RBMO Insights Issue 19: December 2023
Reproductive BioMedicine Online
An international journal dedicated to biomedical research on human conception and the welfare of the human embryo
Welcome to our December issue of RBMO Insights; the final month of a year characterised by successfully productive developments for us at RBMO, with our new editors Nick Macklon and Juan García-Velasco having finished their first full year steering journal, and we hope you have had an excellent year too.
In the past 12 months we have introduced our new article-based publishing to further modernise RBMO, and provide our authors with faster publication to the final ‘version of record’. With this change beginning with our August issue, we have reduced the time from acceptance to final publication in an issue by an average of 71 days.
The RBMO team grew this year, as new Editors David Gardner, Signe Altm?e and Georg Griesinger joined us at the start of the year alongside several changes to our Section Editor team, and a refresh of our whole Editorial Board. This Summer we appointed a second Science Editor, Fiona Warrander to work alongside Catherine Field, providing our authors with a specialist service to ensure our published papers are of the highest quality in both robust science and written word, and the autumn saw Simon Brown join us as Communications Editor to contribute our Talking Points section of this very newsletter.
This year we have also been developing activities with our Partner Societies, and this month we are delighted to officially announce a new collaborative partnership between RBMO and the Association of Reproductive and Clinical Scientists. You can read the full announcement in this issue.
Also in this issue we reveal the biggest papers of the year in the journal, with the articles published in 2023 that have garnered the most attention from a variety of sources, on topics including automated ICSI, pre-eclampsia, endometritis screening, ChatGPT and more.
Finally, we have our regular sections, highlighting forthcoming events from our Partner societies, and a Section Profile this issue showcasing our Reproductive Endocrinology section, with words from Stefano Palomba and a selection of articles.
We hope you enjoy this issue, and may we take this opportunity to wish all those celebrating the festive season a happy and peaceful Christmas.?
Encouraging outcomes following one-minute warming protocol for vitrified blastocysts
Vitrification, today’s favoured cryopreservation technique, is now a central component of most IVF programmes. The latest data on global trends in ART suggest that frozen transfer cycles presently outstrip fresh by around 60 to 40%. Now, a new report in RBM Online (J. Liebermann et al) proposes an even more efficient rehydration protocol for warming vitrified cells; this shortens the standard multi-step protocol - and in this reported study was associated with at least comparable clinical outcomes.
The proposal emerged from a retrospective cohort study of 3439 FETs which included 833 FETs warmed with a one-step abbreviated rehydration protocol. The report explains that currently the standard warming protocol to convert the glass-like embryos back to liquid requires exposure of the rehydrating cells to multiple sucrose solutions at different concentrations, with expansion at each step. High concentrations of sucrose solutions, say the authors, counterbalance the high concentrations of cryoprotectants used in the vitrification. However, this ‘can reduce the speed and magnitude of cell swelling’, say the authors, and thereby survival, which in earlier studies has been shown ‘almost entirely dependent on the warming rate’. This latest study compared outcomes from a multi-step standard rehydration protocol (lasting around 11 minutes) with a one-step protocol (lasting around 1 minute).
Results showed that survival and pregnancy rates were similar in both groups, although ongoing PRs were higher in the one-step warming protocol (60.4% vs 55.4%) than in the standard. Similarly, there was a significant increase in implantation rates and lower miscarriage rates in the one-step versus the multi-step protocol.
The authors highlight two conclusions from their results: first, that the rehydration of cells post-warming can indeed be successfully achieved in a short single step; and second, its implications for laboratory workflow and efficiency, training and staffing are significant.
This is not the first study to compare blastocyst survival between a standard and rapid warming rate. Indeed, most of those reported (in small studies and congress abstracts) have found similarly high survival rates, with higher pregnancy and implantation rates and time savings in the lab. However, this latest report is by far the largest, with a sample size of 3439 blastocysts powered to detect a 5.5% difference in outcome, and findings confidently described to support the concept that a concentrated rehydration of embryos (and shorter time of the out of the incubator) can help improve clinical outcomes after transfer of vitrified-warmed blastocysts.
Probiotic interventions in unexplained infertility. Maybe yes, maybe no, but a definite maybe
Vaginal dysbiosis, defined as an environment of low or absent Lactobacillus spp, has been increasingly implicated in a range of gynecological disorders (PCOS, endometriosis) including infertility. By contrast, a normal vaginal community of Lactobacillus is said to represent a reliable biomarker for a well-balanced vaginal ecosystem. Thus, some studies have suggested that the administration of selected probiotics, often in combination with antibiotic treatment, may help restore symbiotic microbiota to improve conception and the outcomes of ART.
