Equipoise and the RCT.

Clinical decisions in reproductive medicine are often made in uncertainty. To reduce uncertainty and to improve clinical decision-making, RCTs are increasingly called upon. A key concept underpinning the ethics of RCTs is equipoise. Here, we aimed to dissect the basic reasoning behind the concept of equipoise and we proposed a line of thinking delineating under which conditions it is ethical to design and execute an RCT. This might prevent a priori negative trials, reduce research waste and aid in the design of meaningful ones. It is these trials that will provide insight on how to safely and effectively assist subfertile couples.

Selective outcome reporting and sponsorship in randomized controlled trials in IVF and ICSI.

STUDY QUESTION: Are randomized controlled trials (RCTs) on IVF and ICSI subject to selective outcome reporting and is this related to sponsorship? SUMMARY ANSWER: There are inconsistencies, independent from sponsorship, in the reporting of primary outcome measures in the majority of IVF and ICSI trials, indicating selective outcome reporting. WHAT IS KNOWN ALREADY: RCTs are subject to bias at various levels. Of these biases, selective outcome reporting is particularly relevant to IVF and ICSI trials since there is a wide variety of outcome measures to choose from. An established cause of reporting bias is sponsorship. It is, at present, unknown whether RCTs in IVF/ICSI are subject to selective outcome reporting and whether this is related with sponsorship. STUDY DESIGN, SIZE, DURATION: We systematically searched RCTs on IVF and ICSI published between January 2009 and March 2016 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the publisher subset of PubMed. We analysed 415 RCTs. PARTICIPANTS/MATERIALS, SETTING, METHODS: Per included RCT, we extracted data on impact factor of the journal, sample size, power calculation, and trial registry and thereafter data on primary outcome measure, the direction of trial results and sponsorship. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 415 identified RCTs, 235 were excluded for our primary analysis, because the sponsorship was not reported. Of the 180 RCTs included in our analysis, 7 trials did not report on any primary outcome measure and 107 of the remaining 173 trials (62%) reported on surrogate primary outcome measures. Of the 114 registered trials, 21 trials (18%) provided primary outcomes in their manuscript that were different from those in the trial registry. This indicates selective outcome reporting. We found no association between selective outcome reporting and sponsorship. We ran additional analyses to include the trials that had not reported sponsorship and found no outcomes that differed from our primary analysis. LIMITATIONS, REASONS FOR CAUTION: Since the majority of the trials did not report on sponsorship, there is a risk on sampling bias. WIDER IMPLICATIONS OF THE FINDINGS: IVF and ICSI trials are subject, to a large extent, to selective outcome reporting. Readers should be aware of this to avoid implementation of false or misleading results in clinical practice. STUDY FUNDING/COMPETING INTERESTS: No funding received and there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Effectiveness and safety as outcome measures in reproductive medicine.

The aim of reproductive medicine is to help couples with an unfulfilled child wish to have a child by offering them the best treatment option. The choice of treatment reflects effectiveness and safety. While effectiveness refers to the extent to which a treatment increases the chance of a couple in having a baby, safety relates to adverse effects associated with such a treatment. In an attempt to integrate effectiveness and safety, healthy singleton live birth (at term) has been suggested as the ideal outcome measure for evaluative research in reproductive medicine. Although intuitively desirable, this proposal overlooks the fact that assessment of effectiveness and safety in this context cannot be measured as a single outcome. In this paper, we explain why effectiveness and safety outcomes in reproductive medicine should be assessed independently, and later synthesized to inform clinical decision-making.

How are neonatal and maternal outcomes reported in randomised controlled trials (RCTs) in reproductive medicine?

STUDY QUESTION: How do randomised controlled trials (RCTs) in reproductive medicine report maternal and neonatal outcomes, specifically singleton live birth? SUMMARY ANSWER: Despite the widespread appeal to use singleton live birth as the outcome measure in subfertility trials, 80% of RCTs fail to do so, and fail to report on neonatal and maternal outcomes. WHAT IS KNOWN ALREADY: The aim of reproductive medicine is to assist subfertile couples in their wish to have children. A decade ago it was proposed to use singleton live birth as the outcome measure. We assessed whether clinical research has followed this recommendation, and how neonatal/maternal outcomes are reported. STUDY DESIGN, SIZE, DURATION: A review of the published literature from 1 January 1966 to 31 December 2012 was performed using the Cochrane database. We compared the time periods before and after 2004; the year after ESHRE recommended the use of singleton live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched the Cochrane database for RCTs in reproductive medicine, and recorded the number of studies that used singleton live birth as the outcome measure. We also recorded the reporting neonatal and maternal outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 910 RCTs that reported on fertility treatments, of which 182 RCTs (20%) reported on singleton live birth [before 2004 96/518 (19%); after 2003 86/392 RCTs (22%)]. Singleton live birth was the primary outcome in 68 RCTs (7.4%). Only 44 RCTs (4.8%) reported on neonatal outcome, while 52 RCTs (5.7%) reported on maternal outcome. LIMITATIONS, REASONS FOR CAUTION: We only included Cochrane reviews, thus report here only on the higher quality studies. The actual reporting on maternal and neonatal outcome may even be lower when studies of lower quality are included. WIDER IMPLICATIONS OF THE FINDINGS: Although a decade ago singleton live birth was recommended as the outcome measure of reproductive medicine research, this has not been followed; currently most clinical research in reproductive medicine does not report beyond the occurrence of pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the study. The authors have no conflicts of interest to declare.