How effective are the non-conventional ovarian stimulation protocols in ART? A systematic review and meta-analysis

Purpose To compare the effectiveness of starting the ovarian stimulation on the early follicular phase (Conventional) with the newer range of non-conventional approaches starting in the luteal phase (Luteal), random-start, and studies implementing them in DuoStim (Conventional+Luteal). Methods Systematic review. We searched CENTRAL, PubMed, and Embase, on March 2020. We included randomized and non-randomized controlled trials that compared Luteal, random-start ovarian stimulation or DuoStim with Conventional; we analyzed them by subgroups: oocyte freezing and patients undergoing ART treatments, both, in the general infertile population and among poor responders. Results The following results come from a sensitivity analysis that included only the low/moderate risk of bias studies. When comparing Luteal to Conventional, clinically relevant differences in MII oocytes were ruled out in all subgroups. We found that Luteal probably increases the COH length both, in the general infertile population (OR 2.00 days, 95% CI 0.81 to 3.19, moderate-quality evidence) and in oocyte freezing cycles (MD 0.85 days, 95% CI 0.53 to 1.18, moderate-quality evidence). When analyzing DuoStim among poor responders, we found that it appears to generate a higher number of MII oocytes in comparison with a single Conventional (MD 3.35, 95%CI 2.54-4.15, moderate-quality evidence). Conclusion Overall, this systematic review of the available data demonstrates that in poor responders, general infertile population and oocyte freezing for cancer stimulation in the late follicular and luteal phases can be utilized in non-conventional approaches such as random-start and DuoStim cycles, offering similar outcomes to the conventional cycles but potentially with increased flexibility, within a reduced time frame. However, more well-designed trials are required to establish certainty.