role in the interpretation of the outcomes as it has been widely accepted that poor morphology is an indication for ICSI rather than c‐IVF (Dariš 2010; Lundin 1997; Pereira 2015). Poor sperm morphology has been linked to decreased fertilisation rates (Kruger 1988; Obara 2001), which could partially explain decreased fertilisation rates in a c‐IVF compared to ICSI.
Overall completeness and applicability of evidence
Several factors limit the evidence provided in our review. There were only three available randomised controlled trials (RCTs) that compared c‐IVF with ICSI without the method of using sibling oocytes. The use of sibling oocytes for comparing the techniques was more common, however this method reduces the availability of the primary outcome of live birth.
A number of factors complicated the comparison of the three studies, such as blinding, data availability, and older methodology (over 20 years).
These factors may explain the considerable heterogeneity of treatment effects identified in some analyses.
There was a lack of data available to compare the adverse events. Only one study provided these data. This may be also due to the differences in methods as the other two studies were conducted when methodology was less rigorous. The review question was answered; however, the results should be interpreted with caution as only three studies were analysed.
Quality of the evidence
The certainty of evidence for the outcome of Live Birth, was low. This was due to the unclear blinding of one of the studies and overall being downgraded for imprecision.
The certainty of evidence for the adverse events was moderate as this was based on one study. However, the study was also downgraded one level for imprecision. As the number of events for each outcome is less than 400, there is a level of imprecision as the study alone does not represent the whole population.
Clinical pregnancy was also graded as low as the studies were downgraded for unclear blinding alongside imprecision. Viable intrauterine pregnancy and miscarriage were downgraded to moderate due to imprecision.
Potential biases in the review process
We followed the Cochrane Handbook for Systemic Reviews of Interventions to conduct this review (Higgins 2022). A broad search was applied to ensure all related papers were included. Two review authors independently extracted the data and assessed the risk of bias. Conflicts were resolved by a third review author. There should be no bias in the review process with respect to study selection and analysis of available data.
We used random‐effects pairwise meta‐analyses to incorporate heterogeneity. Since sensitivity analysis were unable to be conducted due to the low number of studies, our confidence in effect estimates is reduced.
The other main risk of bias within the review process is the interests of BWM and VD as they are authors on the Dang 2021 study. This bias was avoided as BWM and VD had no part in study screening, data extraction or bias grading. Therefore, the risk was minimised.
Agreements and disagreements with other studies or reviews
Two studies (Aboulghar 1996; Bukulmez 2000) compared ICSI with c‐IVF and had couples as the unit of comparison. They used alternation to allocate couple, so there was no randomisation. In spite of this, we have described these studies here, but we will not base our conclusions on these results. Both studies included couples with males presenting with normal total sperm count and motility. The general characteristics were comparable for the couples in the ICSI and c‐IVF groups. The mean duration of infertility was quite long: in Bukulmez 2000 it was 9 to 10 years, and in Aboulghar 1996 it was7 to 8 years. Approximately three embryos were transferred per cycle. In Aboulghar 1996 116 couples were included, and 76 couples in Bukulmez 2000, which gives a total of 192 couples. In terms of fertilisation, the ICSI group had 53.5% of oocytes fertilised compared to the c‐IVF group where 64.8% of retrieved oocytes were fertilised. This resulted in an odds ratio (OR) of 0.62 (95% CI 0.51 to 0.77), indicating that fertilisation rate per oocyte retrieved was significantly lower in ICSI compared to c‐IVF. Moreover, there was no difference in the pregnancy rate (OR 0.95, 95% CI 0.51 to 1.78; ICSI: 27/96, c‐IVF: 26/96). Neither was there a difference in the miscarriage rate (OR 0.76, 95%confidence interval (CI) 0.15 to 3.84; ICSI: 4/19, c‐IVF: 3/18), nor in live birth rate (OR 0.83, 95% CI 0.25 to 2.73; ICSI: 7/38, c‐IVF: 6/38). In conclusion, there is no statistical difference between ICSI or c‐IVF for conceiving a child within the couples concerned.
