RBMO Insights 25. june 2024
Reproductive BioMedicine Online
An international journal dedicated to biomedical research on human conception and the welfare of the human embryo
Welcome to the June edition of RBMO Insights, where you find us in the midst of conference season, as we write this from the Alpha Scientists conference in Lisbon, and look forward to ESHRE. We will have a full preview of where you can find us at ESHRE in the next issue, but first, we have a packed June edition for you.
Our Talking Points features this month examine the debate around maternal age in euploid transfers, discuss associations between visceral fat and infertility, and how we can future proof IVF labs against potential emergencies. This article is accompanied by a new video interview with project architect David Mortimer, which you can view on our youtube channel.
In this issue we also have a new Guideline from our Affiliated Society ARCS, and several partner society event previews. We shine a spotlight on our Clinical Assisted Reproductive Technologies section with Filippo Ubaldi, and our regular selection of community news and article highlights from the journal.
We hope you enjoy this issue, and hope to see you in person at a meeting soon.
Plan for the worst or hope for the best? Proofing the IVF lab against unforeseen emergencies
An oral presentation at the 2022 annual meeting of ESHRE memorably recalled the life-risking efforts of embryologists in Mariupol and other Ukrainian cities to transport frozen embryos and gametes to secure locations as the attacks on the country began. Within weeks, more than 70,000 frozen embryos and 10,000 frozen eggs had been moved, as well as thousands of testicular and ovarian tissue samples. Few national authorities, let alone clinics, could plan for such an eventuality. Even the Covid pandemic in 2020 found clinics forced into unprecedented emergency measures, following the newly developed guidance of national societies to close centres, suspend non-urgent treatments and adopt mitigating risk policies for resumption.
It's against such a background - and notably the impact of Covid - that a collaborative meeting between the Upper Egypt Assisted Reproductive Symposium (UEARS , the meeting sponsor) and ALPHA Scientists In Reproductive Medicine was held last year to set out clear international recommendations for ‘future-proofing’ IVF laboratories (pictured below).
The consensus report defines futureproofing as ‘proactive planning and protocols to withstand potential disruptions and safeguard the continuity of critical reproductive care services’. These include enhanced infrastructure, better network coordination and the development of robust continuity of operational procedures. The potential disruptors include pandemics, natural disasters, or ‘other emergencies’.
As found at the start of the pandemic - and under instruction from some national authorities - the safest course of action might well be to halt treatment and close shop. Less draconian measures may be to delay procedures or transfer them to other centres.
In outlining essentials for continued tissue and cell cryopreservation, the report ruefully notes that ‘many ART centres are ill-equipped to safeguard their frozen tissue inventory and/or safely evacuate these specimens in a crisis’. However, the report does make many practical recommendations for safeguarding gametes and embryos in cryostorage - as well as for other main areas of responsibility. In case of clinic closure or ‘hibernation’, for example, details are provided for mitigation of infection risk and protection of medical records. In addition, there is practical advice on electrical power generation, equipment, gas supply and consumables.
Yet despite the range and detail of the recommendations, there’s an overriding sense that a lab’s participation in a formal accreditation programme will provide a core set of principles for such quality and risk management. ‘Undergoing an accreditation process provides a sound foundation for both current operational practices and emergency preparedness planning,’ says the report, which would create the framework for future-proofing an ART centre under emergency conditions. The consensus group acknowledged that centres in many countries do not have access to local accreditation schemes, but that need not preclude development of best practice benchmarks and quality management systems. With this in mind, the report concludes by urging development of ‘a universal accreditation technical guide’ for ART laboratories to serve as a worldwide reference - both for labs seeking accreditation and for accreditation bodies hoping to harmonise their own accreditation schemes.
To learn more about the discussion of the consensus meeting, content and goals of the report, we spoke with Professor David Mortimer, one of four core participants in the consensus meeting. The video interview can be found on the RBM Online YouTube channel?here.
Maternal age in euploid transfers: the debate goes on
A decade ago, as a second generation of technologies were introduced for PGT, some of the leading figures in the field proposed that the handicap of increasing maternal age in IVF might be removed by embryo screening and the transfer of euploid embryos. According to the investigators, the study found that implantation rates of euploid embryos were the same at any maternal age up to 42 years, no matter the day of biopsy. ‘Essentially,’ they concluded, ‘second-generation PGS abrogates the maternal age effect on implantation rates observed in ART, except, perhaps, for the most advanced reproductive ages.’ Four years later, a multicentre study from Italy even found that women older than 43 years had a small but reasonable chance of success, despite the low rate of euploid blastocysts found after PGT-A (21%): delivery rate per cycle was 10.6% in patients aged 44.0-44.9 years and 2.6% in patients aged 45.0-45.9 years.
