Recombinant versus urinary derived gonadotrophins for ovarian stimulation in in vitro fertilisation and intra‐cytoplasmic sperm injection cycles
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the effectiveness of recombinant gonadotrophin (rFSH) with all types of urinary‐derived gonadotrophins (including hMG, FSH‐P and FSH‐HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles.
Background
The techniques of in vitro fertilisation (IVF) and intra‐cytoplasmic sperm injection (ICSI) in assisted reproduction are based on a preliminary phase of ovarian induction to produce multiple follicles and the collection of the eggs for fertilisation in‐vitro. The strategy of stimulating the ovaries with exogenous gonadotrophins is well established. This review addresses the use of gonadotrophins for ovarian induction in IVF and ICSI cycles.
The first generation of gonadotrophins, used in the 1970's, was human menopausal gonadotrophin, produced from the urine of menopausal women (hMG, a combination of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in a 1:1 ratio). Since the 1980's, a variety of urinary gonadotrophins have been produced, such as purified FSH (FSH‐P) which contains less than one international unit (IU) of LH per 75 IU of FSH. The third generation of urinary gonadotrophins was highly purified FSH (FSH‐HP) with less than 0.1 IU of LH per 75 IU of FSH. An early systematic review (Daya 1995) reported a higher clinical pregnancy rate per cycle with FSH‐P and FSH‐HP when compared with hMG, but a later review (Agrawal 2000) reported no difference between these urinary gonadotrophin subproducts.
In clinical practice, FSH‐P and FSH‐HP are given for the same purpose, for the same patient groups with similar effects, and in similar doses (Al‐Inany 2003). These preparations of gonadotrophins (FSH‐P, FSH‐HP) have been regarded as subproducts of hMG. (Sykes 2001, Al‐Inany 2003). The fourth generation of gonadotrophins is produced using recombinant DNA technology (recombinant FSH, rFSH) and is highly pure (99.9%) and free from LH activity. The production of rFSH is independent of urine collection, thus guaranteeing a high availability of a biochemically pure FSH preparation that is free from urinary protein contaminants. The production process also yields FSH with minimal batch‐to‐batch discrepancy (Bergh 1999) and low immunogenicity which allows subcutaneous administration.
Two systematic reviews and one international Health Technology Assessment report compared rFSH with urinary gonadotrophins (hMG, FSH‐P, FSH‐HP). Higher pregnancy rates per cycle started were reported with rFSH (Daya 2002, updated from Daya 1999), but no evidence of any difference in pregnancy rates per woman was reported in the other two reports (Van Wely 2003, updated from Van Wely 2002) (Larizgoitia 2000).
The two most recent systematic reviews (Al‐Inany 2003, NCC‐WCH 2004) reported no evidence of difference in pregnancy rate per cycle between rFSH and all types of urinary gonadotrophins. Subgroup analyses of rFSH versus hMG, rFSH versus FSH‐P and rFSH versus FSH‐HP did not suggest any differences between rFSH and the different urinary gonadotrophins in pregnancy rate per cycle started (Al‐Inany 2003).
There are a number of influences on pregnancy rate following IVF/ICSI cycles. Fair comparison of gonadotrophins may be achieved within each randomised trial. However, the relative effect of gonadotrophin therapies may differ according to other aspects of the trial protocol. Two aspects in particular deserve special mention.
Firstly, gonadotrophin‐releasing hormone agonists (GnRHa) are often used in conjunction with gonadotrophins to facilitate cycle control and achieve pituitary down‐regulation in ovarian stimulation during assisted reproductive treatment cycles. There is evidence of effectiveness in increased clinical pregnancy rate with the use of GnRHa when compared with no GnRHa in ovarian stimulation for IVF (Hughes 1992). Long pituitary‐down GnRHa protocols were found to increase clinical pregnancy rates when compared with short or ultrashort GnRHa protocols (Daya 1998).
Secondly, lower pregnancy rates were reported for frozen embryo transfer than fresh embryo transfer (NCC‐WCH 2004). Embryos may be available for freezing either if they are of suitable quality but there are more than can be legally transferred, or if a cycle is abandoned, for example, if there is hyperstimulation. We will include all studies which involved fresh or frozen cycles embryo transfer, then explore any influence different settings have on the treatment differences.
