Fresh and cumulative live birth rates in mild versus conventional stimulation for IVF cycles in poor ovarian responders: A systematic review and meta-analysis

Abstract

Study Question: Are cumulative and live birth rates (LBRs) comparable in poor ovarian response women treated with different protocols of mild stimulation IVF (i.e. oral compounds, lower doses or shorter treatments) versus conventional IVF? Summary Answer: Mild ovarian stimulation (MOS) results in comparable outcomes to those of conventional stimulation in poor ovarian response patients with low ovarian reserve. What is Known Already: Several randomized trials and meta-analyses have been published evaluating the role of mild (MOS) versus conventional ovarian stimulation in poor ovarian response patients. Most report a potentially higher safety profile, patient satisfaction and lower costs, suggesting that the higher cycle cancellation rate and fewer oocytes retrieved following MOS does not affect the final reproductive outcome. Additionally, over the last few years, new publications have added data regarding MOS, and shown the possible benefit of a higher oocyte yield which may also improve prognosis in patients with poor ovarian response. Study Design, Size, Duration: We conducted a systematic search of relevant randomized controlled trials (RCTs). We searched electronic databases, including MEDLINE, EMBASE, LILACS-BIREME, CINAHL, The Cochrane Library, CENTRAL (Cochrane Register), Web of Science, Scopus, Trip Database and Open Grey, to identify all relevant studies published up to March 2020. We examined trial registries for ongoing trials. No publication-year or language restrictions were adopted. We explored the reference list of all included studies, reviews and abstracts of major scientific meetings. The primary outcomes were cumulative and fresh LBR (CLBR and FLBR) per woman randomized. Participants/Materials, Setting, Methods: We included subfertile women undergoing IVF/ICSI characterized as poor responders and compared primary and secondary outcomes between the different protocols of mild stimulation IVF (i.e. oral compounds, lower doses or shorter treatments) and conventional IVF. We used the PICO (Patients, Intervention, Comparison and Outcomes) model to select our study population. Main Results and the Role of Chance: Overall, 15 RCTs were included in the meta-analysis. CLBR and FLBR were comparable between mild versus conventional stimulation (RR 1.15; 95% CI: 0.73 - 1.81; I2 = 0%, n = 424, moderate certainty and RR 1.01; 95% CI: 0.97 - 1.04; I2 = 0%, n = 1001, low certainty, respectively). No difference was observed either when utilizing oral compounds (i.e. letrozole and clomiphene) or lower doses. Similarly, ongoing pregnancy rate (OPR) and clinical pregnancy rate (CPR) were equivalent when comparing the two groups (RR 1.01; 95% CI: 0.98 - 1.05; I2 = 0%, n = 1480, low certainty, and RR 1.00; 95% CI: 0.97 - 1.03; I2 = 0%, n = 2355, low certainty, respectively). A significantly lower oocyte yield (mean differences (MD) -0.80; 95% CI: -1.28, -0.32; I2 = 83%, n = 2516, very low certainty) and higher rate of cycle cancellation (RR 1.48; 95% CI: 1.08 - 2.02; I2 = 62%, n = 2588, low certainty) was observed in the MOS group. Limitations, Reasons for Caution: The overall quality of the included studies was low to moderate. Even though strict inclusion criteria were used, the selected studies were heterogeneous in population characteristics and treatment protocols. We found no differences in CLBR between MOS and COS (95% CI: 0.73 - 1.81.) Wider Implications of the Findings: MOS could be considered as a treatment option in low prognosis poor responder patients, given that it results in similar fresh and CLBRs compared with COS. A milder approach is associated with a lower number of oocytes retrieved and a higher cancellation rate, although treatment cost is significantly reduced. Future research should focus on which type of ovarian stimulation may be of benefit in better prognosis women. WHAT DOES THIS MEAN FOR PATIENTS? The objective of this study was to examine whether a lower (mild stimulation) or higher (conventional stimulation) dose used during ovarian stimulation makes a difference to the chances of a successful outcome (i.e. live birth, pregnancy) in women with a low ovarian reserve (also named 'poor responders') undergoing IVF. For many years, there has been a debate on whether poor responders would benefit from a mild ovarian stimulation regimen (i.e. lower doses, the use of an oral medication (letrozole or clomiphene) or delaying the start of the treatment) compared with conventional stimulation (higher doses to obtain more oocytes and consequently more embryos), with studies yielding conflicting results. We performed a systematic review (i.e. literature review that uses systematic methods to collect data) and a meta-analysis (i.e. a statistical analysis that combines the results of multiple scientific studies) to evaluate whether one strategy was superior to the other. Based on our study, mild stimulation could be considered as an option for women with poor ovarian reserve, as we found similar results between the two strategies. Study Funding/Competing Interests: There were no sources of financial support. N.P.P. received research grants, honoraria for lectures from: Merck Serono, MSD, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex and Gedeon Richter. P.D. received unrestricted grants and honoraria from Merck Serono, MSD and Ferring Pharmaceuticals. I.G.F. received unrestricted grants and honoraria from Merck Serono, MSD, Ferring Pharmaceuticals, Gedeon-Richter and IBSA. P.M.B. reported no conflict of interest.