RBMO Insights Issue 32. January 2025
Reproductive BioMedicine Online
An international journal dedicated to biomedical research on human conception and the welfare of the human embryo
Welcome to the first RBMO Insights of a new year. We hope you enjoyed a reinvigorating break!
This year is a very special one for RBMO. To mark the 25th anniversary year of Reproductive BioMedicine Online, we are preparing a special issue reflecting on the development of our profession since the journal launched?and revisiting the values imparted by our founder Sir Robert Edwards when he set up the journal as a supportive platform for research in the field and to ‘make good papers better’.?? Before we move deeper into 2025, we would like to provide some insights (well, it is in our newsletter name) into some statistics for 2024 in a section we are calling ‘RBMO Wrapped’ as well as highlight some of the most impactful papers from the year past.?
We are pleased to remind you that the recording of our tenth RBMO Live webinar is available on our YouTube channel now. A nice milestone, this webinar features some great presentations on progressive clinical embryology techniques, and an illuminating panel discussion between all our guest speakers.
But for a first issue of the year we cannot only look back, and so we also have three new Talking Points features for you that offer fresh perspectives to recent papers on variability in freeze-all practices, oxidative stress and antioxidant therapy in male infertility, and controversies in anti-Müllerian hormone’s role as a clinical indicator.
On that note, we leave you to enjoy this issue, with our best wishes for the new year.
Planned PGT and risk of OHSS are the foremost indications for freeze-all
Live births derived from frozen embryos continue to increase throughout the world. In the USA the number of cycles using frozen embryos (or embryos from frozen patient eggs) increased four-fold between 2012 and 2021 (from 38,150 to 162,548), with around 40% of the 400,000+ cycles of 2021 described as oocyte or embryo ‘banking’ cycles. As the CDC figure below indicates, frozen egg or embryo cycles continue to make the sharpest progress in the USA, while embryo transfers in fresh cycles are in steady decline.
It seems likely that much of the FET trend over the past decade has been driven by freeze-all cycles, which in the latest registry reports (Australia/New Zealand, ICMART, ESHRE) now account for around one-third of all treatments. However, despite the favourable rationale (a more physiological transfer in an unstimulated cycle, improved survival rates with vitrification) the uncontested march of freeze-all was checked by inconsistent results from several large-scale RCTs.
One RCT, for example, involving 460 women with regular cycles in eight Nordic hospitals found comparable LBRs between the freeze-alls and fresh transfers. Similarly, a Cochrane meta-analysis, albeit with moderate to low-quality evidence, found no significant LBR advantage from either strategy.
If the freeze-all option as an elective procedure is not now as straightforward as it might have been thought (in terms of safety and efficacy), what are its indications in an everyday setting? The answers may now be found in a prospective study of intended freeze-all treatments in 24 fertility centres in Spain in 2021 and 2022, with follow-up until pregnancy or six months after freezing, and published by RBMO as an article in press. A population of 1034 patients (mean age 36.3 years) was eligible for the study, with 22% reporting a fresh ET followed by embryo freezing, and 78% freeze-all with vitrification of all available embryos. The reasons for freezing all embryos were gathered at baseline and not after oocyte retrieval, the authors note in explaining the two eventual strategies.
The most common indications for freeze-all were planned PGT (62%) and risk of OHSS (22%). ‘Usual clinical practice’ was cited by 12% of centres, and PCOS by 6%. With advanced maternal age and previous miscarriage noted as the ‘most common’ indications for PGT, the authors understandably cite maternal age as ‘a significant factor driving the adoption of the freeze-all strategy’ - and indeed maternal age was the second cause of subfertility in the study population.
However, the principal conclusion from the study seems to be that the Spanish data reflect the great variability in freeze-all practices among countries; this too would reflect the variable results found in the RCTs, which seemed to differ according to the population studied, whether high or normal responders, or indeed for planned PGT. But what is also clear is that freeze-all remains an attractive strategy, even preferred in some centres, with consistently high LBRs and high protection against risk of OHSS, which is after all why segmentation with freeze-all was developed.
