RBMO Insights Issue 30. November 2024
Reproductive BioMedicine Online
An international journal dedicated to biomedical research on human conception and the welfare of the human embryo
Welcome to our November edition of RBMO Insights – our monthly journal newsletter bringing you the latest news from the Editor’s desk, updates from our affiliated societies, event previews, showcase papers from the journal and Talking Points features that go deeper into the themes of recent publications.
This month we have a new Talking Points video interview with Iris Martinez, expanding on the pros and cons of artificial blastocyst collapse before vitrification, alongside articles on the unexpected hazards of random-start stimulation and the effect of trophectoderm biopsy on first trimester biomarkers.
Also in this issue we preview Netflix film ‘Joy’, about the work of RBMO founder Sir Robert Edwards and the birth of the first IVF baby, with our own video introduction, ahead of its global release on 15th November, share details of several events including our own RBMO Live webinar in December, and details of the TSRM conference where we will be hosting a peer review workshop.
If you would like to receive RBMO news, events and updates direct to your inbox and have not done so already, you are welcome to sign up to our mailing list and join the ever-expanding community around our journal.
With that, we will leave you to enjoy another interesting issue of Insights.
The pros and cons of artificial blastocyst collapse before vitrification
Vitrification is now central to all IVF programmes, with both blastocysts and oocytes. However, while selection of fresh blastocysts for transfer (and storage) remains largely dependent on morphological grading, protocols and selection post vitrification seem less straightforward - at least according to a new article in press in RBMO. Among the protocol inconsistencies likely to affect outcome are the various compositions of vitrification solutions, open or closed systems, and the application of artificial blastocyst collapse pre-vitrification.
The reported study itself is specifically about artificial blastocyst collapse - and whether its performance is better achieved with laser or pipette - but behind the study lies a wider assumption that removal of the blastocoelic fluid before vitrification by artificially collapsing the blastocyst from its expanded stage will improve survival after warming and treatment outcome. Artificial blastocyst collapse, the authors explain, aims to remove most of the fluid from the blastocoelic cavity ‘to reduce the severity of osmotic changes when blastocysts are exposed to cryoprotectants’ and thereby to decrease the chance of intracellular ice crystal formation.
The procedure, however, whether by pipette or laser, remains controversial, particularly as either process is invasive and no clear outcome benefits have yet been demonstrated. Indeed, one of the authors of this study, Borut Kovačič, reported a case-control study in this journal in 2022 in which artificially collapsed blastocysts had better survival rates post-vitrification than those frozen intact, but which showed only non-significant differences in LBR. Thus, implied in the results of this study was a further lack of evidence to support the routine use of artificial collapse before vitrification, despite its apparently physiological nature. But, as the authors reminded us at the time, even a non-significant 5% increase in LBR may be ‘an important step’ in the move to optimise blastocyst cryopreservation.
The latest reported study takes the arguments a stage further by accepting that the improved survival rates, morphokinetics and faster re-expansion time of artificially shrunken blastocysts will necessarily improve LBRs, but once again this assumption was not realised with either of the two shrinkage techniques studied: LBR of 34% with both laser and pipette vs 30% in intact controls. However, the study did show that the laser-treated blastocysts exhibited significantly shorter re-expansion times than those collapsed with a pipette or left unmanipulated - and faster re-expansion dynamics, the authors insist, ‘are considered a positive predictor of treatment outcome’.
You can learn more about this latest study in our interview with first author Iris Martínez here:
Beware the unexpected hazards of random-start stimulation
The concept of random-start ovarian stimulation emerged more than a decade ago with a greater need for fertility preservation in newly diagnosed female cancer patients. These were often women facing urgent gonadotoxic treatment, with no time to spare for conventional stimulation, which might need up to six weeks depending on the timing of the menstrual cycle. One solution was proposed in starting stimulation at the time of presentation, which in an antagonist cycle would allow cancer treatment to start within two or three weeks, and not five or six. Subsequent studies would show that in these patients random-start stimulation - in either the late follicular or luteal phase - appeared as effective as conventional stimulation in terms of mature oocytes retrieved and fertilisation rates. A meta-analysis published in this journal last year confirmed the comparability of oocyte yield, but warned of longer duration of stimulation and higher FSH consumption in the random-start cycles.