As methodology has progressed and become more rigorous over time, there was uncertainty with regard to some of Bhattacharya 2001's methodology, such as amount of sperm used for fertilisation in c‐IVF. Therefore, contact was made to the original authors o Bhattacharya 2001 to find radiational information on insemination. The leading author was able to provide information on insemination numbers, however the original protocol was not available.
The data provided in the Dang 2021 manuscript for fertilisation and implantation were provided as percentage values. The leading author of the study was contacted, and precise numbers were given for the percentage values, therefore the analysis was able to be matched with Bhattacharya 2001.
Foong 2006 also compared ICSI with c‐IVF on a randomised basis. However, the study only reported results for outcomes as a percentage and did not specify exact numbers. The study also did not report the relative risk intervals. An attempt to contact the author was conducted, but no valid email address or contact details were found.
Authors' conclusions
Implications for practice.
The current available studies that compare ICSI and c‐IVF in couples with males presenting with normal total sperm count and motility, show neither method was superior to the other, in achieving live birth, clinical pregnancy or viable intrauterine pregnancy.
Implications for research.
More studies need to be completed comparingIntracytoplasmic sperm injection (ICSI) with conventional in vitro fertilisation (c‐IVF) in couples with males presenting with normal total sperm count and motility. Outcomes that should be observed include; live birth, viable intrauterine pregnancy, multiple pregnancy, ectopic pregnancy and miscarriage rates. It is important that they are randomised in a methodologically rigorous way. Couples should be the unit of randomisation if the study is to have any implication for clinical practice. Long‐term follow‐up studies should report on live births, birth defects and child development as outcome measures. Importantly, none of the included studies have incorporated the analysis of sperm morphology as male subfertility, thus, it cannot be determined whether sperm morphology plays a role or not in the outcome of ICSI and c‐IVF as insemination techniques.
What's new
| Date | Event | Description |
|---|---|---|
| 15 August 2023 | New citation required and conclusions have changed | The addition of two studies has provided data for more review outcomes, but there remains uncertainty about the relative effectiveness of either treatment. |
| 15 August 2023 | New search has been performed | Two new studies added: Dang 2021; Foong 2006. Review methods revised and updated to current Cochrane standards. The spelling of intracytoplasmic in the review title has been changed by removal of the hyphen to reflect current usage. |
History
Protocol first published: Issue 2, 1998 Review first published: Issue 2, 1999
| Date | Event | Description |
|---|---|---|
| 24 January 2011 | New search has been performed | Review updated and Revman 5 formatting undertaken. No new trials identified. |
| 24 January 2011 | Review declared as stable | This review will no longer be updated as there have been no new studies identified in the most recent update and the likelihood of new studies emerging or ever changing the findings is limited. |
| 11 November 2008 | Amended | Converted to new review format. |
| 4 February 2003 | New citation required and conclusions have changed | Substantive amendment |
Notes
Since ICSI has proven to be the therapy of choice for couples with severe male factor infertility in whom c‐IVF is not possible, the comparison has been narrowed down to ICSI versus c‐IVF in couples with non‐male subfertility. ICSI has by far surpassed PZD and SUZI, therefore the title has been changed from "Inta‐cytoplasmic sperm injection versus partial zona dissection, sub‐zonal insemination and conventional techniques for oocyte insemination during in vitro fertilisation" to "ICSI versus conventional IVF in couples with total normal sperm count and motility – a meta‐analysis".
Acknowledgements
For the previous version of this review, the authors thank Julie Brown (Cochrane Menstrual Disorders and Subfertility Group (MDSG)), Tracy Naysmith (Fertility Plus, Auckland), Anne Lethaby, Sarah Hetrick (former MDSGroup Co‐ordinator), Michelle Proctor (MDSG Co‐ordinator), Sue Furness (former MDSG Trials Search Co‐ordinator) and Ruth Withers (Trials Search Co‐ordinator) for assistance with this review.