Oxidative stress and antioxidant therapy in male infertility
The literature is abundant with reports on the negative impact of oxidative stress on semen quality, notably on sperm count, motility, morphology and DNA integrity. The balance between the production of reactive oxygen species and the defence of sperm cells against oxidative damage has been deemed essential for optimal sperm function - hence the wide support for antioxidants in the treatment of male infertility. However, the latest Cochrane review of antioxidants found 90 RCTs involving 18 different oral preparations, but with ‘very low‐certainty evidence’ that antioxidant supplementation in subfertile men may improve live birth rates.
Now, in a new Commentary for RBMO, Parviz Gharagozloo and Australia-based reproductive biologist John Aitken acknowledge the ‘general agreement that oxidative stress is a major cause of male infertility’, but argue that the technology is still not available to diagnose its presence directly and ‘thereby select those patients for whom antioxidant therapy represents a rational course of treatment’. They thus argue that the wealth of RCTs (as illustrated in the Cochrane review) are in men selected on the basis of a vague diagnosis of low sperm count or poor motility but not on the basis of oxidative stress.
‘If oxidative stress is not involved in the aetiology of a given male patient’s infertility,’ asks the commentary, ‘how can we expect antioxidants to have any impact on their reproductive function?’ Indeed, this lack of appropriate inclusion/exclusion criteria for antioxidant trials, he adds, has led to wasted time and resources, and ‘generated outcomes that are predictably inconclusive and confusing’.
So where’s the solution? The rationale for antioxidant therapy lies as ever in a demonstrable imbalance in the semen between the production of reactive oxygen species and the level of antioxidant protection. But essential for the appropriate function of antioxidants is this redox imbalance; without the imbalance, as defined by a precise measure of oxidative stress in semen, antioxidants are unlikely to be effective. And unfortunately, the commentary argues, ‘traditional assays of total antioxidant capacity do not fulfil this role’.
Aitken et al report that semen contains ‘a large number’ of antioxidants, all designed to provide sperm cells with antioxidant protection, and their ideal assessment should be achieved simply and easily, and as close as possible to the point of care. But that assay, the Commentary argues, is still a way off for use in the management of male infertility. New systems have been introduced but as yet the need remains for simple effective diagnostic procedures for detecting seminal oxidative stress in the everyday population. ‘We still don’t have the tools needed to diagnose its presence directly and thereby select those patients for whom antioxidant therapy represents a rational course of treatment.’
AMH levels may vary over time with transient low levels, especially in over-35s
As our Talking Points column noted in December, AMH remains a matter of controversy in its ability to offer a marker of fertility or time to pregnancy. An emphatic commentary in Fertility and Sterility recently insisted that ‘AMH does not predict natural fertility’ and should not be used as a ‘fertility test’. Now, as a further complication, a new study reported in RBMO as an article in press has found that variations in measurements - albeit rare - do occur over relatively short time periods (years not decades) in ‘a sizable minority’ of patients. This, the authors note, need not exclude the use of AMH as a clinical indicator but might well indicate ‘that obtaining a second test result may sometimes be justified in a small number of cases’, notably where the patient's characteristics are not consistent with low AFC’, as in young patients with regular cycles, for example.
The study was a retrospective analysis of a New Zealand database in which 1871 patients with repeat blood samples were studied to determine the degree of change in AMH levels over time. In blood tests taken less than six months apart, AMH levels were equally likely to increase or decrease over time. But over longer timeframes AMH levels were more likely to decrease, an effect found strongest in women 30 and over, and least in those under 30, an age-related change. Moreover, in patients with low AMH (<1.5 pmol/L, ng/ml) at the time of their first blood test, 42% had risen above this level by the time of their second test.
The authors appeared not to find precise recurring patterns, but did report ‘transiently depressed AMH levels’ in a small proportion of patients, which tended to recover ‘in some cases’. This, nevertheless, is at variance with the view of AMH as a stable indicator of ovarian reserve, and a further example of discordant AMH measurements in which serum AMH levels are not well matched to AFCs or other indicators of ovarian reserve.
By way of explanation the authors suggest the variations found between samples observed in most patients could be explained by cycle variation, but there were small proportions of patients in whom the changes were beyond that simple explanation. They cited recent evidence (from PCOS cases) that follicles can vary their rate of AMH secretion, with a suggestion that AMH release may vary independently of antral follicle counts. A further possible explanation may be found in prior use of oral contraceptives (which in one study was associated with a 17% average decline in AMH). However, the variations in this study, whatever their cause, appear to be rare and that for the majority AMH levels will remain stable over the space of 6-12 months. But a proportion will show variations, and those deemed at risk may benefit from repeat measurements.
