RBMO Insights Issue 26: July 2024
Reproductive BioMedicine Online
An international journal dedicated to biomedical research on human conception and the welfare of the human embryo
Welcome to our July edition of RBMO Insights, number 26 in our monthly newsletters bringing you updates and information from the journal, our affiliated societies and the field of reproductive medicine research publishing.
In this issue our Talking Points focus on egg donation stimulation protocols, birth rates in patients of advanced maternal age, and improving efficiency in the lab’s cryostorage facilities.
We preview RBMO editor appearances at ESHRE from Sunday 7th July and look forward to presentations on the program from many in the RBMO community. We will again have a stand with Elsevier in the Exhibition Hall so please do come and say hello!
This month’s Community News revisits RBMO Live with the link to watch it if you missed the broadcast, plus information and advice on avoiding the ethical pitfalls of Duplicate Submissions; and our Section Profile this month features Fernando Reis and our Female Reproductive Health and Fertility Section.
Last, but by no means least, we mark another milestone along the path of RBMO as we say farewell to our Production Manager Maria Murphy, who is retiring from her role after 18 years of amazing dedicated service to the journal. Maria has been an instrumental figure behind the scenes of the journal, managing our copy-editing, issue compilations and scheduling, and was recently heavily involved in ensuring that our conversion to article-based publishing went smoothly – but these are a few of the many features of the role she has performed for RBMO over the years, for which we are very grateful. Maria has been a wonderful colleague, both professionally and personally and we will miss her.
Taking over from Maria will be Dr Katrina Halliday. Katrina brings a broad wealth of experience and expertise to the role, with a PhD in Immunology from Edinburgh University, certificates in horticulture from the Royal Horticultural Society, and several jobs in academic publishing; spending several years with Cambridge University Press as an executive publisher in life science books, social media freelance work at Cambridge University, and most recently, work with UCL Press as a textbook programme manager for their open access programme.
Join us in bidding a fond farewell to Maria, and a warm welcome to Katrina!
Greater flexibility for egg donors in equally effective early and later start stimulation protocols
Egg donors have long been recognised as a separate patient group from those having routine IVF. It’s been argued that they cannot even be deemed ‘patients’, but are more precisely described as ‘non-patient volunteers’ inasmuch as they have no medical indication for fertility treatment. The ethical case for egg-sharing was partly built on such an argument, that the sharer who supplied the donor eggs was already a patient and was not rendered such by her act of generosity.
Recognition of this paradox in egg donors has long been behind a need for moderation in their treatment - short duration antagonist protocols, low dose stimulation and minimal monitoring. Now, a?new RCT published in the August issue?of Reproductive Biomedicine Online by Sylvie De Rijdt (pictured below) and colleagues indicates that ovarian stimulation in the late follicular phase is equally effective as early follicular phase stimulation and may offer egg donors an even more flexible protocol for their IVF.
While stimulation is routinely started in the early follicular phase, interest in later phase ‘random’ starts has arisen from urgent fertility preservation treatments and from dual stimulation protocols for anticipated low responders. The success of both approaches has suggested that follicular recruitment is not based on a single cohort originating in the early follicular phase but on multiple waves originating throughout the full cycle.?The ‘DuoStim’ protocol?combines conventional follicular phase stimulation with further stimulation in the luteal phase to maximise the number of oocytes retrieved in a single ovarian cycle. Both of these examples have a specific indication behind their application - urgent fertility preservation and predicted poor response - but this latest RCT instead has the more loosely defined efficiency, flexibility and acceptability for egg donors as its rationale.
The study, performed at the University Hospital, Brussels, was a non-inferiority trial of 84 egg donors randomised 1:1 to early or late follicular phase stimulation in a common antagonist protocol with 225 IU starting dose; the number of oocytes retrieved was the primary endpoint. Stimulation in the early start group began on day 2 of the follicular phase with antagonist on the sixth day; in the later start group stimulation began with presence of a dominant follicle and appropriate hormone values, and antagonist given when the serum LH was >10 IU/l after eight days of stimulation and continued until the day of trigger.