It was studies like these and the certainty that chromosomal abnormalities increase with advancing female age which offered a rationale for AMA as an indication for PGT-A. But, as ever in PGT-A, there were many who remained unconvinced. A review reported last year of seven studies (including Harton et al noted above) concluded that AMA is associated with a decline in ART success rates independent of embryo ploidy. Also included in this study was the STAR trial, which in a broad population of subjects found no overall outcome benefit of PGT-A. As ever with PGT-A and its predilection for controversy, the reviewers noted that ‘whether ploidy determination for embryo selection can mitigate all the aspects of age-related fertility drop remains uncertain’.
Now, a retrospective study of almost 2000 single euploid FET cycles from Barbara Lawrenz et al. (pictured) adds another brief chapter to the story in finding no ‘substantial impact’ of maternal age on ongoing pregnancy rates - although OPRs were affected (reduced) by BMI, embryo quality and embryo biopsy on day 6. Specifically, the OPRs were 51.8%, 47.4%, 52.3% and 52.8% for women aged ≤35, >35-≤37, >37-≤40, and >40 years-old at transfer, with similar results at egg collection age. Similarly, age group comparisons of women with ongoing pregnancy and those with no pregnancy or miscarriage did not find any significant difference in terms of female age at transfer or OPU, male partner age or AMH or levels.
The authors acknowledge that their results, derived from 1923 euploid FET cycles between 2017 and 2023, are at odds with the 2023 review referred to above. This, they explain, was based on testing technologies (NGS and array CGH), which ‘could theoretically be attributed to the different accuracy of the platforms in the detection rate of subtle chromosomal abnormalities’. The debate goes on.
However, consistent among all studies - and this one - is the deleterious effect of ovarian ageing on embryo quality, which in turn, say the authors, ‘is a major contributor for the reduced OPR’, although the chronological age of the women ‘did not appear to have a substantial impact on its own’. They also note that the transfer protocol, natural cycle or HRT-primed, appeared to make no difference to outcome, though they acknowledge ‘recent evidence’ of a lower risk for pre-eclampsia and miscarriage in natural cycle FET. Interestingly, the latest ASRM committee opinion on PGT-A, based on a comprehensive literature review, concludes that PGT-A ‘may have a beneficial role in patients of advanced maternal age, especially those with good ovarian reserve’.
A clear association between visceral fat and infertility
In June 2023 the American Medical Association called for more precise metrics to define obesity. BMI, the AMA argued, is a flawed measurement based only on height and weight and fails to take account of body fat or waist circumference, both of which are likely to be implicated in the adverse health effects - including infertility - of obesity.
Yet in the causes of infertility and the pathways to and from its treatment BMI seems the one and only marker of obesity. Indeed, clinics may accept or reject patients for treatment based only on their BMI - with one randomly found clinic warning it ‘does not treat any new patient with a body mass index greater than 35 at the time of treatment’.
Now, Jiexue Pan (pictured below) and colleagues at Fudan University have published a study in RBM Online using data from the US National Health and Nutrition Examination Survey which makes a specific association between visceral adipose tissue and infertility, and has thus taken a step beyond the more loosely defined concept of BMI. This was a statistically complicated study based on DXA (dual-energy X-ray absorptiometry) measurements of total adipose mass within the abdominal walls, whose measurements included both visceral and subcutaneous adipose tissue. More than 3000 participants were enrolled, for whom full data on fertility and DXA findings were available.
While the study was complicated, the conclusions were straightforward: that the areas of visceral adipose tissue were significantly greater in the infertility subjects than in the non-infertility. After adjustment for potential confounders, multivariate analysis showed that an increase in visceral tissue area was associated with a growing prevalence of infertility (OR 2.453). The initial crude association with infertility was high (OR 4.6) but sub-group analysis showed that age and race modified the association further - such that those under 35 years faced an even greater risk of infertility (OR 6.02). The epidemiology of obesity and infertility is well documented, with adverse effects reported on ovulation, oocyte quality and decidualisation.
‘The storage and metabolic activity of visceral fat are the main drivers of obesity-related complications,’ the authors explain, suggesting that body fat, and not simply BMI, is the culprit. However, the practical public health message from this and other studies is likely to be the same, whatever the driver, that weight loss will reduce the areas of visceral adipose tissue as well as reduce BMI.