In this one-off section of Insights we look back at another important?twelve months for RBMOnline, which featured more submissions, more reviewers, more published papers, faster review and publication times, more citations, more readers, more followers on social media, new journal sections, new article types, new affiliated societies, new board members, and new initiatives.
In an incredibly busy, fruitful and celebratory year, we are pleased to acknowledge the hard work of our Editors, Authors and Reviewers, and teams in our Editorial, Production and Publisher offices in supporting the papers and authors that contribute to our journal.?
Here in the sections that follow are some figures and the papers from our pages that held the greatest interest, relevance and impact to our readers and reproductive medicine community
Let’s start our Wrapped journey at the first step of the author experience, in submitting to the journal. ?
Here's how our review times looked in the year, compared with the times across the medical field, as reported in SciRev. ?
Once accepted, our production team post the author version online within an average of 3 days, with a DOI, at which point the articles are accessible and citable, which leaves us at a good juncture to look at the papers across the whole journal that were read most often during the year.
Most downloaded papers in 2024
5519 full text downloads - The future of surrogacy: a review of current global trends and national landscapes
Kirstey Horsey, 2024
This review article considers the possible regulatory future of surrogacy, initially from the perspective of the UK’s legal framework where surrogacy works well (though some cross borders to access it), and then through an assessment of global trends and other national perspectives.
5256 full text downloads - A critical appraisal of safety data of dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis
Alexander Katalinic et al, 2022
This scoping literature review and preliminary meta-analysis confirms previous conclusions of no causal association with fetal abnormalities and challenges the use of low-quality studies to communicate otherwise to clinicians. The authors conclude that dydrogesterone can be used for miscarriage prevention, without undue safety concerns.
Marte Saupstad , 2024
This study is the first to investigate whether there is an association between serum progesterone concentrations on the day of single-blastocyst transfer and clinical pregnancy rate in modified natural cycle frozen blastocyst transfer without luteal phase support.
4991 full text downloads - There is only one thing that is truly important in an IVF lab: everything Cairo Consensus Guidelines on IVF Culture Conditions
Cairo Consensus Group, 2020
This report presents outcomes from an international expert meeting to establish consensus guidelines on IVF culture. Topics reviewed were: embryo culture; temperature; humidity; gas control, pH; workstations; incubators; micromanipulation; handling and assessment; stasis, composition, supplementation, type of culture and storage; equipment and monitoring. More than 50 consensus guideline points were established.
4292 full text downloads - Experiences of users of period tracking apps: which app, frequency of use, data input and output and attitudes
Uma Patel et al, 2024
This study highlights the need for increased education and research into understanding the realities of variations in menstrual experiences. The infrequency of data input and the wide range of symptoms tracked reflects the differing needs of participants in relation to their period tracking apps.
In our 12 issues this year we have published a total of 239 papers across our eight core topic sections, our new Affiliated Society Communications section, and three special formats:
2 Editorials
5 Countercurrent Contributions
10 Commentaries
4 Affiliated Society Communications
领英推荐
30 Experimental Reproductive Biology
52 Clinical Assisted Reproductive Technology
31 Clinical Embryology
44 Female Reproductive Health and Fertility
11 Male Reproductive Health and Fertility
15 Periconception, Pregnancy and Child Outcomes
22 Reproduction, Technology and Society
13 Reproductive Endocrinology and Health
In 2024 we passed another milestone, of monthly full text downloads from our rbmojournal.com website exceeding 100,000 for the first time, in not just one but four months of the year.
Articles from the full history of the journal received 12,251 citations in 2024, and papers published in 2024 have already been cited a total of 304 times within the same year of publication.
On that note, let’s look at the articles from the full journal archive that were referenced most frequently in 2024.
Most cited papers in 2024
80 Citations - Recurrent implantation failure: Definition and management
Carol Coughlan et al. 2014
A Review paper discussing the definition and management of possible underlying causes of recurrent implantation failure.
59 Citations - Sperm cryopreservation: A review on current molecular cryobiology and advanced approaches
Maryam Hezavehei at al. 2018
A review article on freezing techniques and novel strategies that have been developed for sperm protection against cryo-damage, and an evaluation of the probable effects of sperm freezing on offspring health.