Such results and the concept that antral follicles develop not in a single cohort but in multiple waves throughout the cycle encouraged the application of random-start stimulation in other patient groups, particularly those where time is a constraining factor and fresh transfers are unnecessary, such as in elective egg freezing, egg donation or even freeze-all cycles. Earlier this year Guerrero and colleagues in Alicante, Spain, reported a retrospective study of 891 egg donation cycles (with 935 matched recipients) in which stimulation was started on day 1–3 of the menstrual cycle or in the mid/late follicular or luteal phase of a conventional antagonist protocol. Following fresh and vitrified/warmed transfers in the matched recipients, both clinical pregnancy and live birth rates per ET were similar between the conventional and random groups.
However, in the October issue of RBMO, Semrl and colleagues from the Brussels group reported two cases of OHSS in random-start (luteal phase) egg donors, which were attributed to undetected naturally conceived pregnancies. The authors described this as the ‘dark side’ of random-start stimulation, warning that ‘despite medical history, laboratory tests and ultrasound examination, early unintended pregnancies may go undetected’ when initiating random-start stimulation. A recent literature review has described the risk of such naturally conceived pregnancies in luteal phase stimulations as ‘low’.
And now, in a countercurrent article scheduled for December’s RBMO, Barbara Lawrenz and colleagues describe the risk implications associated with such undetected pregnancies in random-start cycles as the ‘ugly’ side of the protocol - for two and second, as in the two cases described from Brussels, the possibility of hCG-derived OHSS, particularly in high-responder patients.
However, alongside the bad and the ugly there was also some good, summarised by the reviewers as a more flexible alternative to conventional protocols, of notable benefit to those with time constraints. They also suggest that a combination of luteal phase stimulation with a personalised start of pituitary suppression with progesterone may represent a step forward in the simplification of ovarian stimulation protocols. But until studies offer more guidance here, the current ‘good’ of random-start stimulation appears still dependent on ‘caution’ and advice to couples to avoid the risk of pregnancy during the follicular phase.
Trophectoderm biopsy and its effect on first trimester biomarkers
Trophectoderm biopsy from blastocysts remains the preferred source for analysis by PGT-A and has largely superseded blastomere biopsy from cleavage stage embryos. The former has been shown to offer a more robust diagnosis (more cells for testing) and to be less harmful to the embryos. Nevertheless, there remains unresolved controversy over the efficacy of the procedure in terms of live birth and pregnancy rates; a Cochrane review of 2020 concluded that ‘currently available evidence is insufficient to support PGT‐A in routine clinical practice’. There have also been concerns raised about the safety of trophectoderm biopsy and a possible negative effect on LBRs, notably expressed in a retrospective study from 2020 which found a decrease in serum β-hCG 12 days after transfer and a lower threshold serum β-hCG level in the biopsy group than in the non-biopsied control group for prediction of live birth. An accompanying editorial described trophectoderm biopsy as ‘perhaps not such a benign intervention’.
A recent review of the obstetric, neonatal and long-term health outcomes of trophectoderm biopsy described its effect on implantation and live birth as ‘unclear’, although an RCT in 2013 had appeared to demonstrate the safety of the procedure. The review authors explained that, because trophectoderm cells ultimately give rise to the placenta, ‘it is plausible that its disruption [through biopsy] might result in abnormalities in placentation’. Although the review found no clear evidence of obstetric or neonatal harm from the biopsy, it still recommended a ‘cautious approach’ in developing a PGT strategy based on biopsy. And added that a non-invasive approach, based on analysis of embryo cell-free DNA from culture media, might be pursued to overcome the ‘potential limitations of embryo biopsy’. Of course, the search for an effective reliable non-invasive method continues.
Now, a new study from the Dexeus group in Barcelona, published by RBMO as an article in press, has shown that trophectoderm biopsy for PGT-A has a significant impact on first trimester levels of two maternal biomarkers long established for the prediction of aneuploidy and pre-eclampsia, pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF). Given the accumulating evidence associating ART pregnancies with higher rates of pre-eclampsia and other complications of placental dysfunction, ‘the effect of trophectoderm biopsy on these biomarkers appears to be of paramount importance’, the authors write.
The study analysed almost 10,000 pregnancies (spontaneous, IVF and PGT-A) where - in most - serum levels of free β-hCG, PAPP-A and PlGF had been measured at 8-13 weeks. Measures of free β-hCG did not differ according to the mode of conception but there appeared to be lower levels of PIGF and higher of PAPP-A associated with the PGT-A pregnancies. However, the authors draw no firm conclusions from these findings, simply noting that the study was designed to see if trophectoderm biopsy alters the production of these biomarkers. Further studies, they add, would be needed to clarify their effect on trophectoderm function and any clinical implications.