The primary endpoint (number of oocytes retrieved) was comparable in both groups (15.5 early start and 14.0 later start). However, while the duration of stimulation was slightly shorter in the control group (10.0 vs 10.9 days), there was a substantial difference in the amount of antagonist used - for approximately six days in the control group but only on one occasion (for just one donor) in the late-start group (because of LH concentration >10 IU/l). This meant a 15% lower cost of medication for the study group.
While the study found no greater or less efficacy between early and late follicular phase start, there were acceptability differences conferred by the flexible protocol - which might, suggest the authors, have additional advantages for recipients of fresh oocytes in cycle synchronisation. The benefits, therefore, are specifically in egg donors, who, as the authors add, are usually young, healthy women undergoing a procedure for which there is no medical indication and for which they receive no health benefit themselves. ‘There is a clear need,’ they conclude, ‘for flexible stimulation protocols that reduce physical demands and minimise disruption for donors.’
‘Consistent’ live birth rates in registry study of women of advanced maternal age
Live birth in women of very advanced maternal age is not such a talking point as it once was. When 30 years ago Paulson and Sauer described a series of pregnancies in postmenopausal women, there were inevitable cries of horror, even though Robert Edwards, with characteristic foresight, had himself described such pregnancies as ‘acceptable’ in a Human Reproduction debate. But majority opinion would surely have concurred with his nemesis Robert Winston, who had claimed at the time that such pregnancies ignored the welfare of the child, then newly enshrined in the UK’s Human Fertilisation & Embryology Act of 1991. Moreover, asked another specialist in a BMJ debate, ‘can older women cope with motherhood?’. How time moves on.
Now, a?new retrospective study of 745 pregnancies?in women over the age of 45 recorded in the national IVF registry of Taiwan describes such treatments as ‘popular’, attributing their attraction to ‘social trends’ and advances in ART, notably today’s hugely successful developments in egg banking and egg donation.
The study by Ta-Sheng Chen et al. (pictured below) currently available in pre-proof form from RBM Online, reviewed 1718 egg donation transfer cycles in 745 women recorded in the national registry of Taiwan between 2007 and 2016, with follow-up to calculate cumulative LBRs. Infertility in all subjects was attributed to ‘maternal aging’, with a three-group age spread: 45-46 (443 cycles); 47-49 (509 cycles); and >50 (274 cycles). The primary endpoint was cumulative LBR, with secondary outcomes including miscarriage and twin pregnancy rates.
Clearly, this was not exclusively a cohort of postmenopausal women (the national registry did not record menopausal status), but it does represent a patient group formerly much neglected in ART but which today, as maternal age rates and success rates increase, is gaining even more public interest and uptake. Indeed, even in the nine years of this study, the proportion of cycles using donor eggs in this very advanced maternal age group rose from 0.4% to 1.6% between 2007 and 2016.
Results of the analysis found that overall IVF outcome in the three groups was ‘stable’, with cumulative LBRs over 50%. However, while the authors described their results as ‘consistent’ across the three age groups, there were non-significant age-related trends in the primary and secondary endpoints - for example, a slightly lower cumulative LBR in the over-50s than in the 45-46 group (54.2% vs 58.0%). This non-significant pattern was also evident in perinatal outcomes, with higher rates of preterm birth, pre-eclampsia and lower birth weights, as maternal age increased - and in twin pregnancy. The authors present evidence that multiple embryo transfers in these patients did not ‘markedly enhance’ LBRs, but did significantly increase the risk of twin pregnancies.
Other registry reports, notably from SART, ICMART and ESHRE’s EIM Consortium, all confirm the growing application of egg donation in older IVF patients - as well as a continuing high rate of success dependent on the age of the donor egg, not of the recipient patient. SART’s preliminary report for 2022 reveals a consistent 37% LBR from fresh and frozen donor eggs across all age groups. SART data (for 2019) also show that only 36.7% of all ART use was in women under the age of 35; 10.9% were over the age of 42, and almost 20% aged 38-40. But remarkably, as LBR declined steeply with age, it remained resolutely fixed at around 40% at all ages in egg donation.