Signe Altm?e et al., 2023
The most recently published paper in this list, on the hottest current global topic – writing with Generative AI. The paper highlights the pros, cons and concerns associated with using LLM-based AI for generating a manuscript.
50 Citations - The Vienna consensus: report of an expert meeting on the development of ART laboratory performance indicators
A proceedings report presenting 12 Key Performance Indicators, 5 Performance Indicators, and 2 Reference Indicators from an international workshop to establish consensus on definitions and recommended values for the assisted reproductive technology laboratory.
Kezhen Li, 2021
This study characterized effects of virus infection on the sex hormone and menstrual changes of COVID-19 females at child-bearing age, focusing attention on the long-term effects of SARS-CoV-2 infection on female fertility.
Our final RBMO Wrapped look-back covers the wider community within which our articles are received – our ‘extra journal’ activities of this newsletter itself, our social media platforms and other activities through which we are reaching new audiences and professional networks.
Our LinkedIn Page ended the year on a notable milestone of over 7000 followers, with over 5000 subscribers to the Insights newsletter on the platform. Our posts this year reached 642,527 impressions, receiving over 40,000 reactions.
Our relatively new Instagram page has 391 followers, with nearly 100,000 impressions, and our even more recently launched Bluesky account has 214.?We have created a Bluesky Starter Pack for anyone looking for a way to get started with the RBMO and the ReproMed community on the platform.
In addition to our social media activity, we held four webinars in our RBMO LIVE series with the International IVF Initiative, featuring 6 hosts and 15 guest speakers, attracting 5289 registrations.
The recordings of these events are available on our YouTube channel, which we launched in full at the start of 2024 with 18 videos including 9 full webinars and 4 interviews which have received 2343 views. The channel currently has 185 subscribers.?Look out for many more interviews, webinars and article highlight videos to come in the New Year.
Which brings us to our final list of articles with the biggest Altmetric scores of 2024.
Most mentioned papers in 2024
Altmetric Score 181 - Periconceptional maternal and paternal alcohol consumption and embryonic and fetal development: the Rotterdam periconception cohort
Melissa van der Windt et al., 2024
This report presents outcomes from an international expert meeting to establish consensus guidelines on IVF culture. Topics reviewed were: embryo culture; temperature; humidity; gas control, pH; workstations; incubators; micromanipulation; handling and assessment; stasis, composition, supplementation, type of culture and storage; equipment and monitoring. More than 50 consensus guideline points were established.
Altmetric Score 76 - First report on successful delivery after retransplantation of vitrified, rapid warmed ovarian tissue in Europe
Nicole S?nger et al., 2024
Ovarian tissue cryopreservation is now a well-established approach to fertility preservation, although there remains significant need for optimisation. Here the first European birth after tissue vitrification, replacement and natural conception is reported: will vitrification of tissue replace controlled slow freezing?
Altmetric Score 66 - Clinical outcomes of vitrified-warmed autologous oocyte cycles with 15-year follow-up at a single UK centre: consistent and predictable results
Jemma Garratt et al., 2024
The outcome of 299 women returning to use their eggs from more than 3000 elective oocyte vitrification cycles in a single UK clinic is reported in this landmark study that shows autologous oocyte vitrification and warming can achieve live birth rates comparable to fresh IVF, with similar variables, such as oocyte age, governing success.
Altmetric Score 57 - Elective co-parenting with someone already known versus someone met online: implications for parent and child psychological functioning
Sarah Foley et al., 2024
The study examines the psychological outcomes for parents and children in elective co-parenting families, comparing those who met online with those who were already known to each other. Results indicate that both groups function well, with no significant differences in wellbeing, although tailored professional advice and support to accommodate individual needs may be beneficial.
Altmetric Score 29 - Surrogacy in the United States: analysis of sociodemographic profiles and motivations of surrogates
José ángel Martínez-López & Pilar Munuera Gómez , 2024
This study surveyed participants in the US to help clarify the profile of the women who become surrogates, their power of decision and their motivations. The results show that surrogate US women 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 motivations are based on prosocial, altruistic factors.
Read more on these Altmetric scores
We posted a top 10 Altmetric scoring articles in December – see a PDF version on LinkedIn, or a thread of individual articles on Bluesky
And with that, we conclude our first 2025 edition of RBMO Insights.
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 or send us an email.
The RBMO Editorial Team