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

Abstract

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. ResultsThe 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.

The (decision) tree of fertility: an innovative decision-making algorithm in assisted reproduction technique

“…As a consequence, a new ART cycle could be planned to modify the COS phase in order to improve the OF17 number and to proceed to pick-up with higher probability of success. Indeed, the COS phase is heterogeneously managed comparing different assisted fertilization centers given the absence of evidence-based protocols, but crucial for ART success [13,33]. Apart from tangible clinic and economic advantages, possible repercussions on the psychological health of the infertile couple have to be taken into account.…”

“…In clinical practice, the physician needs to estimate a priori the female response after the controlled stimulation phase (COS) without clear evidence-based recommendations [13], leaving an extreme variability in the proposed therapeutic regimens [8]. Indeed, the most cost-effective ART management in terms of pregnancy and live birth rates is still far to be achieved [14].…”

Progestin primed double stimulation versus flexible GnRh antagonist protocol in poor responders. A randomized control study.

“…Additionally, Glujovsky et al have demonstrated that the number of mature oocytes was almost doubled after the dual stimulation. [15]. However, we have found a trend towards an increase in mature oocytes retrieved from the dual stimulation protocol but this difference was statistically insigni cant (6 Vs 4.5 oocytes, p = 0.254).…”

“…Glujovsky et al in their systematic review and meta-analysis have studied two RCTs and one pilot study in which dual stimulation was studied in poor ovarian responders against only one wave of conventional antagonist protocol. [15] They have demonstrated a signi cant higher number of retrieved oocytes after the dual stimulation against the conventional stimulation. It must be stressed that we have compared the dual stimulation protocol against two waves of antagonist follicular stimulation.…”

Double stimulation for the management of poor-prognosis patients: where are we going?

“…Over time, several independent groups outlined the consistency and reproducibility of double stimulation in terms of safety and efficiency, thus confirming the evidence initially reported by the Chinese and Italian research articles, albeit these conclusions are not supported by RCTs [28–30]. Several observation studies have shown that double stimulation is an effective treatment in patients requiring a large number of oocytes in order to improve the cumulative chance per ovarian cycle [22,30–33].…”