The authors are especially grateful to the following trialists who provided additional material for this review: Dr Aboulghar, Dr Bhattacharya, Dr Clasen, Dr Calderon, Dr Dang, Dr Hamilton, Dr Kastrop, Dr Moreno and Dr Ruiz.
The authors of the 2023 update are indebted to Helen Nagels (Managing Editor Cochrane) for her assistance with this update and her assistance with the initial review. The authors of the 2023 update also thank Prof Cindy Farquhar and Prof Johannes Evers for their contributions to previous versions of this review. The authors of the 2023 update thank also Ms Jeanette Mackenzie, Fertility Plus, Auckland, New Zealand and Ms Angela Beros, Faculty of Medical and Health Sciences, The University of Auckland for providing peer review comments on the draft, and Ms Heather Maxwell for copy editing the draft.
Appendices
Appendix 1. The Cochrane Gynaecology and Fertility (CGF) specialised register search strategy
ProCite platform
Searched from inception to 22 February 2023
Keyword CONTAINS "IVF vs ICSI" or Title CONTAINS "IVF vs ICSI"
22 records
Appendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy
Web platform
Searched from inception to 22 February 2023
#1 MESH DESCRIPTOR Fertilization in Vitro 1872 #2 (vitro fertilization or vitro fertilisation):TI 1834 #3 (conventional adj4 assisted reproduct*):TI 2 #4 (conventional technique*):TI 174 #5 IVF:TI 2398 #6 #1 OR #2 OR #3 OR #4 OR #5 4934 #7 MESH DESCRIPTOR Sperm Injections, Intracytoplasmic 562 #8 (intracytoplasmic sperm*):TI 446 #9 (intra‐cytoplasmic sperm*):TI 38 #10 ICSI:TI 1119 #11 #7 OR #8 OR #9 OR #10 1758 #12 #6 AND #11 912
Appendix 3. MEDLINE search strategy
Ovid platform
Searched from 1946 to 22 February 2023
1 Fertilization in Vitro/ (33482) 2 (vitro fertilization or vitro fertilisation).tw. (24750) 3 (conventional adj4 assisted reproduct*).tw. (35) 4 conventional technique*.tw. (7942) 5 IVF.tw. (25342) 6 or/1‐5 (55828) 7 Sperm Injections, Intracytoplasmic/ (7130) 8 intracytoplasmic sperm*.tw. (7823) 9 intra‐cytoplasmic sperm*.tw. (334) 10 ICSI.tw. (9133) 11 or/7‐10 (13023) 12 6 and 11 (8129) 13 randomized controlled trial.pt. (539543) 14 controlled clinical trial.pt. (94320) 15 randomized.ab. (529228) 16 randomised.ab. (105385) 17 placebo.tw. (226193) 18 clinical trials as topic.sh. (196868) 19 randomly.ab. (363012) 20 trial.ti. (244908) 21 (crossover or cross‐over or cross over).tw. (90033) 22 or/13‐21 (1456554) 23 exp animals/ not humans.sh. (4870531) 24 22 not 23 (1341063) 25 12 and 24 (1204)
Appendix 4. Embase search strategy
Ovid platform
Searched from 1980 to 22 February 2023
1 in vitro fertilization/ (11815) 2 (vitro fertilization or vitro fertilisation).ti. (12363) 3 (conventional adj4 assisted reproduct*).ti. (6) 4 conventional technique*.ti. (592) 5 IVF.ti. (9903) 6 or/1‐5 (30154) 7 intracytoplasmic sperm injection/ (22448) 8 intracytoplasmic sperm*.ti. (3107) 9 intra‐cytoplasmic sperm*.ti. (105) 10 ICSI.ti. (3975) 11 or/7‐10 (23006) 12 6 and 11 (6068) 13 Clinical Trial/ (999655) 14 Randomized Controlled Trial/ (665763) 15 controlled clinical trial/ (463547) 16 multicenter study/ (295396) 17 Phase 3 clinical trial/ (54945) 18 Phase 4 clinical trial/ (4387) 19 exp randomization/ (91616) 20 Single Blind Procedure/ (43294) 21 Double Blind Procedure/ (183270) 22 Crossover Procedure/ (67599) 23 Placebo/ (355685) 24 Randomi?ed controlled trial$.tw. (263278) 25 Rct.tw. (42933) 26 (random$ adj2 allocat$).tw. (46795) 27 Single blind$.tw. (27049) 28 Double blind$.tw. (214821) 29 ((treble or triple) adj blind$).tw. (1373) 30 placebo$.tw. (323218) 31 prospective study/ (701524) 32 or/13‐31 (2514884) 33 case study/ (79885) 34 case report.tw. (445578) 35 abstract report/ or letter/ (1158139) 36 Editorial.pt. (687451) 37 Letter.pt. (1152411) 38 Note.pt. (858873) 39 or/33‐38 (3280220) 40 32 not 39 (2386228) 41 12 and 40 (1613)
Appendix 5. PsycINFO search strategy
Ovid platform
Searched from 1806 to 22 February 2023
1 Fertilization in Vitro/ or IVF.mp. (621) 2 (in vitro fertilization or in vitro fertilisation).mp. (816) 3 ICSI.mp. or Sperm Injections, Intracytoplasmic/ (81) 4 intracytoplasmic sperm$.mp. (61) 5 intra‐cytoplasmic sperm$.mp. (6) 6 intra cytoplasmic sperm$.mp. (6) 7 or/3‐6 (103) 8 or/1‐2 (967) 9 7 and 8 (64)