Akhil Garg , Jose Bellver, Ernesto Bosch, José Alejandro Remohí, Antonio Pellicer , Marcos Meseguer Escrivá
An artificial intelligence model was designed to predict the trigger day and number of MII to be retrieved from the patient at the start of the ovarian stimulation cycle. The algorithm based on deep learning was proposed by the authors to be more robust and accurate to prediction than the conventional nomogram.
Ana Catarina Neto, Maria Botelho, Adriana Raquel Rodrigues, Sofia Lamas, Beatriz Araújo, João Tiago Guimarães , Alexandra Maria Gouveia, Henrique Andrade de Almeida , Delminda Neves
Metformin treatment at a subtherapeutic dose enhances fertility rates in an endometriosis mouse model by intervening to protect against oxidative stress during pregnancy. Additionally, metformin reduces fibrosis, a process associated with the disease, particularly within endometriosis lesions.
Stefano Palomba , Flavia Costanzi, Donatella Caserta , Amerigo Vitagliano
Direct and indirect evidence suggest that the endometrial receptivity may play a crucial role in the reduced fertility rate of women with polycystic ovary syndrome (PCOS). Various pharmacological and non-pharmacological strategies with potential effects on endometrial receptivity in patients with PCOS have been proposed.
This systematic review summarizes the rationale and the clinical and experimental evidence of interventions tested for improving endometrial receptivity in infertile patients with PCOS. Notwithstanding a strong biological rationale, the authors concludes that no intervention aimed at improving endometrial receptivity in women with PCOS is supported by an adequate body of evidence limiting their use in the clinical practice.
Giles Palmer , Omar Paredes , Andrew Drakeley , Alejandro Chavez-Badiola, MD, PhD , Thomas Woolley, Katerina Kaouri , Jacques Cohen
This study surveyed over 700 ART laboratory professionals around the world to reveal their levels of awareness, adoption and comprehension of AI. As well as directly addressing reproductive scientist’s attitudes towards AI tools, the results also reveal attitudes towards, relationship between AI and women in tech, highlights ongoing debates about data ownership, privacy, and fair compensation in AI, commercial use of data in the field, job security and concepts of data as labor.
The results illustrate an interesting milestone in AI within the field, with many respondents poised to implement AI with proper data and training. However, there is also some hesitation at widescale enthusiasm while developers provide rigorous proof of enhanced IVF outcomes to justify clinical integration.
Two companion papers from a Californian research group test the efficacy of ultra-fast vitrification and rapid elution treatments to support reliable, high survival rates and sustained functionality.
Mitchel Schiewe , Ryan Reichelderfer , Kathryn Wozniak , Claudia De Romana, Melanie Smith Nordbak , Kelly Baek , Karine Chung
Blastocyst development following ultra-fast vitrification/rapid elution (UFV/RE) of mature human oocytes was verified, continuing to pave the way to clinical application. The consistently high oocyte survival rates following UFV/RE are within rates expected for vitrified blastocysts, making oocyte cryopreservation a more reliable and time efficient preservation method for women and ART laboratories, respectively.
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Kathryn Wozniak , Ryan Reichelderfer , Seyed Ghaemi , Danielle Hupp, Peter Fuzesi , Guy Ringler , Richard Marrs , Mitchel Schiewe
Ultra-fast vitrification and rapid elution treatment significantly improves the time/labour efficiency of oocyte vitrification, while sustaining higher levels of post-warming viability. This extreme non-equilibration dehydration approach to vitrification reduces potential cytotoxic cryoprotective agent exposures and may eliminate the batch and technical variation commonly observed with conventional semi-equilibration vitrification of mature oocytes.
Sir Robert Edwards: from the science of human conception to the reality of IVF birth
November sees the global release of Netflix film ‘Joy’ which dramatises the work of RBMO founder Sir Robert Edwards along with Patrick Steptoe and Jean Purdy in the 1970s as they pioneer the techniques leading to the birth of Louise Joy Brown, the world’s first IVF baby.
Our Editors mark the release of this film with a video introduction to their ‘Ode to Joy’ Editorial, and a commentary from Dr Kamal Ahuja, co-founder of our journal, in which he recalls the inspirational role that the late Sir Robert Edwards played in his own career.
Tuesday 10 December, 3pm ET, 8pm UK
The tenth episode of our quarterly webinar will focus on our Clinical Embryology section. The event will be hosted by Editor Mina Alikani , Thomas Ebner and BASAK BALABAN , with presentations from Michael Collins on manual operation of reproductive health cryostorage facilities, and Lucie Delaroche on the assessment of bisphenol accumulation from disposable devices in IVF procedures.