Most fertility clinics won’t be using DXA scanning machines (which will likely be measuring bone density for fracture prevention), so will like everyone else be relying on BMI as a surrogate marker of body fat. The AMA called BMI an ‘imperfect’ measurement, but still recognised that BMI is easy to calculate and cost-free. The AMA added approvingly that BMI has specific cut-off points for overweight and obesity - but is only ‘correlated’ with body fat and unable to measure or visualise it directly.
Sònia Gayete Lafuente. M.D., Ph.D., OBGYN, REI, Clinical Researcher. , Anna Vilà Famada, Nazli Albayrak, Juan José Espinós Gómez, Miguel ángel Checa Vizcaíno, José Moreno-Sepulveda
This systematic review and meta-analysis provides a comprehensive perspective on the relationship between ovarian endometriomas (OMA) and IVF outcomes. ?The paper reveals similar fertilization and blastulation rates between patients with and without OMA, and comparable Ovarian Sensitivity Index (OSI).
Contrary to assumptions of adverse effects on oocyte quality, the paper reveals that OMA does not significantly impact indirect markers of oocyte quality, as reflected by comparable fertilization and blastulation rates in comparison to patients without OMA. However, the study also highlights a notable reduction in the number of total and MII oocytes retrieved, accompanied by a non-significant trend of reduced OSI. To confirm and build upon these findings, the authors state that a larger and more homogenous RCT focusing on direct markers of oocyte quality would be necessary.
Aisling Ahlstr?m , J?rgen Berntsen, Martin Johansen, Christina Bergh, Danilo Cimadomo, Thorir Hardarson, Kersti Lundin
iDAScore v2.0 recognizes and uses visual features or patterns that correlate with morphological characteristics and can discriminate between embryos more or less likely to result in a live birth in the same cohort of embryos preselected for transfer by morphology on day 2 and day 3.
Jasmin Hassan, Katri Knuus, Atte Lahtinen, Ilmatar Rooda, Marjut Otala, Timo Tuuri, Sebastian Gidl?f, Erik Edlund, Judith Menezes, Johan Malmros, Petra Bystr?m, Mikael Sundin, Cecilia Langenski?ld, Hartmut Vogt, Per Frisk, Cecilia Petersen, Pauliina Damdimopoulou, Kirsi Jahnukainen
Assessing ovarian reserve in patients undergoing ovarian tissue cryopreservation is essential for predicting usability of their tissue in future fertility restoration. The authors developed reference standards for cortical follicle density for ages 0-25 years and associated Z-score cutoffs for normal and reduced reserve and ?recommend the adoption of Z-scores into fertility preservation programs.
Iveta Yotova, Katharina Proestling, Isabella Haslinger, Matthias Witzmann-Stern, Barbara Widmar, Lorenz Kuessel, Heinrich Husslein, René Wenzl, Quanah J. Hudson
DIRAS3 expression in highly elevated in the epithelial layer of endometriosis lesions. Experiments in an endometriosis epithelial cell line show that DIRAS3 promotes cell survival by activating autophagy, a mechanism that may contribute to endometriosis lesion establishment and survival.
Fady Sharara , G. Charles Ostermeier, Alexander Travis
Younger men presenting with fertility problems are more likely to have higher traditional semen analysis metrics than older men, but are equally likely to have defects in capacitation ability, making this assessment more sensitive to male infertility across age groups.
M.M.J. van den Berg, E. van den Boogaard, R.P.M.G. Hermens, F. van der Veen, M. Goddijn, P.J. Hajenius
Non-adherence to guideline-based quality indicators for an early pregnancy assessment unit (EPAU) was about the same for hospitals with and without an EPAU in the Netherlands. Provision of a discrete waiting area, accepting self-referrals for women with a previous ectopic pregnancy and certified ultrasound training for staff members needs improvement.
Balsam Al Hashimi , Elena Linara-Demakakou, Simon Harvey, Kate Harvey, Darren Griffin, Kamal Ahuja, Nick Macklon
Double vitrification of blastocyst was not shown to have any impact on pregnancy rate and no notable influence on birth weight or gestation period was evident. While the authors advise caution due to the study size, the findings provide some assurance regarding the efficacy and safety of double vitrification.
Embryologist illustrator Diana Tain has produced a new infographic for He et al. paper, Seeking arrangements: cell contact as a cleavage-stage biomarker.
The pilot study from the research team at Apricity Fertility provides a strong case for further investigation into spatial biomarkers and three-dimensional morphokinetics. Evidence is provided for the clinical relevance of cleavage-stage cell arrangement in the human preimplantation embryo beyond the four-cell stage, which may improve selection techniques for day-3 transfers.