Data and analyses
Comparison 1. ICSI vs. c‐IVF.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Live birth | 2 | 1124 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.94, 1.30] |
| 1.2 Multiple pregnancy | 2 | 1479 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.66, 1.20] |
| 1.3 Ectopic pregnancy | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4 Pre‐eclampsia | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Prematurity | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.6 Clinical pregnancy | 3 | 1539 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.88, 1.13] |
| 1.6.1 Overall | 3 | 1539 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.88, 1.13] |
| 1.7 Viable intrauterine pregnancy | 2 | 1479 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.86, 1.16] |
| 1.8 Miscarriage | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.9 Fertilisation per oocyte inseminated | 2 | 14041 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [1.09, 1.15] |
| 1.9.1 Fertilisation per oocyte inseminated | 2 | 14041 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [1.09, 1.15] |
| 1.10 Fertilisation per oocyte retrieved | 2 | 17178 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.97, 1.02] |
| 1.11 Fertilisation failure | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.12 Implantation rate | 2 | 2567 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.83, 1.06] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Bhattacharya 2001.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial
Study grouping: Parallel group Comments: four participating centres It is not specified within the manuscript of Bhattacharya to what concentration of sperm was used for insemination via c‐IVF. The leading author of the study was contacted regarding the method and stated the following "“I have no reason to believe that normal protocols were not followed cannot confirm what was done across all the recruiting centres. As many of the relevant embryologists may have retired by now, this information is unavailable.” |
|
| Participants |
Baseline Characteristics IVF ‐ 206 ICSI ‐ 209 Overall Included criteria: eligible couples were awaiting IVF for an indication other than severe male‐factor infertility. The inclusion criteria;
Excluded criteria: Exclusion criteria;
|
|
| Interventions |
Intervention Characteristics IVF ICSI |
|
| Outcomes |
Implantation Rate
Clinical Pregnancy
Fertilisation Rate per oocyte retrieved
|
|
| Identification |
Sponsorship source: Serono UK Country: United Kingdom Setting: four centres Authors name: S Bhattacharya Institution: Assisted Reproduction Unit, Aberdeen University, AberdeenMaternity Hospital; Assisted Conception Unit, Guy’s and St Thomas’ Hospital Trust, London; Assisted Conception Unit, Leeds General Infirmary, Leeds; Centre for ReproductiveMedicine, Walsgrave Hospital Address: Assisted Reproduction Unit, Aberdeen University, AberdeenMaternity Hospital, Foresterhill, Aberdeen AB25 2ZD, UK |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Low risk bias as the randomisation system incorporated stratification by centre and minimisation of key prognostic variables including age, parity, and previous treatment with IVF. |
| Allocation concealment (selection bias) | Low risk | Low risk bias as randomly assigned an IVF or an ICSI treatment cycle by means of a centralised telephone system based in Aberdeen. The randomisation system incorporated stratification by centre and minimisation of key prognostic variables including age, parity, and previous treatment with IVF. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding occured as per Bhattacharya 2001. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not stated |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Low risk as attrition (per cycle) is documented |
| Selective reporting (reporting bias) | Low risk | Low risk as outcomes are described in methods and published in results |
| Other bias | Low risk | No other concerns for bias. |
Dang 2021.