The six systematic reviews discussed above reported conflicting results. Each of these reviews used different inclusion and exclusion criteria for trials. All (Daya 1995; Agrawal 2000; Daya 2002; Al‐Inany 2003; Larizgoitia 2000; NCC‐WCH 2004) based their conclusion on rates per cycle that had been invalidly analysed as if each woman contributed a single cycle. Legitimate but different choices of meta‐analytic model (fixed or random effects, odds ratio or risk ratio) complicate comparison further. Our aim in producing this review is to bring together all randomised studies in this field under common inclusion criteria with consistent and valid statistical methods.
Objectives
To compare the effectiveness of recombinant gonadotrophin (rFSH) with all types of urinary‐derived gonadotrophins (including hMG, FSH‐P and FSH‐HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials only. Quasi‐randomised controlled trials, in which allocation was, for example, by alternation or reference to case record number or to dates of birth, will be excluded. Crossover trials will also be excluded since the design is not appropriate in this context (Vail 2003).
Trials in which fresh and frozen embryos are transferred will be included.
Types of participants
Normogonadotrophic (defined as having normal serum concentration of FSH and LH) women undergoing fresh and frozen IVF or ICSI treatment cycles.
Types of interventions
Ovarian stimulation with recombinant gonadotrophin (rFSH) versus all types of urinary‐derived gonadotrophins (including hMG, FSH‐P and FSH‐HP), with or without the use of GnRHa protocol in women undergoing IVF and ICSI cycles.
Types of outcome measures
Primary outcomes
Effectiveness:
One or more live birth(s) per woman or, if not reported, one or more pregnancy ongoing beyond 20 weeks per woman
Adverse:
Rate of ovarian hyperstimulation syndrome per woman
Secondary outcomes
Effectiveness:
Clinical pregnancy rate per woman (as confirmed by the presence of foetal heart rate)
Patient acceptability/satisfaction
Number of oocytes produced per cycle
Adverse:
Multiple pregnancy rate per woman and per pregnancy
Miscarriage rate per woman
Process outcomes:
Amount of gonadotrophins used per woman per cycle ( total dose in IU [international units])
Duration of ovarian stimulation per woman per cycle
Search methods for identification of studies
We will search the Menstrual Disorders & Subfertility Group's Specialised Register of controlled trials, The Cochrane Central Register of Controlled Trials (CENTRAL) on the latest issue of the Cochrane Library, MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), National Research Register, and web‐based trials databases such as Current Controlled Trials. There will be no language restriction. Additionally all references in the published reviews, identified trials and background papers will be checked and authors contacted if necessary. The following search strategy will be used see Appendix 1
Data collection and analysis
Trials identification
Two reviewers (IK and AB) will independently examine the electronic search results for reports of possibly relevant trials and these reports will be retrieved in full. Both reviewers will apply the selection criteria independently to the trial reports, rechecking trial eligibility and resolving disagreements by discussion with the other reviewers (HI, AV and JT).
Risk of bias assessment
Four reviewers (IK, AB, HI, AV) will extract information regarding the methodological quality on a number of levels.
Internal validity
Assessment of selection bias will examine the process involved in the generation of random sequence and the method of allocation concealment. These will be judged as adequate or inadequate using the criteria inTable 1 . Performance bias will be examined with regards to which parties were blinded in the trials, i.e. patient, caregiver, outcome assessor or analyst. Details of blinding will be sought from the authors. All details will be presented in the Table of Included Studies. Any differences will be resolved by discussion.
| Methodology | Adequate | Unclear | Inadequate |
| Randomisation | Computer‐generated, random number table, lots, coin toss, etc | 'random' stated without further explanation | [Study excluded] |
| Concealment | Third party, sequentially numbered coded drugs containers or envelopes | Missing or inadequate detail e.g. "sealed envelopes" | Open, not able to validate e.g. lots, coin toss, shuffle |
External validity
Issues around clinical heterogeneity in the trials will be examined with regards to day of embryo transfer, different ratio of IVF:ICSI among trials, number of previous failed cycles within and between trials. All details will be presented in the Table of Included Studies.