This latest report from Taiwanese data confirms the trends seen in other registries, that egg donation is a viable option in women of advanced maternal age, but warns of the risk of perinatal complications and the ‘crucial’ need for counseling and monitoring.
Every little helps: improving efficiency in the lab’s cryostorage facilities
Are there any areas in the IVF lab where automated systems fear to tread? With each issue, this and other journals rarely fail to publish some report in which microfluidics, robotics, time-lapse systems and AI have?all been tested to improve procedures in the lab. Automation, it is argued, will increase standardisation and reduce the risk of human error, while algorithms based on computer-based annotation systems may also offer a more efficient process of embryo selection. What will be left for the embryologist, other than evaluating data and overseeing the automation?
However,?a new report currently available in-press in RBM Online?suggests that even such a rapid development of automated processes has not yet removed the everyday burdens from the shoulders of today’s embryologist. Indeed, Michael Collins (pictured below) and colleagues, following a two-week ‘time and motion’ surveillance of cryostorage procedures in four IVF labs in the USA, report that working conditions which rely on manual processes and lack software assistance, may still continue to result in evident levels of ‘occupational stress, fatigue, anxiety, and burnout’. Although electronic witnessing, digitisation of inventories and other automated systems may save time, increase efficiency and lower patient costs, many IVF clinics ‘still rely on handwritten labels and paper ledgers in addition to manual monitoring of environmental storage conditions without the benefits of software’.
The study comprised an unusual assembly of data from hand-held cameras focused on 12 subjects in four labs performing routine tasks related to cryostorage. A total of 95 specimen camera retrievals were evaluated and a mean of 27.8 recorded per site. The study’s aim was to identify the specific workflows and processes in IVF cryostorage that would benefit from automation and software improvements.
The most striking result was the amount of ‘fatiguing’ work recorded, with almost 50% of total time spent working with equipment ‘of a fatiguing nature’. This was defined as lifting heavy objects (tanks), bending over (looking into Dewars) and standing on a stool (typically with large format tanks or lifting items from shelves).
There were also time discrepancies in filling the tanks, with all four sites using a dipstick to measure liquid nitrogen levels and handwritten ledgers/clipboards for checking. Thus, the variability in specimen retrieval arose from its ‘inherent manual nature and lack of software assistance’. Autofill systems, add the authors, may improve efficiency and limit the amount of liquid nitrogen wastage (through spillage and overflow). In addition, software monitoring would allow greater efficiency without having to transcribe data and manually monitor trends.
Cairo consensus on accreditation as the basis for future-proofing the ART Laboratory Cairo Consensus Group
This report details 16 core consensus points reached during a symposium hosted by ALPHA Scientists In Reproductive Medicine and Upper Egypt Assisted Reproduction Symposium to create an ethos and framework that will support future-proofing for laboratories in all regards. Each point is supported by extensive practical recommendations that cover the gamut of ART laboratory operations.
In addition to the paper itself, watch our Talking Points interview with David Mortimer, one of the key authors and organising members of the symposium, to learn more about the consensus points, practical recommendations, background and wider goals of the project.
Hilde Grens , Aleida Huppelschoten, Wiep de Ligny , Rudolf Kool, Jan Kremer, Jan-Peter de Bruin
This review describes a broad field of possible internet interventions for fertility patients. The goal say the authors is firstly to lower the threshold for use in daily practice, and secondly to emphasise the importance of developing new and solid methodological standards for the development and implementation of new E-health initiatives.
Surrogacy in the United States: an analysis of surrogates’ sociodemographic profiles and motivations
José ángel Martínez-López & Pilar Munuera Gómez
This study surveyed participants in the US, given the country's long history of surrogacy, to help clarify the profile of the women who become surrogates, their power of decision and their motivations. The study showed that women who become surrogates in the US do not have low socioeconomic status, have medium to high education, participate in the labour market, earn above the average income for their state, have health insurance and affirm that their primary motivation is prosocial/altruistic.