| Study characteristics | ||
| Methods |
Study design: randomised controlled trial
Study grouping: parallel group Comments: two participating IVF centres |
|
| Participants |
Baseline characteristics IVF ‐ 532 ICSI ‐ 532 Overall Included criteria:
Excluded criteria:
Allocation: Couples were randommised (1:1) to undergo either ICSI or c‐IVF, using block randomisation with variable block size of 2, 4, or 8 and a telephone‐based central randomisation method. |
|
| Interventions |
Intervention characteristics IVF ICSI |
|
| Outcomes |
Implantation Rate Outcome type: Dichotomous outcome Clinical Pregnancy Outcome type: Dichotomous outcome Live birth Rate Outcome type: Dichotomous outcome Fertilisation Rate Outcome type: Dichotomous outcome Miscarriage Outcome type: Dichotomous outcome Ongoing Pregnancy Outcome type: Dichotomous outcome Twin Pregnancy Outcome type: Dichotomous outcome Twin Delivery Outcome type: Dichotomous outcome Ectopic Pregnancy Outcome type: Dichotomous outcome |
|
| Identification |
Sponsorship source: My Duc Hospital Country: Viet Nam Setting: two IVF centres in Ho Chi Minh 110City, Viet Nam: IVFMD, My Duc Hospital and IVFAS, An Sinh Hospital Comments: partly supported by a grant from MSD [MISP #57508] Authors name: VinhQuang Dang Institution: IVFMD, My Duc Hospital Email: bsvinh.dq@myduchospital.vn Address: IVFMD, My Duc Hospital, 4 Nui Thanh, Tan Binh District, Ho Chi Minh City, Vietnam Telephone: +84 908225481 |
|
| Notes |
Included
532 couples IVF 532 couples c‐ICSI The trial is registered with ClinicalTrials.gov, NCT03428919 It must be noted that within the original groups, 41 patients who were randomised to c‐IVF chose ICSI and 2 randomised to ICSI chose c‐IVF. It must be noted that the results reported within this review are based on the groups at randomisation. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Low risk bias as a computer‐generated random list was prepared by an independent statistician who had no other involvement in the study, using the ‘blockrand’ package in R statistical program, version 4·0 R Core Team, 2020. |
| Allocation concealment (selection bias) | Low risk | To ensure allocation concealment, a telephone‐based central randomisation method was used. The randomisation system incorporated stratification by centre and minimisation of key prognostic variables including age and previous treatment with IVF. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Low risk as clinicians performing embryo transfer (ET) were unaware of study group allocation. Embryologists and couples were not blinded, however this would not have affected the primary outcome (live birth). The fact that only clinicians performing ET were blinded to study group allocation has potential to introduce another source of treatment bias. Attempts to minimise this bias included the performance of all interventions in the laboratory were strictly adhered to standard operation procedures and similar management in both groups. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear as not stated if obstetricians knew if pregnancy was conceived after ICSI or c‐IVF. Although this is not expected to influence the outcomes. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | The results have been analysed based on intention to treat. It must be noted that within the original groups, 41 patients who were randomised to c‐IVF chose ICSI and 2 randomised to ICSI chose c‐IVF. It must be noted that the results reported within this review are based on the groups at randomisation. |
| Selective reporting (reporting bias) | Low risk | Low risk as study protocol is available and all outcomes reported in the protcol were also reported in the final report. |
| Other bias | Low risk | No other concerns for bias. |
Foong 2006.
