Published 02 February 2021
At a time when European pregnancy rates have plateau’d a well attended Campus meeting in January reviewed new (and old) concepts in the planning and strategies of treatments to improve success rates. The debates continue, some after many years.
With ‘success’ in ART still not agreeably defined and, according to recent registry figures, apparently stalled for the past few years, a Campus course organised by the SIG Reproductive Endocrinology in January picked off a list of ‘new concepts, new strategies’ aiming to make improvements. The list included topics from the planning of cycles – programming, hormone tests, add-ons and investigations – and from treatment itself – antagonists and agonists, freeze-all, oocyte maturation, luteal phase support, endometrial receptivity and even personalised embryo transfer as proposed with endometrial receptivity arrays. In addition and as befits the times, Antonio La Marca reviewed what we know so far about IVF in the COVID-19 era and how best to stimulate patients safely and effectively.
But, as the opening presentations of this well attended Campus forewarned, evidence-based consensus was hard to find, with only the better tried and tested concepts passing the level of acceptability. And ironically nowhere was a more fluid concept described than in the very definition of ‘success’ itself, a concept which Sesh Sunkara proposed had now advanced to cumulative delivery rates (as itemised in the 2017 international glossary of ICMART) and even ‘time to pregnancy leading to live birth’ (proposed as ‘long-awaited’ by Sunkara herself and itemised in the recent core outcomes for fertility research).(1,2,3) Hovering in the background of these definitions was safety (healthy singleton deliveries and OHSS-free) as a further measure of success.
Thus, Sunkara’s idea of success emerged as a ‘one and done’ concept – by which family plans might be achieved from one started IVF cycle with perhaps two healthy live births derived from it, one fresh and one frozen. And this set against an overall background of higher cumulative LBRs, a shorter time to live birth, zero risk of OHSS and happy families. Of course, the picture was not so simple. Recent months, reported Sunkara, have seen leading calls for ‘ongoing pregnancy’, ‘sustained implantation rate’ and a range of key performance indicators from the IVF lab as still the most meaningful measure of success.
Cycle programming is hardly an emerging concept, its introduction three decades ago, according to Juan Garcia-Velasco from the IVI centre in Madrid, a function of necessity to avoid egg collections at weekends. Since these first attempts to improve clinic efficiency, three methods of cycle scheduling have been extensively studied: a flexible start to stimulation, a one-day delay or advance for hCG, and pretreatment with estradiol or the contraceptive pill in both long agonist and antagonist protocols. Studies of the three strategies have shown no negative effects on outcome, the most recent last year when a retrospective analysis of more than 4000 treatments found that the pill given for an interval of 12 to 30 days and with a 5-day washout period did not affect clinical pregnancy or live birth.(4)
However, another report from last year, while acknowledging the everyday advantages from cycle scheduling as outlined by Garcia-Velasco, asked if the literature based largely on cleavage-stage transfers, variable stimulation doses and various types of pills, was still relevant to today’s antagonist cycles and blastocyst transfers.(5) The commentators’ doubts arose from an accompanying RCT which actually found pretreatment with the pill associated with a reduction in LBR and cumulative LBR, and thus contrary to the perceived wisdom of the past decades.(6) Despite the continuing debate, however, especially about the pill as pretreatment, Garcia-Velasco insisted that cycle scheduling was needed in busy units to distribute the work load, but with benefits (cycle scheduling, synchronised follicle cohorts) now necessarily balanced against potential drawbacks (higher FSH use, reduced LBR?).
Endometrial receptivity figured prominently in this meeting, with Nick Macklon asking how ovarian stimulation affects the endometrium and Christos Coutifaris, a former President of the ASRM, examining the evidence for personalised embryo transfer in the form of endometrial receptivity analysis. Macklon’s presentation began with the biological fact that ovarian stimulation has a proliferative effect on the endometrium, which may be explained by supraphysiological levels of estradiol. He thus added that ‘it seems reasonable to assume’ that high levels of estradiol do have an effect on implantation in IVF - and reasonable to enquire if aromatase inhibitors, which are known to reduce estradiol levels but not block receptors, might prove an effective alternative. That enquiry has now been completed in the ‘RIOT study’, a placebo-controlled trial of letrozole as co-treatment during ovarian stimulation aiming to assess the effect of reduced estradiol levels on endometrial receptivity. The study, which will specifically assess endocrine factors on the day of hCG and in the mid-luteal phase and uterine contractility on the day of embryo transfer, has now been completed and submitted for publication, said Macklon.
