Published 13 March 2023
Despite promising results in observational studies, a small RCT in patients with a predicted poor ovarian response has found comparable rates of live birth in those randomised to a same-cycle dual stimulation protocol as in those randomised to conventional stimulation in two consecutive cycles.
It's now more than a decade since the Bologna criteria setting out a definition of poor ovarian response was published, and there still seems little that can confidently be done to improve oocyte yield in those likely to respond sub-optimally to ovarian stimulation.(1) The criteria made it clear that, while oocyte number need not reflect oocyte quality, a sub-optimal number is a limiting factor for embryo selection and transfer of viable embryos. ESHRE’s latest guideline on ovarian stimulation for IVF published in 2020 still had little to offer the predicted poor responder, with variations in FSH dose and stimulation agent either ‘unclear’ or ‘not recommended’.(2) There was no evidence to recommend any adjuvant treatment.
However, one possible approach, described in the guideline as potentially able to allow recovery of 'more oocytes in a shorter time period', was suggested in a dual stimulation strategy, now known as ‘DuoStim’. Behind its interest lay the biological finding that two or three waves of follicular development might occur in the same cycle, and that stimulation in each of the follicular and luteal phases might yield a greater number of follicles than found with a single conventional attempt. This has appeared to be the case in several recent retrospective studies and a systematic review of ‘non-conventional’ protocols, which concluded that in predicted poor responders stimulation in the late follicular and luteal phases seems to offer ‘similar outcomes to the conventional cycles but potentially with increased flexibility, within a reduced time frame’.(3) In 2020 a study from the group of Ubaldi in Rome in 100 patients meeting the Bologna criteria for POR obtained more oocytes after luteal phase stimulation (and with similar developmental and chromosomal competence) than after follicular phase stimulation. Cumulative LBR increased from 7% after conventional stimulation to 15% after DuoStim.(4) The study described the DuoStim strategy as a ‘promising’ protocol to manage this group of patients, ‘especially to avoid discontinuation after a first failed attempt’.
Now, in what is described as the first RCT to compare the birth-rate outcomes of two stimulations in the same cycle (DuoStim) with two stimulations in consecutive cycles, results have failed to show any benefit from DuoStim in POR patients in terms of numbers of eggs collected.(5) The study, performed in France, randomised 44 women with defined POR according to the Bologna criteria (AFC <5 and/or anti-Mullerian hormone <1.2 ng/ml) to DuoStim and 44 to conventional follicular-phase stimulation in two cycles. In the DuoStim group oocytes were pooled and fertilised after the second retrieval, with a freeze-all protocol, while fresh transfers were performed in the control group (with FETs in both control and DuoStim groups in natural cycles).
The cumulative number of oocytes collected from the two DuoStim pick-ups were no different from those from the two conventional cycles (5.0 vs 4.6), although the total number of usable embryos for FET was less in the DuoStim group. The authors explain that this might be because all oocytes collected from the first stimulation were vitrified (according to French law) and then warmed and pooled with the fresh oocytes from the second stimulation. After fertilisation, the embryos were then vitrified, and thereafter thawed for transfer. The authors propose that, even if low, the wastage rate of oocytes and embryos at each warming ‘may put oocytes/embryos at a higher risk of loss’ with the DuoStim protocol, ‘particularly in women with POR’.
The trial, particularly in its recruitment and treatment, was affected by the Covid pandemic, although the authors note that the number of patients calculated to test the statistical hypothesis (that more oocytes can be obtained with a luteal phase stimulation after a follicular phase stimulation) was reached in the DuoStim group. However, this was a small trial, which nevertheless failed to demonstrate the benefit of DuoStim in patients with predicted poor prognosis, selected by low ovarian reserve markers but not specifically by advanced maternal age. The main benefit of Duostim thus seems to be a shorter time to a second retrieval (by around two weeks), important in circumstances such as fertility preservation when the rapid accumulation of oocytes/embryos may be required.
This is a similar conclusion to that drawn very recently in another small DuoStim RCT in predicted poor responders having PGT-A.(6) This too randomised patients to two protocols, two ovarian stimulations in consecutive cycles and DuoStim in a single cycle, with the main outcome now euploidy rate and not LBR. This study too found comparable results in the two groups, although the time to obtain an euploid blastocysts was reduced in the DuoStim group.
Ubaldi’s group in Rome, having similarly tested DuoStim in poor prognosis patients scheduled for PGT-A, found that a second stimulation in the luteal phase had the potential to ‘rescue poor blastocyst yields after conventional stimulation’, and ‘prevent drop-out or further aging between attempts’.(7) Reduction in drop-out rate was one benefit of DuoStim already identified by the Rome group. However, the latest RCT from France suggests that benefits in improving LBR may not be so evident and, as the authors themselves now suggest, further studies are needed to evaluate LBR in DuoStim cycles in POR, as well as the effects of shorter treatment time and cost when compared to two conventional protocols.
1. Ferraretti AP, La Marca A, Fauser BC, et al. ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria, Hum Reprod 2011; 26: 1616-1624.
2. The ESHRE Guideline Group on Ovarian Stimulation. Hum Reprod Open 2020; 2: hoaa009, https://doi.org/10.1093/hropen/hoaa009
3. Glujovsky D, Pesce R, Miguens M, et al. How effective are the non-conventional ovarian stimulation protocols in ART? A systematic review and meta-analysis. J Assist Reprod Genet 2020; 37: 2913-2928.
4. Vaiarelli A, Cimadomo D, Conforti A, et al. Luteal phase after conventional stimulation in the same ovarian cycle might improve the management of poor responder patients fulfilling the Bologna criteria: a case series. Fertil Steril 2020; 113: 121-130.
5. Massin N, Abdenebbi I, Porcu-Buisson G. The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF. Hum Reprod 2023; doi.org/10.1093/humrep/dead038
6. Cerrillo M, Cecchino GN, Toribio M, et al. A randomized, non-inferiority trial on the DuoStim strategy in PGT-A cycles. Reprod Biomed Online 2023; 46: 536-542. doi.org/10.1016/j.rbmo.2022.11.012
7. Vaiarelli A, Cimadomo D, Gennarelli G, et al. Second stimulation in the same ovarian cycle: an option to fully-personalize the treatment in poor prognosis patients undergoing PGT-A. J Assist Reprod Genet 2022; 39: 663-673. doi.org/10.1007/s10815-022-02409-z
DAY 2: BEST OF ASRM & ESHRE
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