| Study characteristics | ||
| Methods |
Study design: randomised clinical trial Sixty patients with unexplained infertility were randomised to either IVF or ICSI. Ethical approval was obtained from the institutional review board and all patients provided written informed consent. Pituitary downregulation was achieved with luteal phase gonadotropin‐releasing hormone (GnRH) agonist (Lupron, TAP Pharmaceuticals, St. Louis, Missouri, USA or Suprefact, Hoechst AG, Frankfurt, Germany). Ovarian stimulation with Gonal‐F injection was started after confirmation of downregulation and cycle monitoring was performed by US and serum E2. Treatment with Gonal‐F was discontinued in cases of poor ovarian response as defined by a plateau or drop in serum E2 after three consecutive days at the maximum Gonal‐F dose of 450 IU/day. When the diameter of the largest follicle was ≥18 mm, with at least two other follicles ≥16 mm, human chorionic gonadotropin (Profasi; Serono Canada Inc., Oakville, Ontario, Canada) was administered followed by transvaginal oocyte retrieval 35 h later. Insemination for IVF or ICSI was performed using sperm collected on the day of retrieval. The best embryos (maximum of four) were transferred on day #3 post retrieval. Profasi injections or natural progesterone vaginal suppositories were used for luteal support. Serum βhCG was assessed 16 days post embryo transfer, followed by US at 6–7 weeks gestation. Study grouping: parallel group Comments: unspecified blinding and limited information regarding sperm preparation. |
|
| Participants |
Baseline characteristics IVF ‐ 30 ICSI ‐ 30 Overall Inclusion:
Exclusion:
Allocation:quote: "patients were randomised to IVF or ICSI" |
|
| Interventions |
Intervention characteristics IVF ICSI |
|
| Outcomes |
Fertilisation Rate Outcome type: Dichotomous outcome Implantation Rate Outcome type: Dichotomous outcome Clinical Pregnancy Outcome type: Dichotomous outcome Embryo Quality Outcome type: Dichotomous outcome Live birth Rate Outcome type: Dichotomous outcome |
|
| Identification |
Sponsorship source: Serono Canada Inc. Country: Canada Setting: one IVF clinic in Toronto Canada Authors name: Shu C. Foong Institution: Department of Obstetrics and Gynaecology, University of Toronto, Ontario Canada Email: sfoong@mtsinai.on.ca Address: Mount Sinai Hospital, OPG 3rd Floor, Suite 3155, 600 University Avenue, Toronto, Ontario, Canada |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | No information on randomisation method, "patients were randomized to either IVF or ICSI" |
| Allocation concealment (selection bias) | Unclear risk | No information provided regarding allocation concealment. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No information provided regarding blinding. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No information provided regarding blinding. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Data was only provided as percentages with no relative risk or odds ratio. Only p‐value significance provided if outcome proved significant. |
| Selective reporting (reporting bias) | Unclear risk | No original protocol available |
| Other bias | Unclear risk | Limited methodology available |
AMH: anti‐Müllerian hormone; COC: cumulus–oocyte complex; FSH: follicle stimulating hormone; HCG: human chorionic gonadotropin; ICSI: intracytoplasmic sperm injection; IU: international unit; IVF: in vitro fertilisation; LH: luteinising hormone