More details will be revealed in the coming weeks.
Register now and join us in closing the year out with a milestone event.
November 14-17, 2024, Antalya, Turkey
RBMO will be hosting a practical workshop during the 12th meeting of the Turkish Society of Reproductive Medicine. This session will be held in the Blue Room on Saturday 16 November, hosted by RBMO Development Editor Duncan Nicholas , offering participants a uniquely engaging, interactive, thought-provoking exercise that will stimulate debate around the practices, policies and ethics of the peer review process. Duncan will also be on hand throughout the conference at the RBMO both to chat about journal publishing should you wish to discuss anything.
The full conference will feature over 20 leading global opinion leaders including RBMO Section Editors Marcos Meseguer Escrivá , Nikolaos Polyzos , Shari Mackens , Thomas Ebner, and board members Barbara Lawrenz , Danilo Cimadomo , Luca Gianaroli , Necati Findikli , Santiago Munne , and Yacoub Khalaf with presentations and discussion panels on new topics including embryology, endometriosis, infertility, assistive technologies for infertility, reproduction-related endocrinology, surgery, biology and genetics.
We hope to see many of you there.
January 8-11 2025, Liverpool, UK
The 18th Annual Fertility Conference, hosted by our society partners The Association of Reproductive and Clinical Scientists , along with the British Fertility Society and the Society for Reproduction and Fertility, will centre around the important topic of Reproduction - Facts, Myths & Evidence.
Speakers include RBMO Section Editors and Board Members Professor Alan H Handyside , Antonio Capalbo , Catherine Racowsky , Monica M. Laronda , and Willem Ombelet .
Attendees can look forward to gaining valuable insights and updates on the latest research and trends in fertility, in addition to practical advice and guidance for healthcare professionals and patients. Registration is open now.
Canadian Fertility & Andrology Society new President
We extend our congratulations to the Canadian Fertility and Andrology Society and Dr Paul Chang on his appointment as the new President of the Society.
Dr Chang shared news of his presidency in a LinkedIn post, remarking ‘As we enter our 71st year, we not only honor our legacy but also embrace the opportunities that lie before us.’
See details of everyone involved in the full CFAS Governance and Leadership board on their website.
This issue we spotlight our Experimental Reproductive Biology Section, with Section Editor Dr Mark Fenwick.
This section of RBMO focuses on basic science studies in reproduction, including both animal and human research – relating to the development and function of male and female reproductive organs in health and disease, gametogenesis, fertilization, placenta, embryo development and early pregnancy.
Mark Fenwick, The University of Sheffield
Dr Fenwick has a broad background in reproductive science with a particular interest in ovarian biology and the very early stages of follicle development. Recent work has focused on the molecular signals that maintain and regulate the primordial reserve.
‘Although different species have their own reproductive strategies, it’s remarkable how the most basic molecular mechanisms are often conserved, offering a great deal of potential for reproductive scientists to harness this reality and design clever experiments to understand normal and diseased physiology and apply that knowledge to reproductive medicine’
A selection of papers from the Experimental Reproductive Biology Section
Shokichi Teramoto et al. - Anticentromere antibodies most strongly reduce in reducing live birth outcomes after intracytoplasmic sperm injection among antinuclear antibodies
Cristina Subiran Adrados et al. - Exploring the effect of PRP on vascularization and survival of follicles in human ovarian tissue transplanted to immunodeficient mice
Shenghui Zhang et al. - Poorly controlled type 1 diabetes mellitus seriously impairs female reproduction via immune and metabolic disorders
Julie Fiscus et al. - Metabolic signature of follicular fluid in infertility-related diseases: a narrative review
Elizabeth Victoria Soczewski et al. - miRNAs associated to endoplasmic reticulum stress and unfolded protein response during decidualization
Yidong Chen et al. - Integrated multiomics reveal the molecular characteristics of conjoined twin fetuses
Christian Kramme, PhD et al. - Ovarian support cell in vitro maturation (OSC-IVM) results in healthy murine live births with no evidence of reprotoxicology in a multigenerational study
Mustafa Makav et al. - The effect of hydrogen-rich water on letrozole-induced polycystic ovary syndrome in rats
That brings us to the end of another Insights Newsletter. We hope you found much to enjoy in this issue.
If you have any thoughts or ideas you’d like to share with us about the newsletter, please do leave us a comment below, send us a message here, or an email.
The RBMO Editorial Team