Human Reproduction, Vol. 18, No. 5, 947-954,
May 2003
© 2003 European Society of Human Reproduction and Embryology
Gaps in the evidence for fertility treatment—an analysis of the Cochrane Menstrual Disorders and Subfertility Group database
1 Cochrane Menstrual Disorders & Subfertility Group Editorial Base, 2 University of Auckland, and 3 Fertility Plus, Obstetrics & Gynaecology Department, National Women’s Hospital, Auckland, New Zealand
4 To whom correspondence should be addressed at: The University Department of Obstetrics & Gynaecology, National Women’s Hospital, Claude Road, Epsom, Auckland, New Zealand. e-mail: n.johnson{at}auckland.ac.nz
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Abstract |
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BACKGROUND: The randomized controlled trial is considered the best approach to assess the effectiveness of treatments. The aim was to summarize the available evidence and determine gaps in the evidence for clinical decision making in subfertility. METHODS: A search of the Cochrane Library for Menstrual Disorders and Subfertility Group reviews was undertaken and, where the reviews were related to subfertility, the authors’ conclusions were appraised and correlated with the results and meta-analysis sections of the reviews. Each review was then categorized as to what extent it had answered the clinical question posed by the reviewers. RESULTS: Of 38 subfertility reviews currently or previously published on the Cochrane Library from the Menstrual Disorders and Subfertility Group, 12 reviews concluded that there was evidence of effectiveness of the interventions studied. There was insufficient evidence of effectiveness in 26 reviews, from which the authors of 23 reviews called for further research. A tabulated summary of the review conclusions is presented. CONCLUSION: Cochrane subfertility reviews have eliminated some gaps in the evidence and highlighted others. Future clinical trial design should focus on adequate power and reporting the major outcome of live-births per couple as well as adverse events.
Key words: Cochrane systematic review/evidence-based/gaps/infertility/subfertility
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Introduction |
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The randomized controlled trial (RCT) is considered the best approach for ascertaining the effect of a health care intervention. In 1979, Archie Cochrane criticized the medical profession "that we have not organised a critical summary, by specialty or subspecialty, updated periodically, of all relevant randomised controlled trials" (Cochrane, 1979
). The challenge to create a comprehensive register of all RCTs was initially taken up in perinatal medicine. This ultimately led to the publication of a ‘Guide to Effective Care in Pregnancy and Childbirth’ and the electronic publication ‘The Oxford Database of Perinatal Trials’. Following the launch of the Cochrane Collaboration in 1992, these publications became the prototype for the present day Cochrane Library, which publishes more than 1500 systematic reviews covering most areas of health care represented by 50 collaborative review groups. The goal of the Cochrane Collaboration is to improve decision making in health care by "preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions". In addition to providing up to date, unbiased evidence on health care, systematic reviews can also identify ‘gaps’ where there is insufficient or no evidence. Gaps in the evidence for clinical decision making may arise for a number of reasons—where no research has been performed; where trials of insufficient power to determine an important treatment effect have been undertaken, but no meta-analysis has been performed; and where there is insufficient evidence from trials even after a thorough systematic review and meta-analysis.
The first comprehensive review of robust evidence for fertility treatments (Vandekerckhove et al., 1993) was published a decade ago. This report aims to summarize the findings of the Menstrual Disorders and Subfertility Group (MDSG) reviews in the field of subfertility, to assess qualitatively how successful MDSG membership has been in the ‘coverage’ of this field and to assess where gaps in the evidence remain.
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Methods |
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Each of the 38 reviews addressing subfertility from the 70 MDSG reviews currently or previously published on the Cochrane Library (Issue 1, 2003, Oxford Update Software) were sub-grouped as unexplained infertility, tubal infertility, anovulatory infertility, other female infertility, male infertility or assisted reproductive technology (ART). The following information was collected from each review: the number of trials available for meta-analysis, the total number of trial participants available for meta-analysis and whether there was an answer to the primary clinical question—into which category from (A) to (C), below, the review fell.
(A) Where there is evidence of effectiveness or harm from a meta-analysis of trial data. The term ‘relative effectiveness’ was used when two interventions were compared and the term ‘effectiveness’ was used when the treatment was compared with either placebo or no treatment.
(B) Where there is insufficient evidence of effectiveness and the review authors have called for further research.
(C) Where there is insufficient evidence of effectiveness and the review authors have not called for further research.
Those reviews withdrawn from publication by virtue of not having been updated for at least 2 years have been highlighted in Tables I–VI by suffixw.
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Results |
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The findings of the MDSG subfertility reviews are summarized in Tables I–VI. Overall, from the 38 MDSG subfertility reviews, there was sufficient evidence of effectiveness of the interventions from primary trial data or from meta-analysis of trial data in 12 reviews and insufficient evidence of effectiveness in 26 reviews (from which the authors of 23 reviews called for further research).
Two of the three reviews, which did not find evidence of effectiveness and where the reviewers did not feel that further research was warranted, have now been withdrawn from publication on the Cochrane Library because they had not been updated for >2 years.