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Aboulghar 1995 | Couples were not the unit of randomisation. |
| Aboulghar 1996 | Couples were not the unit of randomisation. |
| Aboulghar 1996b | No randomisation. |
| Bhattacharya 2018 | Wrong study design. |
| Bukulmez 2000 | Not random. Alternation was used to allocate patients after oocyte retrieval by one of the authors. |
| Calderon 1995 | Couples were not the unit of randomisation. |
| Catt 1995 | Couples were not the unit of randomisation. |
| Chamayou 2022 | Wrong study design ‐ Sibling Oocyte. |
| Chargui 2018 | Wrong study design. |
| Chatterjee 2021 | Wrong study design ‐ Sibling Oocyte. |
| Chi 2012 | Wrong study design ‐ Sibling Oocyte. |
| ChungCHS 2018 | Wrong study design ‐ Sibling Oocyte. |
| Clasen 1996 | This was a pilot study which was never continued. Fertilisation was the endpoint. |
| DeMunck 2020 | Wrong study design ‐ Sibling Oocyte. |
| Drakopoulos 2019 | Wrong study design. |
| Eftekhar 2012 | Wrong study design ‐ no randomisation. |
| Elizur 2004 | Wrong study design ‐ Sibling Oocyte. |
| Isikoglu 2021 | Wrong study design ‐ Sibling Oocyte. |
| Johnson 2013 | Wrong study design. |
| Kastrop 1999 | Couples were not the unit of randomisation. This was a comparison of ICSI versus additional IVF. |
| Khamsi 2001 | Wrong study design ‐ Sibling Oocyte. |
| Kim 2007 | Wrong study design. |
| Lattes 2019 | Wrong study design. |
| Levran 1995 | Comparison of ICSI versus SUZI, not IVF. |
| Liu 2011 | Wrong study design ‐ Sibling Oocyte. |
| Makwana 2022 | Wrong study design ‐ Sibling Oocyte. |
| Mateizel 2020 | Wrong study design ‐ Sibling Oocyte. |
| Micara 2000 | Wrong study design. |
| Moreno 1998 | Method of randomisation was not stated. Even after contact with one of the authors randomisation could not be clarified. Data were presented in percentages and not the actual numbers. These numbers were not available. |
| Mortier 2000 | Wrong participant population ‐ moderate teratozoospermia. |
| Ombelet 2022 | Wrong study design ‐ Sibling Oocyte. |
| Payne 1997 | No randomisation. The oocytes were pooled in order of retrieval. The first group of 4 oocytes went to the ICSI group. The second group (05‐08) went to IVF. The third group (09‐12) went to ICSI, and so on. The minimum number of oocytes in the IVF group is 4 and the maximum is 6 and in some cases 8. The rest of the oocytes were given ICSI. The mature state of the oocytes was also taken into consideration. If there were not enough mature oocytes, the first mature oocytes starting with group 2 were allocated to the IVF group. |
| Plachot 2002 | Wrong patient group & Sibling Oocyte. |
| Poehl 1998 | Not a randomised control trial |
| Rakic 2011 | Wrong study design ‐ Sibling Oocyte. |
| Ruiz 1997 | No randomisation. |
| Staessen 1998 | Couples were not the unit of randomisation. |
| Tannus 2017 | Wrong study design. |
| Thondehal 2020 | Wrong study design. |
| Urfan 2017 | Wrong study design ‐Sibling Oocyte. |
| vanderWesterlaken 2006 | Wrong study design. |
| Wu 2023 | Wrong study design. |
| Wyns 2004 | Wrong study design ‐ ivf‐icsi split insemination versus conventional insemination. |
| Yang 1996 | Couples were not the unit of randomisation. |
| Youssef 2009 | Wrong study design ‐ Sibling Oocyte. |
ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation
Characteristics of ongoing studies [ordered by study ID]
Berntsen 2021.