@China Harrison, Chau Thien Tay , Maureen Busby , @Aya Mousa, Helena Teede , Jacky Boivin
Interactions with healthcare professionals for patients with PCOS were identified to be challenging when medical news was not shared in the best way, information and deliberation opportunities were insufficient, patient activation was not supported and when system level barriers were present. Challenges identified could, the authors suggest, be addressed using evidence-based frameworks.
Reproductive failure spurs innovative solutions. 3D bioprinting, a promising approach, combines biomaterials, cells, and growth factors to mimic reproductive tissues. Recent advances focus on strategies, bioinks like gelatin and alginate, and various cell sources. Applications range from ovarian function restoration to male germ cell bioengineering, holding untapped potential. This systematic review puts a perspective on the topic for better understanding of the applications in several branches of reproductive medicine.
The recording of our special RGE Prize winners RBMO Live webinar is now available on our?YouTube channel.
Nick and Juan hosted this session of presentations and discussion from our award-winning authors and their cutting edge research and insights into reproductive medicine techniques
Dr Santiago Munne presented on the innovative procedures reports in ‘First babies conceived with Automated Intracytoplasmic Sperm Injection’, which won the Robert G. Edwards Prize Paper Award. Prof. Baris Ata expands on his group's critical review of current understandings of endometrial thickness and embryo transfer outcomes, and Dr Mina Alikani discussed the collaborative project aimed at raising awareness and interventions to improve sustainability in the IVF laboratory. The webinar concluded with a very interactive and productive Q&A session.
While you visit our channel, look for our playlist of all eight RBMO Live episodes, Talking Points interviews, and article highlights - and don't forget to Like, Share and Subscribe!
Duplicate Submissions
In this installment of our regular publishing tips and useful resources for researchers we would like to draw attention to a common form of ethical misconduct – duplicate submissions.
Duplicate submissions refers to the act of submitting a manuscript simultaneously to several journals at once, and is considered unethical behaviour in academic publishing. Authors may find the prospect of multiple submissions tempting, to circumvent the frequently long reviewing times at journals, and create the chance to ‘shop around’ for a favoured journal based on the reviews and decisions received from each one.
In theory it seems like a good idea to save time, but in practice it can be very costly to authors and journals. There are several reasons why this is not a healthy practice for the research community and risks compromising the scholarly records.
Should duplicate submissions be accepted, they would result in duplicated publications, possibly with different versions of the same text, and the different references to what are essentially the same paper. This distorts the body of literature on a topic, and may affect meta-analysis and reviews. ?Multiple publications also artificially inflate authors’ publication records. Additionally, the submissions across multiple journals duplicate the burden on editorial review processes, drawing resources from editorial staff and peer reviewers unnecessarily. There is even a chance that the same reviewers could be invited to review these multiple submissions, which will not leave a good impression. Duplicate submissions are also an indicator of ‘paper mill’ activity – the systematic commercialised fabrication and publication of fraudulent research.
As such, duplicate submissions are dealt with very seriously by journal editorial teams and the publishing industry. Recent developments have improved systems to identify duplicate submissions from individual peer review platforms and within publishers, to launching industry-wide initiatives such as the STM Integrity Hub, which is developing a cloud-based network for publishers to check submitted articles for research integrity issues and deal with issues more efficiently in a more collaborative manner.
Whether performed through innocent inexperience or deliberate attempts to subvert or deceive the submission process, duplicate submissions are dealt with seriously, and are a practice that must be avoided – something which can be best achieved by carefully choosing appropriate journals to submit to, which in turn can improve your chances of successful submission.
This was the topic of our Publishing Tips presentation during RBMO Live in March, which?you can watch on our YouTube channel.For more information on the issue of duplicate submissions and further standards of ethical research publishing, we recommend completing the?Elsevier Researcher Academy module on Ethics.