Unexplained infertility
From eight reviews of unexplained infertility, two meta-analyses provided evidence to answer the clinical question and there was insufficient evidence in six reviews, four of which called for further research (Table I). In unexplained infertility, there was evidence of effectiveness of clomiphene citrate (CC) for women (Hughes et al., 2003a) and of tubal flushing with oil-soluble contrast media, although there was insufficient evidence for the relative efficacy of oil-soluble versus water-soluble media (Johnson et al., 2003a). There was insufficient evidence of the effectiveness of bromocriptine (Hughes et al., 2003b) and danazol (Hughes et al., 2003c) for women and kinin-enhancing drugs for men (Vandekerckhove et al., 2003a). There was also insufficient evidence for oral versus injectable ovulation induction agents for controlled ovarian stimulation (Athaullah et al., 2003), for double versus single intrauterine insemination (IUI) (Cantineau et al., 2003) and for the relative effectiveness of IVF versus expectant management, IUI with or without ovarian stimulation and gamete intrafallopian transfer (GIFT) (Pandian et al., 2003).
Tubal infertility
In the five reviews of tubal infertility, one meta-analysis provided evidence of effectiveness and there was insufficient evidence in four reviews (Table II). In tubal infertility, there was evidence of effectiveness of laparoscopic salpingectomy for hydrosalpinges prior to IVF (Johnson et al., 2003b). Although there was evidence of effectiveness of Interceed, Gore-tex and Seprafilm adhesion barriers and of superiority of Gore-tex over Interceed in terms of adhesion reduction, there was no evidence these interventions were associated with an increased chance of pregnancy (Farquhar et al., 2003a). There was insufficient evidence for various microsurgical techniques (Watson et al., 2003a), various intra-operative liquid and fluid agents for adhesion prevention following subfertility surgery (Watson et al., 2003b) and post-operative hydrotubation or laparoscopic adhesiolysis following pelvic reproductive surgery (Johnson and Watson, 2003).
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Anovulatory infertility
From five reviews of anovulatory infertility, one provided evidence of effectiveness and there was insufficient evidence in four reviews (Table III). In anovulatory infertility, there was evidence of effectiveness of CC for oligo-amenorrhoea (Hughes et al., 2003d
). In polycystic ovary syndrome (PCOS), there was insufficient evidence of: relative effectiveness of FSH versus hMG (Nugent et al., 2003); effectiveness of addition of GnRH analogue to gonadotrophins (Hughes et al., 2003e); effectiveness of pulsatile LH releasing hormone (LHrH) (Bayram et al., 2003a); relative effectiveness of recombinant FSH (rFSH) versus urinary FSH (uFSH) nor of a preferential dose regime for rFSH (Bayram et al., 2003b).
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In clomiphene-resistant PCOS, there was no evidence of a difference in treatment pregnancy outcomes between laparoscopic ovarian drilling and gonadotrophin injections (Farquhar et al., 2003b
).
Other female causes of infertility
The one review in this category (Table IV), provided evidence of effectiveness of laparoscopic surgical treatment of endometriosis for increasing the chance of pregnancy (Jacobson et al., 2003).
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Male infertility
From seven reviews of male infertility, two meta-analyses provided evidence of effectiveness and there was insufficient evidence in five reviews, four of which called for further research (Table V). In male infertility, there was evidence of increased effectiveness of IUI over timed intercourse (Cohlen et al., 2003
) and IUI versus cervical insemination (O’Brien and Vandekerckhove, 2003). There was insufficient evidence of effectiveness of anti-estrogens (Vandekerckhove et al., 2003b), androgens (Vandekerckhove et al., 2003c), bromocriptine (Vandekerckhove et al., 2003d) or of surgery or embolization for varicocele (Evers et al., 2003) for subfertile men. There was insufficient evidence to support any particular technique of surgical retrieval of sperm for men with azoospermia undergoing ICSI (Van Peperstraten et al., 2003).
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ART
For the sub-group ART, of the 12 reviews, six found evidence of effectiveness and there was insufficient evidence of effectiveness in six reviews (Table VI). In ART cycles, there was evidence of increased effectiveness in terms of pregnancy outcomes of recombinant over urinary FSH (Daya, 2003a
; Daya and Gunby, 2003), long course over short course pituitary desensitization with GnRH agonists (Daya, 2003b), and long course GnRH agonists over GnRH antagonists (Al-Inany and Aboulghar, 2003). There was insufficient evidence of effectiveness of growth hormone in IVF protocols (Kotarba et al., 2003) and of depot versus daily administration of GnRH agonists (Albuquerque et al., 2003). There was evidence of increased effectiveness of ICSI over standard IVF in the case of borderline semen but not with normal semen (Van Rumste et al., 2003). There was insufficient evidence of effectiveness of blastocyst versus cleavage-stage embryo transfer (Blake et al., 2003). In the prevention of ovarian hyperstimulation syndrome (OHSS), there was evidence of effectiveness of i.v. albumin (Aboulghar et al., 2003), but insufficient evidence of effectiveness for cryopreservation (D’Angelo and Amso, 2003a) or coasting versus early unilateral follicular aspiration (D’Angelo and Amso, 2003b).