However, such studies are inconsistent in their therapeutic approach, with different lactobaccilli delivered via different routes. Now, a new critical commentary published in RBM Online (Mine Orlu et al) explores the association between the concentrations of microbiota in the cervicovaginal region and gut of women and their potential contribution to infertility - and in so doing hopes to suggest a conclusive assessment of their efficacy.
However, because of the heterogeneity of the studies analysed, the review fails to reach that conclusion, noting that scientific investigations ‘are still at the stage of discovering and understanding the role of the vaginal and gut microbiota on fertility outcomes’. But, from the studies considered in this commentary ‘it is possible’, write the authors, that probiotics and other related interventions ‘may find their way into mainstream care, offering new avenues for couples struggling with infertility’.
What have the studies suggested so far? First, a systematic review from 2020 reflected in women with tubal or primary infertility an association with low or high vaginal microbiota, with a significant negative correlation between Lactobacillus spp abundance and infertility (OR 0.83) - that is, a healthy vaginal microbiota was associated with a reduced risk of infertility. Other studies have considered the microbiota additionally found in the endometrium, with one similarly suggesting that a higher abundance of lactobacilli was positively correlated with live birth. Conversely, Lactobacillus depletion in the endometrial environment was significantly associated with unsuccessful IVF pregnancies.
So if indeed there is an association between the composition of microbiota in the uterine and vaginal environments and infertility, will probiotics improve the outlook, notably in patients for whom no cause of infertility can be found? So far, the study results are not encouraging, with several, following short intravaginal interventions, showing comparable outcomes. However, one recent study in women with bacterial vaginosis given six days probiotic treatment before IVF did find higher pregnancy and live birth rates than in non-treated controls. The probiotic may have helped restore a healthier vaginal microbiome and reduce reproductive complications, noted the authors. They also noted the variability of content in the probiotic products, in terms of type, concentration and route of delivery.
Thus, say the authors, the variability in the design of these studies ‘represents a clear limitation in the interpretation and comparison of the results’. Not surprisingly, the role of vaginal microbiota testing and probiotic supplementation as an adjunctive measure to improve results in treated unexplained infertility was considered without much enthusiasm, and not routinely recommended in the latest European guidelines, but only in a research setting.
The detection and transfer of mosaic embryos remain a challenge, despite accumulating data and professional guidelines
It is only eight years since the landmark study of Fiorentino’s group in Rome reported healthy births following the transfer of blastocysts tested as mosaic. Yet in that short time the potential viability of mosaic embryos has become one of the hottest topics in reproductive medicine and the subject of several formal statements on their prioritisation and transfer. A narrative review of developments just published in RBM Online on behalf of the Spanish Society of Fertility, lead by Elkin Mu?oz , sets out discussions in detail, with hopes that it will ‘serve as reference material’ for practitioners managing mosaic embryos after PGT-A.
The viability potential of mosaic embryos - which originally were all deemed abnormal and discarded - was initially thought solely dependent on the proportion of cells affected, which in this review is identified as ‘low level’ (<40%–50% affected) or ‘high level’ (>40–50%). However, the review also identifies other classification parameters to have emerged over the past few years - notably the number of chromosomes involved (simple, complex, chaotic), the number of cell lines affected (inner cell mass, trophectoderm only, or both), and type (whole or segmental).
Detection of mosaicism is today mainly by next generation sequencing of biopsied trophectoderm cells, but the review warns that many factors seem to affect accuracy, notably the biopsy technique, the NGS platform, the threshold set for data interpretation, the cut-off applied for mosaicism, and the chromosomes involved.
The literature search for this review threw up 14 eligible studies in which the transfer of euploid embryos defined the control group. However, outcome results still proved inconclusive, variously dependent on copy number or classification. For example, the review cites Capalbo’s 2021 study which found that, when ‘intermediate’ copy number is defined as up to 50%, outcomes have not been found worse than for uniformly euploid embryos.
Drawing on results from several large studies, including the largest to date with results on the transfer of 1000 mosaic embryos, the authors conclude that several reproductive outcomes are less favourable than those found with euploid transfers - a lower implantation rate, lower pregnancy rate, and higher miscarriage rate. However, the review notes that the chance of mosaicism persistence during pregnancy ‘appears to be low’, although only a few cases have been reported. Nevertheless, in its final conclusions the review encourages ‘detailed follow-up of mosaic embryo transfers’, with prenatal diagnosis ‘highly advised’.
