Randomized controlled trials (RCTs) are the gold standard of study design, but they achieve this goal only if rules of good study design are followed. Deviations can cause significant damage, exactly because RCTs carry so much weight. Zhang et al recently reported a noninferiority trial of minimal stimulation in comparison to conventional in vitro fertilization (IVF) with limits of –10%, and claimed randomization “at cycle start.” Because of greatly diverging treatments requiring patient preparation this appears unlikely. Although not necessarily disqualifying, randomization was not blinded and obviously biased because one treatment arm consciously did not use standard treatment since professional guidelines recommend that young patients with good prognosis, as investigated in this study, receive elective single embryo transfer (eSET). Yet, only the minimum stimulation arm was offered eSET.

Even such breaches of proper randomization would be excusable if only the study’s primary outcome (live birth rate) had been evaluated. Multiple births were, however, a formal secondary outcome and turned it into a “competing” primary outcome by suggestions that lower multiple births in minimal stimulation compensated for lower live birth rates (–14%). The authors created a self-fulfilling prophecy of higher multiples in conventional IVF by transferring 2 embryos (while the other study arm received eSET), and then used this artifact of bias to claim compensatory benefits for minimal stimulation.

Most importantly, the study completely rejected the primary hypothesis of noninferiority by exceeding –10% specified borders (–14%), although this principal failure was never acknowledged. Their claim of higher multiples with conventional IVF is incorrect because the biased study design does not permit this conclusion.

In their conventional IVF arm only 120 of 279 patients (43.0%) had fresh embryo transfers, most certainly not representing “conventional” IVF. Such embryo “banking” distorts outcome reporting, and is used to artificially inflate pregnancy chances.

Minimal stimulation IVF is not only, cycle to cycle, inferior to conventional IVF but also over a cumulative 6-month schedule. Outcome advantage for standard IVF may be underestimated since a majority of conventional cycles were deprived of fresh embryo transfers. Finally, this study investigated only patients with good prognosis. Minimal stimulation IVF is also widely propagated for patients with poor prognosis, where outcomes will, likely, be even worse.