Types of studies

• Randomised controlled studies

• Quasi‐randomised controlled trials (e.g. allocation by alternation, reference to case record number or date of birth) will be excluded

• Cross‐over trials will be excluded since the design is not appropriate in the context of this intervention

Types of participants

Inclusion criteria

• Couples undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) for therapeutic reasons or for oocyte donation and randomised to receive either a GnRH agonist or HCG for final oocyte maturation triggering

Exclusion criteria 

• Women who were not IVF or ICSI patients, i.e. intrauterine insemination (IUI) patients

Types of interventions

• GnRH agonists in comparison with HCG for final oocyte maturation triggering in GnRH‐antagonist controlled hyperstimulation cycles, IVF, or ICSI followed by embryo transfer (ET) with or without luteal phase support

• GnRH agonists versus HCG for final oocyte maturation in donor cycles

Types of outcome measures

Electronic searches

All reports that described or might have described randomised controlled trials comparing GnRH agonists and HCG in the treatment of subfertility, using IVF or ICSI, will be obtained using the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group.

We will search the bibliographic databases Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, and EMBASE. We will also search the National Research Register (NRR) which is a register of ongoing and recently completed research projects funded by or of interest to the United Kingdom, the Medical Research Council's Clinical Trials Register, and the NHS Centre for Reviews and Dissemination database.

We will use the following medical subject headings and keywords: "GnRH a" or "GnRH agonist" or "GnRH agonists" or "GnRHa" or "GnRHa‐gonadotropin" or "Gonadorelin" or "Gonadotrophin releasing agonist" or "gonadotropin releasing hormone agonist" or "Goserelin" or "goserelin acetate" or "Gosereline " or "buserelin" or "Buserelin Acetate" or "buserelin naferelin" or "busereline" or "Leuprolide" or "leuprolide acetate" or "leuprolin" or "leuprorelin" or "leuprorelin acetate" or "Nafarelin" or "triptoielin" or "triptorelin" or "triptoreline" or "triptoreline pamoat" or "triptorelyn" or "triptrolein" or "Lupron" or "deslorelin" or "Zoladex" or Title CONTAINS"GnRH a" or "GnRH agonist" or "GnRH agonists" or "GnRHa" or "GnRHa‐gonadotropin" AND "trigger" or "triggered ovulation" or "*Ovulation Induction" or "ovulation trigger" or "oocyte maturation" or Title AND "trigger" or "triggered ovulation" or "*Ovulation Induction" or "ovulation trigger" or "oocyte maturation" AND "human chorionic gonadotrophin" or "human chorionic gonadotropin"  or "HCG" or "r‐HCG" or "chorionic gonadotrophins" or Title AND "human chorionic gonadotrophin" or "human chorionic gonadotropin"  or "HCG" or "r‐HCG" or "chorionic gonadotrophins" IVF/ICSI/ART AND "randomised controlled trial(s)"" randomised controlled trial(s)".

The following databases will be searched from their inception. Searches will be ongoing.

EMBASE (1980) (Appendix 1).

MEDLINE (1950) (Appendix 2).

CENTRAL (current Issue) (Appendix 3).

Searching other resources

The reference lists of all known primary studies, review articles, citation lists of relevant publications, abstracts of major scientific meetings (for example ESHRE, ASRM), and included studies will be examined to identify additional relevant citations. Grey literature will be searched through the open SIGLE database and by searching Google. We will also search national and international research registers (including the Register of Controlled Trials which shows any trials that may be not yet published (www.controlled‐trials.com/), and conference proceedings. Known experts and personal contacts will be contacted regarding any unpublished materials.

Selection of studies

Titles and abstracts of trials will be reviewed independently by two review authors (MY, MW) using the a priori criteria for inclusion. The full manuscripts of trials will be obtained for the short‐listed papers considered potentially eligible for inclusion. Further information will be sought from the authors of trials that do not contain sufficient information to make a decision about eligibility. These trials will be independently critically appraised by two review authors (MY, MW) and any disagreements will be resolved by referral to a third review author (FvdV or HGA). The trials that are determined to be suitable for inclusion will be assessed for risk of bias and data extracted by two review authors (MY, MW). Subsequently, a detailed 'Characteristics of excluded studies' table will be constructed for those trials that do not satisfy the inclusion criteria. A similar table 'Characteristics of included studies' will be constructed for those trials considered suitable for inclusion.