The report also concludes that all those having IVF with PGT-A should receive pre-test genetic counselling to explain the potential risks, benefits and limitations of the technique, and those considering the transfer of a mosaic embryo should be referred to a post-test genetic counselling session.
RBMO Wrapped!
To reflect on the successes of some of the papers we have published over the year, and to champion our authors, we present the top 10 most popular papers from the pages of RBMO in 2023. New studies may continue to inform practice and research over years to come, but these are the papers that have had a rapid impact on our community with the most readers, shares and discussion on social media, blogs and news platforms, saves to bibliographic tools, and citations in newer research papers. It is testament to the current intense focus on text generation technology, and the speed at which modern research publishing moves, that the Altm?e, Sola-Leyva and Salumets paper Artificial intelligence in scientific writing: a friend or a foe? has already received many citations, despite being published in September.? That one really is a hot topic!
Anna Aulitzky , Julia Lanbach, Sophie Falkensteiner, @Sarah Maier, Hanno Ulmer , Bettina Toth, Beata Seeber
First measured hCG following single embryo transfer appears to serve as an early marker of poor placentation. Specifically, extremely high values of hCG were associated with later development of pre-eclampsia, even after controlling for age, BMI, parity and fresh vs. frozen embryo transfer. Corroboration of these findings in larger populations and subsequent evaluation of preventative therapies, such as early initiation of acetylsalicylic acid, is needed.
Birgit Alsbjerg , Ulrik Schiler Kesmodel, Peter Humaidan
This cohort study of endometriosis patients explores the effect of progesterone concentrations during luteal phase in hormone replacement therapy frozen embryo transfer. Concentrations above 118 nmol/l (37.1ng/ml) resulted in significantly higher live birth rate compared with lower serum progesterone levels, suggesting that a threshold for optimal serum progesterone exists.
Nuno Costa Borges , Santiago Munne , Eduard Albó, Sergi Mas, Carolina Castelló, Guillem Giralt, ZHUO LU , Charles Chau, Monica Acacio Espinosa , Enric Mestres Gonzalvo , Queralt Matia Algué , Laura Marquès, Mariona Rius Mas , Carmen Márquez, PhD , Ivette Vanrell Barbat , A?da Pujol, Daniel Mataró , Michelle Seth-Smith, Luis Mollineo, Gloria Calderon , John Zhang, PhD, MD
The team behind this landmark project developed an ICSI (ICSIA) robot to automate the sperm injection procedure. ICSIA was first tested in mouse, hamster and rabbit oocytes, and subsequently using discarded human oocytes. Next, a clinical pilot trial was conducted with donor oocytes resulting in the first baby born from automated ICSI. This is a milestone that undoubtedly will hasten development of more (and fully) automated technologies in the IVF laboratory, in turn (and in time) increasing consistency and improving efficacy of laboratory procedures.
Xin Dai, Jingyi Li, Tian Fu, Xuefeng Long, Xiaoou Li, Ruiwen Weng, Yi Liu, Ling Zhang
领英推荐
Sequential letrozole/HMG is more effective than letrozole alone in inducing ovulation and promoting pregnancy, with no increase in side effects, and so provides a promising option for the treatment of patients with PCOS infertility.
Women with self-reported endometriosis adhering to the endometriosis diet reported higher quality of life scores. This effect was even higher when strict adherence to the endometriosis diet was reported. Future studies should aim to identify the facilitators and barriers to dietary adjustments in endometriosis patients.
Signe Altm?e , Alberto Sola Leyva , Andres Salumets
Our experiment of using ChatGPT for scientific writing demonstrates that ChatGPT has a high potential for helping researchers to overcome the ‘blank-sheet syndrome’ that all authors face from time to time, designing their study, performing analyses and drafting the study results into a scientific article. Nevertheless, it should not be considered as a replacement for authors’ work, as it clearly requires human oversight at all stages and final input for guaranteeing the accuracy and reliability of the results.
Evangelia Katsika , Julia Bosdou , Dimitris Goulis , Grigoris Grimbizis, Efstratios Kolibianakis
Testosterone pretreatment increases both live birth and clinical pregnancy rates in women with poor ovarian response undergoing ovarian stimulation for IVF. These findings confidently highlight the importance of this intervention in women with a poor ovarian response, in whom numerous other interventions do not appear to be beneficial
The impact of chronic endometritis on reproductive outcomes following IVF remains questionable given the lack of proper data convincingly showing an improvement after diagnosis and treatment. This article aims to provide the reader with a critical appraisal of current diagnostic methods, treatments and patient populations to be tested for chronic endometritis.