Future Proofing IVF labs – an Interview with David Mortimer
In support of the Talking Points article in this issue that highlights recent RBMO publication, Cairo consensus on accreditation as the basis for future-proofing the ART Laboratory, we spoke with David Mortimer, one of the key authors and organising members of the symposium from which the paper came, to learn about the core consensus points and practical recommendations that cover the gamut of ART laboratory operations.
Watch the interview here: https://youtu.be/r2TAClUPinU
领英推荐
Peer Review Week theme: Innovation and Technology
After a month of voting, the theme for September’s Peer Review Week has been decided. The hottest topic of the year remains the focus of attention, as Innovation and Technology received the most votes to determine the scope of activities for this years’ events.
Blog posts on the PRW website, and STM Association blog, Scholarly Kitchen provide more details of the event, including examples of the questions the week will hope to address, such as, can AI be used in a way that it complements the value that the reviewer brings in? How can it be used to broaden the pool of reviewers providing equal opportunities to scholars from under-represented countries? Can the industry’s research integrity crisis be tackled with the help of new approaches and technology?
Assisting Peer Review with Technology and Large Language Models
The transformative power of AI and Large Language Models is bringing excitement for a future of potential technologically assisted advances, but also concerns around the reliability and quality of outputs, and the social implications for machines replacing the human element.
This webinar hosted by the Peer Review Committee of European Association of Science Editors (EASE) discusses how the landscape of peer review and research assessment is already changing with these new technologies, addressing idea generation, study conduct, writing of manuscripts and research dissemination, and quality control.
The panel features James Zou , Associate Professor of Biomedical Data Science at Stanford, Lu Sun of Design Lab, University of California San Diego, Mike Thelwall , Professor of Data Science at Sheffield, and Mario Mali?ki , Editor-in-Chief of Research Integrity and Peer Review journal and METRICS team member at Standford.
Watch the webinar recording here: https://youtu.be/hPOxK8K3xoY
The Association of Reproductive and Clinical Scientists
RBMO is pleased to publish a new clinical practice guideline from The The Association of Reproductive and Clinical Scientists (ARCS).
The ARCS describes this Good Laboratory Practice framework as appropriate and effective to ensure the best possible care for all individuals undertaking fertility treatment. The document has been written in such a way that it may serve as a core reference for laboratories in countries internationally that do not have prescribed local guidance and/or regulation.
Clinical embryology is a dynamic and ever evolving field, as such clinical practice guidelines must be regularly reviewed and updated. This article is an update of the 2012 ACE Guideline (Hughes and Association of Clinical Embryologists 2012) that reviews previously published guidelines, current practices used in clinical laboratories today and the literature to provide evidence-based clinical and laboratory guidelines with recommendations for laboratories within an ART service.
The guidance provided within this new document, aims to be relevant within an international context, incorporating the range of regulatory considerations affecting clinical embryology laboratories, changes in ‘routine’ technologies, diversity of service users, digital record-keeping practices and many other key processes and activities.
RBMO Live Episode 8
Online, Tuesday June 11. 3pm EST / 8pm UK
Join us for the latest edition of our quarterly webinar, broadcasting live on 11 June, at 8pm UK time / 3pm EST, where we will be celebrating the Robert G. Edwards Prize Paper Award and significant contributions with our Chief Editors Juan Garcia-Velasco and Nick Macklon.
The session will feature talks and discussion between our RGE prize winners, Santiago Munne , Scientific Director at Progenesis and Founder of Overture Life lab, who will provide insight into his groundbreaking automated ICSI project that resulted in a live birth last year.
Baris Ata , IVF Specialist at ART Fertility Clinics Dubai, Professor of Obstetrics and Gynecology at Ko? University School of Medicine, and President of the Turkish Society of Reproductive Medicine will expand on his critical appraisal of studies on endometrial thickness and embryo transfer outcomes.
Mina Alikani , Senior Director of Northwell Health Fertility Laboratories, President of Alpha Scientists, and RBMO Editor will discuss the development and progress of the project that produced the Sustainability in IVF paper, and next steps for a greener IVF industry.
The panel will debate future threads of progress and innovations in reproductive medicine in this eighth edition of our webinars.
In addition to experiencing talks from fantastic speakers, our webinars are hosted by the International IVF Initiative, so attendees will receive certification of Continuing Education Units and synopsis for participating for an added benefit of registering!