Data extraction
Three reviewers (IK, AB, AV) will independently extract the data and information on the following:
method of allocation concealment, number of randomised patients, type of participants, interventions and treatment outcomes. Data extracted from the trials will be analysed on an intention to treat basis. Where randomised cases are missing from outcome assessment, we will assume that they have failed to achieve pregnancy and have not suffered reported adverse events. For the primary efficacy and safety outcomes, we will assess the effect of this assumption by comparison with the 'complete case' analysis presented in original publications. Results will be compared and any differences resolved by discussion among reviewers. Where there is insufficient information in the published report, we will attempt to contact the authors for clarification. If missing data become available, they will be included in the analysis. It is anticipated that trials conducted over 10 years ago may not have data on live birth rates of the study participants.
We will also contact drug companies for any published, unpublished or ongoing studies not identified with our search strategy.
In trials where reporting is poor, clarification will be sought from authors. If this clarification is not available, methodological issues will be reported as unclear. We will examine issues of the influence of trial quality on effect size in a sensitivity analysis, by removing trials in which allocation concealment was inadequate or unclear.
Details of the studies including methods, participants, inclusion and exclusion criteria, intervention, outcomes, allocation concealment, power calculation and any other details, such as violation of protocol, will be entered into the Table of Included Studies. Studies which appeared to meet the inclusion criteria but were excluded from the review, will be presented in the Table of Excluded Studies, briefly stating the reason for exclusion, but no further information.
Studies which would have met the inclusion criteria had they not used a cross‐over design will be listed in a separate table. Details of other aspects of internal and external validity will be recorded as for included trials. This table will also record the original authors' conclusions, first phase data if available, and our subjective comments on a case‐by‐case basis of the strength of evidence from each study.
Analysis
The effect of the interventions on the outcomes will be summarised in meta‐analyses. All binary outcomes will be analysed using odds ratios (OR) and reported in absolute terms. Review Manager software will be used to perform the meta‐analysis using Mantel‐Haenszel method and a fixed effect model. Analyses of primary outcomes will be repeated using a random effects model to explore whether different conclusions would be reached. It is our main concern in this review to identify clearly that the trials included provide a fair comparison within themselves. The odds ratio has been selected to cope with the outcome rates differing between trials due to clinical heterogeneity. Stratified analyses will be carried out for the primary outcomes to explore whether relative effects differ due to key features of the trials as follows:
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different urinary gonadotrophins (hMG, FSH‐P and FSH‐HP)
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different GnRH protocols (no GnRHa, long GnRHa and short/ultrashort GnRHa protocol
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different policies regarding fresh and frozen cycles
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different sponsors (commercial, non‐commercial)(Lexchin 2003)
If there is uncertainty that the pregnancy outcome was the result of patients participating in more than one cycle, we will contact the authors.
Ordinal scales used in patient acceptability, amount of gonadotrophin used and duration of ovarian stimulation will be treated as continuous outcomes unless and until accepted meta analytic techniques for ordinal outcome data become available. Means and standard deviations will be abstracted, calculated or requested. Where possible, results for continuous outcomes will be combined using weighted mean difference by a fixed effect model. However, it is anticipated that studies will use different scales to measure patient acceptability. If this is the case, the standardised mean difference will be used.
Sensitivity analysis will be performed to assess the impact of loss‐to‐follow‐up by removing trials which did not carry out intention‐to‐treat analyses. All sensitivity analyses will be reported for primary outcomes only.
Completion of the review is expected within 12 months of publication on the Cochrane Library of the protocol (approximately April 2006).
| Methodology | Adequate | Unclear | Inadequate |
| Randomisation | Computer‐generated, random number table, lots, coin toss, etc | 'random' stated without further explanation | [Study excluded] |
| Concealment | Third party, sequentially numbered coded drugs containers or envelopes | Missing or inadequate detail e.g. "sealed envelopes" | Open, not able to validate e.g. lots, coin toss, shuffle |