@Nuria Pellicer, Mauro Cozzolino , César Díaz García , Daniela Galliano , @Ana Cobo, Antonio Pellicer , Sonia Herraiz Raya
There is a clear demand to preserve fertility and/or prevent injury in the ovaries. Follicle reactivation shows promising experimental outcomes in women with premature ovarian insufficiency or diminished ovarian reserve, but clinical evidence is scarce. The focus should be on increasing not only the number of follicles, but also, more importantly, oocyte quality.
Isotta Magaton , Anja Helmer, Markus Eisenhut, Marie Roumet, Prof. Dr. med. Petra Stute , Michael von Wolff
Oocyte maturity, oocyte fertilization and morphology of the cleavage-stage embryo are affected by high-dose gonadotrophin stimulation in fresh IVF cycles. However, whether this effect also has an impact on pregnancy and live birth rate remains to be evaluated.
Reproductive BioMedicine Online and the Association of Reproductive and Clinical Scientists announce a new partnership.
Reproductive BioMedicine Online (RBMO) and the Association of Reproductive and Clinical Scientists (ARCS) are delighted to announce a new collaborative partnership.
ARCS is a professional body of reproductive scientists, founded in 2020 to support the research and development interests and needs of those involved in reproductive sciences in the UK, and worldwide. The Association’s mission is to promote the highest standards of research, diagnosis, patient care and educational outreach in the fields of fertility and reproductive science.
RBMO is proud to support these goals through the journal’s own mission as an internationally renowned publication of 24 years, dedicated to supporting progressive, high quality research and discussion across the full range of human reproductive health and disease, and the societal implications of fertility care.
RBMO is published in collaboration with Elsevier, and together we are pleased to help ARCS better serve its members, the RBMO community, and the wider profession through this collaboration.
Speaking on the new partnership, ARCS Chair Professor Jackson Kirkman-Brown said: ‘ARCS partnership with RBMO provides us the basis for international reach of our guidelines and best practice, as well as valued access for our members to the journal we believe comprehensively covers their interests at the highest standards. Working together we can globally impact and guide future excellence in our field.’
RBMO Co-Chief Editor, Prof. Nick Macklon said ‘RBMO is a truly international journal and is proud to have affiliations that serve prestigious professional associations world-wide.? We are delighted to announce this new partnership with the ARCS in the UK that will enhance mutual accessibility to the best science and best practice for all.’
Co-Editor Prof. Juan A. García Velasco said ‘Since the early days, RBMO has had a strong focus on embryology and scientists. Our partnership with ARCS will bring RBMO closer to its members and facilitate a close academic engagement with them.’ We look forward to working with our new partners into the future.
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30 May - 2 June 2 2024
The conference will feature workshops and industry-sponsored symposia covering a wide range of topics of interest to ART laboratory practitioners, including Gamete and Embryo Selection Beyond Morphology; Cryopreservation and Storage update; Preimplantation Genetic Testing Controversies and Advances; Emerging Research Tools in Embryology; and Global Challenges in Clinical Embryology. The progressive themes of the Conference will feature renowned plenary speakers Dr. Jacques Cohen (founding RBMO Chief Editor) discussing The Next Big Thing In IVF, and RBMO Editor Professor David Gardner, AM, FAA reflecting on The Future Of Human Embryo Culture.
See the dedicated event website for registration details.
10 – 13 January 2024
The 17th Annual Fertility Conference organised by the Association of Reproductive and Clinical Scientists (ARCS), the British Fertility Society (BFS) and the Society for Reproduction and Fertility (SRF). The theme of the conference is Rethinking Reproduction and the event will feature Rapid Fire sessions, poster sessions and the introduction of the RBMO Prize Winner presentation as part of the collaboration between ARCS and RBMO, with a talk from Dr Sonya Diakiw on Image-based AI solutions for gametes, embryos, and endometria. The presentation will be introduced by RBMO Chief Editor Nick Macklon. Access the programme, further information and registration details from the conference website.
This month we put a spotlight on our Reproductive Endocrinology and Health section, with some details and recommended papers from Section Editor Stefano Palomba.
The Reproductive Endocrinology and Health section of RBMO focuses on endocrine control and function of the reproductive system and its disorders in both men and women, contraception, reproductive ageing, PCOS, menopause and gender-related health
Selected papers from our Reproductive Endocrinology and Health section
That brings us, not just to the end of another Insights Newsletter, but a second year of Insights, and in view of 2024. We hope your 2023 was enriching, and we wish you the best for the coming year. If you have any thoughts or ideas you’d like to share with us about the newsletter, please do send us an email. The RBMO Editorial Team