Criteria for considering studies for this review

Search methods for identification of studies

See: the Menstrual Disorders and Subfertility Group search strategy.

All randomised controlled trials comparing the administration of glucocorticoids to women undergoing IVF and ICSI to no glucocorticoids or placebo administration will be obtained using the following search strategy. The search will not be restricted by language.

(1) We will search the Menstrual Disorders and Subfertility Group Trial Register. A full description of this register is given in the group's module on the The Cochrane Library.

(2) The following electronic databases are to be searched:
Cochrane Central Register of Controlled Trials (CENTRAL) (current issue);
MEDLINE (1966 to present);
EMBASE (1976 to present);
Science Direct (1966 to present);
CINAHL (1982 to present).

These databases will be searched using the following subject headings and keywords.
"Steroids"[MeSH] or "Adrenal cortex hormones" [MeSH] or corticosteroid* or "Glucocorticoids" [MeSH] or 16 beta methylprednisolone or adrenocorticotrophic hormone or ACTH or "Corticotropin" [MeSH] or corticotrophin derivative or "Corticotropin‐releasing hormone" [MeSH] or corticotrophin releasing factor or CRH or adjuvant steroid* or anabolic steroid* or deltacortisone or dexol

AND
" Reproductive techniques" [MeSH] or controlled ovarian stimulation or ovarian stimulation or ovarian superstimulation reproduction

AND
"infertility"[MeSH] or subfertility or subfertile or implantation failure or "embryo implantation" [MeSH]

AND (Cochrane search strings for randomised controlled trials)
(randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ("latin square" [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow‐up studies [mh] OR prospective studies [mh] OR cross‐over studies [mh] OR control* [tw] OR prospective* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh])

(3) We will handsearch the reference lists in relevant publications.
(4) We will handsearch abstracts from meetings of the American Society for Reproductive Medicine (1991 to 2003) and the European Society for Human Reproduction and Embryology (1991 to 2000).

When important information is lacking in the original publications we will try to contact the authors. Additional information will be incorporated in the review.

Data collection and analysis

Study selection
CM Boomsma and NS Macklon will independently select the trials to be included according to the above‐mentioned criteria. Disagreements will be resolved through arbitration by SD Keay.

Data extraction and quality assessment
The type of study, quality of the selected studies, type of participants, type of interventions and the type of outcome measures as mentioned in the 'Criteria for considering studies' section will be extracted and assessed by the same two review authors. The information from the quality assessment will be presented in a 'Table of included studies' and will help to provide a context to discuss the quality of the results. Further information will be sought from the authors where papers contain insufficient information to make a decision about eligibility.

Quality assessment
‐ Method of randomisation adequately described: Yes, No, or Not clear (for example not stated or stated without further description).
Studies in which where the method of randomisation is not clear will be included in the review and the authors will be contacted.
Quasi‐randomised studies (for example alternating record numbers, dates of birth, or odds and even numbers) will not be included.
‐ Concealment of allocation: the quality of allocation concealment will be graded as adequate (A), unclear (B), or inadequate (C).
Adequate allocation: for example by a third party or sequentially numbered sealed opaque envelopes.
Inadequate allocation: for example using an open list of random numbers, open envelopes or tables.
Not clear: for example not stated or stated without further description.
‐ Trial design: studies with a cross‐over design (the second or subsequent cycles) will be excluded in a sensitivity analysis. The first‐cycle data of cross‐over studies will be included.
‐ Prospective power calculation: were they performed?
‐ Drop‐out details and number: were there more than 10% of dropouts (couples)?
‐ Cancelled cycles: were the reason for and number (was it more than 10%) of cancelled cycles reported?
‐ Blinding: if possible (only if placebo administration was given).
‐ Single‐centre or multi‐centre study.
‐ Intention‐to‐treat analysis: was it performed?

Characteristics of the study participants
‐ Baseline characteristics: age, primary or secondary infertility, duration of infertility, and other demographic information.
‐ Other subgroup criteria:

• women with recurrent implantation failure or not;

• cause of infertility.

Treatment characteristics
‐ Glucocorticoid administration: dosage, duration, timing, type of steroids used.
‐ What ART was performed: IVF, ICSI, or both.
‐ Success from ovarian stimulation and fertilisation: number of oocytes retrieved, quality of transferred embryos (converted into three groups of excellent, average, and poor).
‐ Number of embryos transferred and day of embryo transfer.
‐ Ovarian stimulation characteristics: amount and duration of gonadotrophin stimulation.
‐ Luteal support: dosage, type, and duration.

Ovarian stimulation is known to be detrimental to endometrial receptivity. It has been proposed that the mechanisms behind the disruption of endometrial receptivity may include an effect of excess estrogen levels on NK cell count in the endometrium (DeLoia, 2002; Ledee 2004). For this reason we have decided to assess the study protocol of ovarian stimulation as well.

Statistical analysis
Statistical analyses will be performed in accordance with the guidelines for statistical analysis developed by the Cochrane Menstrual Disorders and Subfertility Group (MDSG).

For dichotomous data, the results for each study will be expressed, when appropriate, as odds ratios with 95% confidence intervals (CI) and combined for meta‐analysis with RevMan software using the Peto method and a fixed‐effect model. Outcomes will be pooled statistically if the amount of heterogeneity between the studies is acceptable.

Heterogeneity (variations) between the results of different studies will be examined by inspecting the scatter in the data points on the graphs and the overlap in their confidence intervals and, more formally, by checking the results of the chi‐squared tests. Additionally, trials will be re‐studied to detect clinical heterogeneity. If the degree of clinical heterogeneity is too great the trials will not be pooled statistically.

Publication bias refers to the phenomenon by which trials with positive results are more likely to be published (and thus identified) than trials with negative results, which applies particularly to smaller trials (Begg 1989). A funnel graph, plotting sample size versus effect size, will be constructed to detect such a bias. The graph is symmetrical when bias is absent.

The outcome of live birth rate is considered a positive consequence of treatment, therefore, a higher proportion of women with a live birth will be considered a benefit. For adverse outcomes such as multiple pregnancy rate and OHSS rate, higher numbers are considered to be detrimental (increased odds signify relative harm). This needs to be taken into consideration when the meta‐analyses are viewed.

Subgroup analyses will be performed on the contribution of the following factors.

• Subgroup A

Studies including all women undergoing IVF and ICSI versus studies in which only women with recurrent implantation failure were included. Recurrent implantation failure is usually defined as three or more failed attempts of IVF and ICSI, or implantation failure after the replacement of more than 10 embryos.

• Subgroup B

Studies in which women undergoing IVF were included versus studies in which women undergoing ICSI were included.

• Subgroup C

Studies including only women with unexplained subfertility versus studies including women with different kinds of subfertility.

• Subgroup D

If possible, subgroup analyses will be performed on different methods of administration (parenteral versus oral), dosage (high versus low), and duration of glucocorticoid (until embryo implantation or until after embryo implantation).

Enough studies should be included (at least four) to make subgroup analyses possible. These features might be influential, however, they have not been reported in the literature. For this reason we think it is safe to use a secondary analysis on these features. Some trials will include a mix of these factors and this will be discussed.

If there are more than five trials included in the meta‐analysis, the following sensitivity analyses are planned to examine stability regarding the direction of outcomes, using:

• a random‐effects model, in addition to the fixed‐effect model, to combine the data;

• studies in which adequate concealment of allocation was used;

• studies reporting the method of randomisation;

• studies with a parallel design, or first‐cycle data of cross‐over studies.

It is the intention of the review authors that a new search for RCTs will be performed every two years and the review updated accordingly.