Dual stimulation and PGT-A for all: more topics for debate

Richard Paulson taking an unfamilar position on PGT-A for all

Published 16 April 2021

The menu of debates, back-to-back reviews and cutting-edge lectures to explore emerging themes continued on the second day of this Best of ASRM & ESHRE online meeting. Among themes explored were the emerging technique of double stimulation in predicted poor responders in IVF and the ever present conundrum of testing for aneuploidy in all patients.

Dual stimulation in poor responders
ESHRE’s 2019 guideline on ovarian stimulation protocols in IVF made two recommendations for dual stimulation: first, that in predicted low responders DuoStim ‘should only be used in the context of clinical research, and second, the technique ‘can be considered for urgent fertility preservation cycles’.(1) Both were featured in a back-to-back session.

Filippo Ubaldi, whose group in Rome have been behind much of the emerging data on DuoStim, concluded that (in predicted poor responders especially) oocyte number is ‘critical’ for maximising cumulative LBRs and that dual stimulation in the same ovarian cycle has the potential for finding a competent embryo in these challenging patients and for reducing their rates of drop-out. He presented persuasive data that mild stimulation is comparable to conventional (as in the early follicular phase) in terms of oocytes retrieved. The question is whether DuoStim can achieve the same or better results.

A multicentre study from Italy, published in November 2020 and reported here by Ubaldi, provided further evidence that stimulation in the luteal and then follicular phases of the same ovarian cycle confirmed it as a ‘feasible and efficient approach’ from clinical, obstetric and perinatal perspectives when applied in patients who need to reach blastocyst transfer in the shortest time possible.(2) Of 827 patients completing a DuoStim cycle, 145 had an euploid blastocyst after follicular phase stimulation, 186 after luteal phase, and 157 after both. The study reported a similar LBR to those found in previous studies, with no difference in reproductive competence between blastocysts derived from the follicular or luteal phase. Data from this and other independent studies, said Ubaldi, ‘have outlined the consistency and reproducibility of this approach’. Another recent meta-analysis found that DuoStim in patients with poor ovarian reserve favours ‘an enhanced clinical outcome’ in terms of total number of oocytes retrieved, mature oocytes and available embryos, ‘along with the quality of obtained embryos’.(3)

Time, or lack of, was a feature in Ubaldi’s and in the fertility preservation presentation. Using an antagonist protocol, DuoStim cuts the treatment time between a first and second egg retrieval to around 14 days, whereas waiting for a second conventional cycle might take several months. This, said Ubaldi, is an important factor in avoiding discontinuation after a first failed attempt.(4)

Clarisa Gracia from the University of Pennsylvania described DuoStim in an oncofertility setting as ‘particularly useful’ in fertility preservation patients with only a short timeframe available - and additionally so in those with limited ovarian reserve. Its use has become increasingly applicable with the greater number of predicted – and actual - survivors of female cancers with their greater risk of POI and infertility. Survivors, she said, are 13 times more likely to experience premature menopause, and around 30% of those treated with both alkylating agents and pelvic radiation will inded have premature menopause.

Time is usually of the essence – both before cancer treatment and to avoid any delay. The multiple waves of follicle growth throughout the entire menstrual cycle – as also explained by Ubaldi – means that stimulation needn’t start with menses and may be repeated within the same ovarian cycle to maximise oocyte yield. ‘Success rates,’ said Gracia, ‘are highly dependent on the number of oocytes frozen.’ DuoStim will increase the number of oocytes and embryos cryopreserved.

While the benefits of DuoStim in female fertility preservation looked persuasive, Gracia noted costs and treatment delays as possible downsides – and inevitably a lack of strong evidence in terms of cost and efficacy in sub-groups.

PGT-A for all
The big audience logging in for Friday’s programme had to wait to the final session for a little light relief and for a properly staged debate – ie, with a motion, proponents and rebuttals. But what made this debate even more entertaining was that the two protagonists – Richard Paulson from the University of Southern California and Luca Gianaroli from Bologna – were taking a position not familiarly associated with them, Paulson now in favour of the motion, and Gianaroli against. ‘I hope he wins,’ said Gianaroli after taking us through his own personal retrospective of 30 years in aneuploidy screening.

Paulson’s main argument in favour of PGT-A for all was rhetorical. ‘Why would you not want to know everything possible about an embryo before transferring it to a patient?’ he asked, while adding more practically that PGT-A is cost effective, is accurate and does no harm to the embryo. Cost savings, he argued, are in the avoidance of multiples, which by his calculation differed by around $80,000 between singleton and twin deliveries. SART data, he added, suggests that PGT-A can halve the US twin rate, from 15 to 7%. Citing a study just published from Scott’s group in the USA, Paulson contrasted a zero delivery rate with an aneuploid blastocyst with one of around 60% when tested as euploid.

So PGT-A, he concluded, is reliable and ‘still improving’, is cost effective and appealing to patients, and eliminates the inevitable failure of aneuploid embryo transfers. Indeed, he added, with no hint of understatement, ‘If patients refuse PGT-A, they should be informed of the risks: lower success, higher rate of miscarriage, and aneuploid pregnancy.’

Luca Gianaroli’s apologia pro vita sua began with his own sketches on the back of a napkin with Santiago Munne and his long-standing colleague Cristina Magli on the principle of PGS, and, after 30 years of FISH, arrays and NGS, concluded ‘there are still doubts about its efficacy’. This latter conclusion has been commonly heard, not least by the Cochrane group, with doubts wide spread of any improvement in LBRs, in Europe especially. The thrust of Gianaroli’s case was that just as the technology has moved on so have the patients. And, although there will be indications in some patients for PGT-A, there is no good evidence that universal application will derive benefit. ‘It seems best to focus on the individual patient,’ said Gianaroli. ‘The best patient is the one asking why she can’t get pregnant.’

A vote taken before the debate began found around 80% of this lively audience against the motion of PGT-A for all; such were the persuasive powers of these two speakers and their answers to a multitude of live questions that the final vote was exactly the same. But, as co-chairman Michael Thomas said, ‘this was one of our best debates’ – so who was worried about votes, or even evidence?

1. ESHRE guideline: ovarian stimulation for IVF/ICSI.
The ESHRE Guideline Group on Ovarian Stimulation.
Hum Reprod Open 2020, 2, hoaa009.
2. Viarelli A, Cimadomo D, Alviggi E, et al. The euploid blastocysts obtained after luteal phase stimulation show the same clinical, obstetric and perinatal outcomes as follicular phase stimulation-derived ones: a multicenter study. Hum Reprod 2020; 35: 2598-2608
3. Sfakianoudis K, Pantos K, Grigoriadis S, et al. What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach. J Assist Reprod Genet 2020; 37: 181-204.
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 2019; 113: 121-130.
5. Tiegs A, Zhan Y, Whitehead C, et al. A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy. Fertil Steril 2021; 115: 627-637.

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