Data extraction and management

A standardised data extraction form will be developed and piloted for consistency and completeness. Trials will be considered for inclusion and the data extracted. Data extraction will be performed independently by two review authors (MY, MW). The two sets of extracted data will be compared and discrepancies will be resolved by discussion. The data extraction forms will include methodological quality and allocation scores. This information will be included in the review and presented in the tables of the characteristics of included and excluded studies, following the guidance of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Assessment of risk of bias in included studies

The methodological quality of each trial will be assessed in terms of randomisation, blinding of the patients, sample size, and the extent of follow up. Each trial characteristic will be judged and given a quality rating as: adequate (A), unclear (B), or inadequate (C).

1. Randomisation

Randomisation will be considered to be adequate if any random method of allocation is described and is verifiable, that is:

• using a computerised random number generator;

• referring to a number table.

2. Concealment of allocation

This will be considered adequate if a third‐party system; serially‐numbered sealed, opaque envelopes; or a similar system has been described. Concealment will be stated as 'unclear ' if no information is available pertaining to allocation concealment.

3. Blinding

This will be examined with regard to who was blinded in the trials. All levels will be sought and categorised as follows: single or double blinding, no blinding (both investigator and participant knew the allocated treatment), or unclear.

4. Incomplete outcome data

A low risk of bias will be allocated if there are no missing outcome data, or the missing outcome data are balanced in numbers across intervention groups with similar reasons for missing data across groups.

5. Selective outcome reporting

A low risk of bias will be allocated if the study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in this review have been reported in the prespecified way.

Measures of treatment effect

Data extraction and management will be conducted using Review Manager software (RevMan 5) (The Cochrane Collaboration, Oxford, UK). For binary data, we will calculate odds ratios (OR) with 95% confidence intervals (CI) for each individual trial. No continuous outcome data are anticipated for consideration, based on the a priori outcomes.

Unit of analysis issues

The primary analysis will be per woman randomised (for example, live birth rate per randomised woman defined as the number of women achieving a live birth divided by the number of women treated). Data per cycle will not be included in the analysis.

Dealing with missing data

If data from the trial reports are insufficient or missing, we will contact the investigators of individual trials via email for additional information in order to perform analyses on an intention‐to‐treat basis. In circumstances where we cannot resolve data issues we will assume that data are randomly missing and perform a sensitivity analysis to determine the impact of this decision upon our final results, which may mean that we are unable to include a particular study.

Assessment of heterogeneity

Presence of statistical heterogeneity of treatment effect among trials will be determined by visual inspection of the outcome tables, overlap of CIs, and by using the Breslow‐Day Chi² test for heterogeneity with a 10% level of statistical significance. We will also interpret the I² statistic in the following broad terms: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; 75% to 100%, considerable heterogeneity present (Higgins 2008).

Assessment of reporting biases

We shall attempt to reduce publication and any related bias through the use of alternative, robust search strategies including handsearching (Hopewell 2007); the use of the Internet (for example, Google and other search engines); comprehensive searching of the grey literature (Hopewell 2007a); alternative sources of data or synthesised evidence; and contacting experts and the research community (Hopewell 2007b). Graphical, descriptive and analytical methods will be used to detect and mitigate the problem. Subject to adequate numbers, funnel plots will be constructed to illustrate the effect size versus measure of precision. A visual inspection of the plot(s) will be used to confirm the presence and magnitude of publication and reporting bias (Song 2002). Furthermore, the asymmetry observed in the funnel plot may be due to serious methodological flaws (Stuck 1998) or the fact that the intervention is highly effective. We will avoid duplication bias by contacting the author in any cases of suspicion about double publication. There will be no language barrier to avoid language bias.

Data synthesis

For the meta‐analysis, the number of women experiencing the event in each group of the trial will be recorded. Meta‐analysis of binary data will be performed using the Mantel‐Haenszel method with a fixed‐effect model and the odds ratio (OR) and 95% CI will be calculated. Individual outcome data will be included in the analysis if they meet the pre‐stated criteria. Where possible, data will be extracted to allow for an intention‐to‐treat analysis, defined as including all randomised participants in the denominator. We will also undertake a separate analysis for oocyte donor‐recipient cycles. Where it is not appropriate to combine primary studies they will be summarised in a narrative form.

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses will be performed:

• luteal phase support versus no luteal phase support;

• different types and durations of luteal phase support;

• separate analysis in oocyte donor‐recipient cycles.

Sensitivity analysis

A sensitivity analysis, if we have identified a clinical or statistical heterogeneity during the review process, will be carried out using the random‐effects model. That is, if the eligibility of some studies in the meta‐analysis is dubious because the studies do not contain full details, a sensitivity analysis may involve undertaking the meta‐analysis twice by:

• first, including all studies;

• second, only including those that are definitely known to be eligible.