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Discussion |
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In spite of increasing recognition of the need for trials to have sufficient power to answer a clinical question, many of the included trials in Cochrane subfertility reviews, even those performed in recent times, have been under-powered. There are many reasons for this, including difficulty recruiting subfertility patients to clinical trials and using surrogate or intermediate outcomes to calculate power. It is therefore unusual in subfertility for a single RCT to provide sufficient evidence to answer a clinical question. By comparison, large multi-centred trials of women with pre-eclampsia and breech presentation have now been undertaken, by adopting a multi-centred approach throughout both the developed and developing world. Although further trials are planned using this approach in obstetrics, no similar networks of clinical trials exist on such a scale in subfertility and there has been a paucity of multi-centre trials in subfertility. Therefore meta-analysis of the results of randomized trials, which involves pooling of trial results in a statistically appropriate manner, has been, and will continue to be, a valuable technique.
There is a perception that Cochrane reviews rarely give a clear answer to a clinical question. This is clearly not the case since almost one third (12 out of 38) of the subfertility reviews did provide evidence of effectiveness of the interventions studied. Furthermore, the conclusion ‘not enough evidence’ is important to emphasise the need for further research before adopting a new treatment that might be more invasive or expensive.
A common mistake of authors of trials and systematic reviews is to conclude that there is ‘no difference’ or ‘no effect’ of a treatment (Alderson and Chalmers, 2003). The preferred terminology is ‘no evidence of effectiveness’ (Alderson and Chalmers, 2003) since the null hypothesis can never be proved, only disproved, and there is always some uncertainty around the estimates of a treatment effect. In this report, where reviewers have concluded no evidence of effectiveness but suggested that no further research is required, this implies that the review has ruled out a pre-specified clinically important effect of the treatment based on the numbers included in the meta-analysis. Reviewers should only draw this conclusion if the individual trials are adequately powered or if clinically important differences between treatments have been excluded. The width of the confidence intervals around the point estimate may also give some indication of whether or not there is a need for further research. However the methodology for power calculations in systematic reviews (unlike power calculations in RCTs) is not well established.
There are particular methodological challenges for subfertility trials and in particular, many trials do not report live-birth outcomes, clearly the most important outcome to a couple with a fertility problem (Vail and Gardener, 2003). Whilst awareness of the likelihood of conceiving after one cycle of treatment is of some interest, the one piece of information that a woman or a couple really want is the likelihood of having a baby at the end of a course of treatment, not necessarily after each cycle. Yet there has been a preference to report implantation rates or ‘per cycle’ data in subfertility trials. ‘Per woman’ or ‘per couple’ data are not always reported but reporting and pooling of ‘per cycle’ data is statistically inappropriate when it is women or couples who are randomized in trials, as many of the women will have undergone more than one cycle. Furthermore, few trials report by intention-to-treat; the inappropriate use of cross-over trial design and the failure to use a secure method of randomization is also common (Vail and Gardener, 2003). The design of future clinical trials needs to consider these issues in order to improve the utility of the research undertaken.
Whilst this paper may serve as a reference for the best available evidence for infertility treatments, indiscriminate use of the summary tables is not appropriate. The strength of systematic review evidence inevitably reflects the quality of the original trials within the review. Vandekerckhove et al. (1993a) noted the poor quality, or even lack, of true randomization, a major potential source of bias. Thus each trial contributing to a systematic review must be scrutinized in detail.
Cochrane review work can help to ‘plug’ gaps in the evidence. Firstly, a meta-analysis may demonstrate effectiveness of an intervention where the relevant primary trials had not shown a significant effect. Secondly, conclusions of insufficient evidence assist with the definition of a research agenda and may lead to the commissioning of trials. There are numerous examples of trials being commenced after a Cochrane systematic review has highlighted deficiencies in the evidence. Indeed, there is a compelling argument in favour of performing a systematic review prior to the design of any new trial. Thirdly, a strategic appraisal of the ‘coverage’ of the scope of a collaborative review group enables reviews to plug other gaps—this is the principle of registering titles through the editorial base of a Cochrane Collaborative Review Group to minimize the likelihood of duplication and overlap within reviews. Table VII summarizes the published protocols, registered titles and proposed titles on subfertility within the MDSG. Those interested in registering a review title for a clinical question in subfertility not covered by the titles, protocols and reviews outlined in this paper should contact Michelle Proctor, Collaborative Review Group Co-ordinator, on e-mail m.proctor@auckland.ac.nz. In conclusion, there are many gaps in the evidence for clinical decision making in subfertility and Cochrane review work has eliminated some gaps in the evidence and highlighted others.
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Acknowledgements |
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Carolyn Bilbrough assisted with the initial extraction of data from subfertility reviews in the Cochrane Library. We are grateful to all current and previous members of staff at the office of the MDSG Editorial Base in Auckland and to those who have contributed to MDSG subfertility reviews.
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Submitted on January 10, 2003; accepted on March 3, 2003.
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