| Study name | In vitro fertilisation (IVF) versus intracytoplasmic sperm injection (ICSI) in patients without severe male factor infertility: Study protocol for the randomised, controlled, multicentre trial |
| Methods | Randomised, controlled, multicentre trial |
| Participants | Patients without severe male factor infertility |
| Interventions | ICSI, IVF |
| Outcomes |
Primary Outcome measures
Secondary Outcome measures
|
| Starting date | November 15, 2019 |
| Contact information | +45 38625414 nina.la.cour.freiesleben@regionh.dk |
| Notes |
Fancsovits 2020.
| Study name | Intracytoplasmic sperm injection versus conventional in vitro fertilization in non‐male factor infertility. Interim analysis of a prospective randomized study |
| Methods | Data of interim analysis from an ongoing prospective randomised study performed in a university setting are presented here. Two hundred and thirty two IVF cycles were randomised into ICSI or conventional IVF group between January 2018 and November 2019 |
| Participants | Semen parameters suitable for conventional IVF fertilisation, number of oocytes >4 and/or female age <40 years |
| Interventions | ICSI, IVF |
| Outcomes |
Primary outcome
Secondary outcomes
|
| Starting date | April 30, 2018 |
| Contact information | Fancsovits P fancsovits.peter@noi1.sote.hu |
| Notes |
Zheng 2019.
| Study name | Intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilisation (IVF) in couples with non‐severe male infertility (NSMI‐ICSI): Protocol for a multicentre randomised controlled trial |
| Methods | Multicentre randomised controlled trial |
| Participants | Couples with non‐severe male infertility |
| Interventions | ICSI, IVF |
| Outcomes |
Primary Outcome measures
Secondary Outcome measures
|
| Starting date | April 4, 2018 |
| Contact information | Danni Zheng, Bachelor +86‐010‐82266630 danilinda136@163.com |
| Notes | null |
ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation
Differences between protocol and review
Adverse events were updated from the original review to include multiple pregnancies, ectopic pregnancy, stillbirth, pre‐eclampsia and prematurity.
Pre‐eclampsia and prematurity were also added to the SoF table as approved by the editorial board.
Secondary outcomes added included: clinical pregnancy rate (per couple), viable intrauterine pregnancy (previously called 'pregnancy rate)', fertilisation rates (per oocyte retrieved, inseminated and fertilisation failure) and implantation rates.
Another difference to note between the original review and the 2023 update, is the use of a risk ratio (RR) in replacement of the odds ratio (OR). RR was preferred over OR as we believe an odds ratio is harder to understand and apply to practise. Misinterpretation of the OR as if it was the same as RR will lead to overestimation of the intervention effect.
Contributions of authors
For the original review, M van Rumste: took the lead in writing the protocol and review, performed searches of databases for trials, was involved in selecting trials for inclusion, performed independent data extraction and quality assessment of the included trials, was responsible for statistical analysis and interpretation of the data. Professor Evers: performed independent data extraction and quality assessment of the included trials, added clinical expertise to the review. Professor Farquhar: commented on drafts of the review and added clinical expertise to the review.
For the 2023 review, E Cutting updated the background information and was involved in selecting trials for inclusion, performed independent data extraction and quality assessment of the included trials. M van Rumste and F Horta also assisted with screening of trials, data extraction, quality assessment, reviewed the manuscript and added clinical expertise to the review. Professor Mol was involved with study inclusion and exclusion, reviewed and added clinical expertise to the review. V Dang reviewed the manuscript and added clinical expertise to the review.
Sources of support
Internal sources
-
Monash University, Department of Obstetrics and Gynaecology, Australia
None
-
University of Auckland, School of Medicine, Auckland, New Zealand
None
External sources
-
SWOL, Netherlands
None
Declarations of interest
It is important to declare that BWM and VD took no part in selection of studies, assessment for risk of bias through GRADE or extracting the data.
EC, VD, FH and MvR have no interests to declare.
BWM is supported by a NHMRC Investigator grant (GNT1176437). BWM reports consultancy for ObsEva. BMW has received research funding from Ferring and Merck.
New search for studies and content updated (conclusions changed)
References
References to studies included in this review
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