Published 06 March 2020
Despite several different approaches, variable doses and adjuvant therapies, the successful treatment of poor responders in IVF remains a stubborn clinical challenge. Now, a new observational study of a dual stimulation protocol appears to offer 'a very promising strategy'.
ESHRE's second venture into diagnostic consensus - following the 'Rotterdam criteria for PCOS - came in 2011 with a bid for agreement in the definition and diagnosis of poor ovarian response.(1) The working group's final consensus meeting took place in Bologna, Italy, and, while the 'Bologna criteria' met some criticism from the outset, its diagnostic conclusions remain largely accepted today. The criteria, for a standard definition of POR, required the presence of at least two of three features: advanced maternal age or any other risk factor for POR; a previous episode of POR; and an abnormal ovarian reserve test. POR would ultimately be evident in ‘cycle cancellation or retrieval of fewer than four oocytes with a conventional ovarian stimulation protocol’.
ESHRE's latest guideline on controlled ovarian stimulation for IVF, published last year, were emphatic that the aim of stimulation in a predicted poor responder is to generate as many eggs as possible. But to this end, while the guidelines were 'unclear' whether an FSH dose over 150 IU would result in a greater oocyte yield, a dose higher than 300 IU was strongly not recommended.
However, one stimulation protocol described in the guidelines as potentially able to allow recovery of 'more oocytes in a shorter time period' was a dual stimulation protocol within the same menstrual cycle. The first stimulation, performed in the follicular phase, was then, after oocyte pick-up, followed by a second in the luteal phase of the same cycle - with the pick-ups performed approximately two weeks apart. However, except in urgent fertility preservation cases and in the absence of any strong RCT evidence, this 'duostim' approach in poor responders was consigned to research only and not recommended routinely.
Now, however, that evidence gap has been somewhat filled by a new observational study of almost 300 patients who met the Bologna criteria for poor response.(2) Of these, 100 agreed to a duostim protocol, with the remainder following a conventional single stimulation in the follicular phase. All patients were treated in an antagonist cycle with agonist trigger, and had PGT-A for euploid single blastocyst transfer. When the outcomes from the two patient groups were compared, cumulative LBR (per intention to treat) in the duostim group was higher than after a single conventional stimulation (15% vs 7%). With LBRs comparable after the single stimulation protocol and after the first follicular phase stimulation of the duostim protocol, any added value, say the authors, was clearly 'the contribution of the second stimulation'. Indeed, cumulative LBR even after two separate conventional stimulations within the three-year study period did not increase beyond 8%. These findings were reflected in the rate of patients with one or more euploid blastocysts for transfer, increasing from 14% after conventional stimulation to 31% with duostim.
It was also evident that the duostim strategy lessened the patient drop-out rate, which, said the authors, 'is highly likely after a failed attempt with conventional COS'. 'Our promising results,' they add, 'suggest that DuoStim might prevent treatment discontinuation in poor responders fulfilling the Bologna criteria.' Indeed, an accompanying editorial in the same issue of Fertility and Sterility notes that 'DuoStim is proposed as an ideal strategy to prevent treatment discontinuation'.(3)
Although the Rome group reporting this study describe it as the largest of duostim with live birth as its primary outcome, and although they describe duostim as 'a valuable protocol' for patients fulfilling the Bologna criteria, they conclude that their results because of the small sample size cannot yet support duostim as preferable to two separate stimulation cycles in terms of LBR. Until further studies confirm these preliminary findings, they conclude that the successful treatment of women meeting the Bologna criteria continues to represent 'a conundrum in modern IVF'. But the concept of duostim, they report, is at least 'promising', noting that 'any strategy of controlled ovarian stimulation as adopted at present, encompassing different protocols, gonadotropins, and adjuvant therapies', has failed to increase cumulative LBR, with a rate stubbornly fixed at between 6% and 10%.
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. 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.
3. Labata E. DuoStim: a new strategy proposed for women with poor ovarian response. Fertil Steril 2020; 113: 76.
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