CFAS/ASRM Business in Medicine: A Leadership and Management Summit
July 19-20, 2024, Banff, Alberta https://cfas.ca/ASRM_Business_in_Medicine_2024.html
This workshop from the Canadian Fertility and Andrology Society explains how to apply Lean Six Sigma methodology to healthcare services. It aims to provide tools to the participants to enable them to use to cut down effort, time, costs and provide a better patient and employee experience.
ARCS symposium
September 13, 2024, Birmingham, UK
The annual Symposium of the The Association of Reproductive and Clinical Scientists will be held on Friday 13th?September at the Edgbaston Park Hotel, University of Birmingham. The event comprises a full day of specialist presentations and poster exhibitions, including an evening formal dinner under the auspices of a University with a rich legacy in the field of reproduction.
CFAS 70th Annual Meeting: Past Present and Future, Celebrating 70 Years of Innovation and Science
September 12-14, 2024, Vancouver, Canada
This September, CFAS hold their 70th annual conference at The Westin Bayshore in Vancouver, British Columbia. The event is themed on the ‘Past, Present and Future, Celebrating 70 Years of Innovation and Science’. The agenda for the meeting is currently taking shape, and features an opening keynote from RBMO founding Editor, Dr Jacques Cohen discussing the change of laboratory processes, from artisanal craft to automated technologies since the inception of IVF.
TSRM 2024
November 14-17, 2024, Antalya, Turkey https://www.tsrm2024.org/en
The 12th meeting of the Turkish Society of Reproductive Medicine will feature 20 high-profile global opinion leaders and thought leaders from the country, with presentations and discussion panels on new topics including embryology, endometriosis, infertility, assistive technologies for infertility, reproduction-related endocrinology, surgery, biology and genetics. RBMO will also be attending the event, details of which we will reveal in the coming months.
This issue we highlight our Clinical Assisted Reproductive Technologies section, with comments from one of our Section Editors, Prof. Filippo Ubaldi, and a selection of papers.
The CART section of the journal focuses on clinical aspects of assisted reproductive treatments, encompassing ovarian stimulation, prediction models, and clinical trials, including IVF/ICSI, and PGT, as well as fertility preservation and gamete donation/surrogacy.
GENERA, Centre for Reproductive Medicine, Italy
Section Editor Clinical Assisted Reproductive Technologies
‘As a Section Editor for RBMO, my goal is to curate high-quality research that pushes the boundaries of traditional practices, ensuring that each manuscript undergoes rigorous peer review. I am particularly interested in innovative approaches that advance our practical and theoretical knowledge, ultimately enhancing clinical outcomes in reproductive medicine.
I am deeply committed to contributing to advancements in the field of reproductive medicine. I have a special focus on reproductive endocrinology, especially in exploring unconventional ovarian stimulation protocols and management strategies for poor responders.’
Selected papers from our Clinical Assisted Reproductive Technologies section
Baris Ata - Should the trigger to oocyte retrieval interval be different in progestin primed ovarian stimulation cycles?
Carlos Alonso Mayo et al. - Modified natural cycle allows a window of seven days for frozen embryo transfer planning
Fenghua Liu et al. - New biopsy after antibiotic treatment: effect on outcomes of assisted reproduction in patients with infertility and chronic endometritis
Carlos Hernandez Nieto et al. - Effect of various contraceptives on oocyte yield and maturation in patients undergoing planned oocyte cryopreservation: a retrospective cohort study
Barbara Lawrenz et al. - Ongoing pregnancy rates in single euploid frozen embryo transfer remain unaffected by the female age at embryo creation and transfer: A retrospective study of 1923 single euploid frozen embryo transfer cycles
?afak Hat?rnaz et al. - Comparison of luteal phase versus follicular phase in-vitro maturation in women with oocyte maturation abnormalities
Kay Neumann & Georg Griesinger - Does follicular flushing increase oocyte number in poor responders? An update of a systematic review
Chiara Dallagiovanna et al. - The neglected role of preimplantation genetic testing for Lynch syndrome
Ying Huang et al. - The time interval between oocyte retrieval and frozen embryo transfer does not impact reproductive outcomes
Elena Labarta et al. - Luteal phase support using micronised vaginal progesterone as pessaries or capsules in artificial cycles: is there any difference?
That brings us to the end of another Insights Newsletter. If you know anyone who would enjoy this newsletter, please do forward it on to them.
We will return next month with news from the Alpha Scientists conference, a preview of our booth at the ESHRE conference, and more of our regular features.
The RBMO Editorial Team