It's a similar transition from histology to molecular assessment of the endometrium which lies behind the development of endometrial receptivity analysis and a concept of ‘personalised’ embryo transfer based on an individual’s window of implantation. The much talked about endometrial receptivity array has now been tested in a five-year, three-arm RCT whose results were published last year.(7) The three study groups, explained Coutifaris, comprised fresh, frozen and ‘personalised’ embryo transfers, with a primary outcome of LBR after the first transfer. With 569 women assessed for enrolment, only 458 were randomised with a further 139 excluded for protocol non-compliance. Results showed no difference in LBR among the three groups after a first transfer in both the intention-to-treat and per-protocol analyses. So, asked Coutifaris, could endometrial receptivity analysis step forward based on these results? There are still too many questions, not least, he said, even the evidence that molecular endometrial dysfunction represents a major clinical problem. Indeed, just days before this Campus meeting a report from one of the USA’s leading PGT groups described recurrent implantation failure as a result of endometrial pathology as ‘rare’ (following the transfer of euploid embryos), and with respect to this RBMO publication there have been criticisms of its methodology (which were explained by the authors). Nevertheless, when during the question session Coutifaris was asked to rate the endometrial receptivity analysis according to the HFEA’s traffic light system, he opted for amber in certain patient groups, but red if proposed for routine use. ‘It’s not about theory,’ said Coutifaris, ‘but about data, and we don’t have it yet.’
It was to avoid embryo transfer in a stimulation cycle that the aims of a freeze-all policy were extended from safety to improved success. More than a decade ago Paul Devroey’s group in Brussels had proposed the concept of an IVF-free clinic based on an ART principle of segmentation, which included freeze-all and transfer in a later natural cycle.(8) As Nick Macklon had suggested, Stratis Kolibianakis also presented evidence that ovarian stimulation for IVF (via uterine contractility) has a deteriorating effect on endometrial receptivity and the probability of pregnancy. So will, asked Kolibianakis, freeze-all improve success rates over fresh transfers? Several large-scale RCTs and a recent meta-analysis suggest that there is a benefit in high responders, but, he said, in normal responders the evidence is conflicting (and generally neutral).(9) However, the data remain persuasive in the prevention of OHSS with agonist triggering, despite some recent evidence of hazards beyond OHSS in the shape of pregnancy-related hypertension. This risk in a freeze-all treatment, said Kolibianakis, now appears associated with the type of endometrial preparation (or not) before transfer. A 2019 study concluded that the absence of a corpus luteum increased the risk of pre-eclampsia.(10)
However, at a time when live birth rates appear to have plateau’d – certainly in ESHRE’s EIM registry data – and clinics have other priorities in their minds, Antonio La Marca was generally reassuring about the threat of COVID-19 to fertility clinics. The key, of course, is to remain infection-free, and he reaffirmed in detail the risk mitigation measures set out in ESHRE’s phase 3 guidance, notably in reduced patient flow, patient (and staff) triage, PPE for staff, minimal monitoring visits and applied telemedicine. A reduced risk of over-response in ART patients will also reduce the risk of complications, said La Marca, preferably in an antagonist protocol. A report just published suggests that follicular monitoring during stimulation can be streamlined and reduced, with no obvious compromise to treatment.(11) Already, said La Marca, fertility services have ‘demonstrated great resilience, adaptiveness and willingness to transform’ in order to safely restart their treatments last year. And in these high-risk times, there can be no greater marker of ‘success’ than that.
1. Zegers-Hochschild, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017; Hum Reprod 2017; 1; 32: 1786-1801.
2. Sunkara SJ, Zheng W, D’Hooghe, et al. Time as an outcome measure in fertility-related clinical studies: long-awaited. Hum Reprod 2020; 35: 1732-1739.
3. Duffy JMN, AlAhwany H, Bhattacharya S, et al. Developing a core outcome set for future infertility research: an international consensus development study. Hum Reprod 2020; 35: 2725-2734. doi: 10.1093/humrep/deaa241.
4. Montoya-Botero P, Martinez F, Rodríguez-Purata J, et al. The effect of type of oral contraceptive pill and duration of use on fresh and cumulative live birth rates in IVF/ICSI cycles. Hum Reprod 2020; 35: 826-836.
5. Shaia K, Price TM. Cycle scheduling with oral contraceptives: Are we compromising rates for convenience? Fertil Steril 2020; 114: 743-744.
6. Lu Y, Wang Y, Zhang T, et al. Effect of pretreatment oral contraceptives on fresh and cumulative livebirth IVF outcomes in ovulatory women. Fertil Steril 2020; 114: 779-786. doi.org/10.1016/j.fertnstert.2020.05.021
7. Simon C, Gomez G, Cabanillas S, et al. A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF. Reprod Biomed Online 2020; 41: 402-315.
8. Devroey P, Polyzos N, Blockeel C. An OHSS-free clinic by segmentation of IVF treatment. Hum Reprod 2011; 26: 2593-2597. doi:10.1093/humrep/der251.
9. Roque M, Haahr T, Geber S, et al. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019; 25: 2-14.
10. von Versen-Hoynck F, Schaube AM, Chi YY, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension 2019; 73: 640-649.
11. Robertson I, Chmiel FP, Cheong Y. Streamlining follicular monitoring during controlled ovarian stimulation: a data-driven approach to efficient IVF care in the new era of social distancing. Hum Reprod 2021; 36: 99-106. doi:10.1093/humrep/deaa251.
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