We also recommend familiarising yourself with the guidance of ethical standards and best practice by professional bodies such as?Committee on Publication Ethics (COPE),?European Association of Science Editors (EASE), and?International Committee of Medical Journal Editors (ICMJE). COPE European Association of Science Editors (EASE)
ALPHA Scientists In Reproductive Medicine
Alpha have updated their dedicated RBMO page with the latest Hot Topics from recent issues of the journal. The page includes other highlights, including links to our Insights monthly newsletter, quarterly Digest issues, and Alpha/RBMO related activities.
The Alpha website also highlights the Alpha and RBMO webinars hosted by International IVF Initiative, including RBMO Live Episode 8 which broadcast earlier this month. Visit their website to find all these RBMO-related highlights, and of course, the benefits of Alpha membership and their many initiatives and projects that help support, elevate, and promote scientists in reproductive medicine.
Canadian Fertility and Andrology Society
Fertility preservation in patients undergoing gonadotoxic treatments: a Canadian Fertility and Andrology Society clinical practice guideline
This new CFAS guideline outlines the current understanding of social and medical issues associated with oncofertility, and the medical and surgical technologies available to optimize future fertility.
ESHRE 2024 Preview
RBMO will be present at ESHRE, with many of our Editors and Editorial Board members chairing or presenting sessions, and our editorial office team on hand at the Elsevier stand. Please do come and find us at the Elsevier Booth No:12.013 in Exhibition Hall 12, on the first floor. We will be happy to answer your questions about the journal and publishing in general.
Now, as has become tradition in Insights, we have rounded up RBMO Editor and Section appearances across ESHRE sessions in this handy conference guide – keep an eye on our social media platforms for posts highlighting appearances from our Board Members, and of course, updates on our activities during the event.
Sunday, July 7th, 09:00 - 17:00, Elicium 2 Individualisation of Ovarian Stimulation & Beyond, the full day precongress course on the Sunday features morning sessions with RBMO Co-Chief Editor Nick Macklon and Clinical Assisted Reproductive Technologies Section Editor Shari Mackens ‘Investigating the endometrium and microbiome’.
RBMO Editor Georg Griesinger debating ‘Fat but fit? Is weight loss a necessity before ART’, and chairing a session alongside Shari’s fellow CART Section Editor Christophe Blockeel on ‘The art of ovarian stimulation’.
In the afternoon Christophe also chairs The art of supporting the luteal phase, and the course closes with a debate on Frozen embryo transfer cycle – natural is the best! Involving Nick Macklon and Board Member Michael Feichtinger .
Sunday, July 7th, 09:00 - 17:00, Room E102 In the morning of the pre-conference course on Management of endometriosis-and adenomyosis-associated infertility, Co-Chief Editor Juan A. García Velasco will chair the opening debate on causation and association of endometriosis, and present a session titled ‘The impact of endometriosis- and adenomyosis on oocyte and embryo quality’.
Sunday, July 7th, 09:00 - 17:00, Room G103 In the parallel precongress course, RBMO Editor Richard Anderson hosts a discussion session on Alternative etiologies requiring fertility preservation, in the session Preserving possibilities, restoring hope: Advancements in fertility preservation and restoration.
Sunday, July 7th, 09:00 - 17:00, Room D203 Nick Macklon and Clinical Embryology Section Editor Marcos Meseguer Escrivá feature in session PCC13: Academic Authorship: Navigating Scientific Integrity in the Digital Age: The Role of AI and Recent Notions in Scientific Publishing and artificial intelligence. (Honesty and dishonesty? Trustworthiness of scientific output at stake).
Nick will give a talk entitled ‘ChatGPT friend of foe for journals and patients?’ that draws from recent publications in the journal, including an editorial from Nick and Juan, and Marcos will speak on ‘‘The application of artificial intelligence for reproductive medicine consultation and the laboratory; a critical appraisal’.
Sunday, July 7th, 09:00 - 17:00, Room G102 Nico Garrido, RBMO Male Reproductive Health And Fertility Section Editor, will give two talks during Session PCC01: Bacterial or Viral Infection in males and reproductive health:
10:30 Session 2: viral infections and the male genital tract
15:00 Session 4: bacteria or viruses in males and medically assisted reproduction
Monday, July 8th, 11:45 - 12:45, Forum The live ESHRE journal club will be joined on the panel by Nick Macklon, discussing ‘Good practice recommendations on add-ons in reproductive medicine’.
Tuesday, July 9th, 10:00 - 11:30, Park Foyer Clinical embryology Section Editor Antonio Capalbo chairs session 45: Advancing clinical PGT-A: steps towards an evidence-based consensus.
Tuesday, July 9th, 10:00 - 11:30, Forum Clinical Assisted Reproductive Technologies Section Editor Nikolaos Polyzos will present on the effect of ambient exposure to air pollutants on live birth rates in frozen embryo transfer cycles during Session 46: Socially and environmentally sustainable reproductive care.
Tuesday, July 9th, 14:00 - 15:00, Forum Female Reproductive Health and Fertility Section Editor Rita Vassena will chair session 57: ‘To err is human: building a safer fertility clinic’, which also features Alessandra Alteri with a section titled ‘To err is human, also for those working in ART’.
Wednesday, July 10th, 10:00 - 11:30, Forum Clinical Assisted Reproductive Technologies Section Editor Shari Mackens presents ‘The lower reproductive tract microbiota composition alters upon ovarian stimulation and is associated with, but not accurately predictive of reproductive outcomes following ART‘ during session 84: Microbiome matters: insights into maternal infections, treatments outcomes and reproductive health.
Wednesday, July 10th, 11:45 - 12:45, Elicium 2 Rita Vassena will argue for the motion against Lucy van de Wiel in session 89, Chaired by Lucy Frith and Heidi Mertes debating whether commercialisation is a necessity for ART to flourish
This issue we showcase our?Female Reproductive Health and Fertility?section, with comments from one of our Section Editors, Professor Fernando Reis, and selected papers.
The FRHF section of RBMO focuses on general infertility including diagnostic and screening procedures, anovulation, ovulation induction, PCOS, endometriosis, fibroids, adenomyosis, abnormal uterine bleeding, tubal and vaginal disorders, infection, and reproductive surgical interventions.
Professor Fernando Reis, Universidade Federal de Minas Gerais, Brasil. Section Editor
‘The Female Reproductive Health and Fertility section of RBMOnline publishes incremental and sometimes disruptive advances in the understanding of conditions that threaten women’s reproductive planning and family building.
By exploring the causes, mechanisms, and opportunities to manage reproductive disorders, the studies published in this RBMOnline section contribute to overcoming barriers, revisit concepts and open frontiers in reproductive biology and medicine.’
Papers specially selected by Prof. Reis to showcase the FRHF section:
Maíra Casalechi et al. Is endometrial receptivity affected in women with endometriosis? Results from a matched pair case-control study of ART treatments.
Chenyu Mao et al.Reduced endometrial expression of histone deacetylase 3 in women with adenomyosis who complained of heavy menstrual bleeding.
Dr Eliza Colgrave et al.Distribution of smooth muscle actin and collagen in superficial peritoneal endometriotic lesions varies from the surrounding microenvironment.
Sezcan Mümü?o?lu & Aaron Hsueh . Is endometriosis due to evolutionary maladaptation?
Marie d'Argent et al. Are lower levels of apoptosis and autophagy behind adenomyotic lesion survival?
That brings us to the end of a bumper Summer edition of RBMO Insights.
If you have any thoughts or ideas you’d like to share with us about the newsletter, please do leave us a comment or send us an?email?– or better yet, come to our booth for a chat at ESHRE, should you be attending.
The RBMO Editorial Team
Lab accreditation= more training, more standardization, more accuracy+++ = higher costs. Will IVF clinics and lab directors balance needs of PE backers with patient care? Access issues (high prices) are necessary to support costs associated with best practices.
Excellent interview with Dr. Mortimer. Always relevant.