RBMO Insights Issue 27: August 2024

elcome to the August edition of RBMO Insights – our monthly journal newsletter bringing you news from behind the scenes of the Editor’s desk, specially selected article highlights, section editor profiles, activities from our Affiliated Societies, forthcoming events, community news and in depth features on recent papers in Talking Points.

This month, Talking Points looks at the results and implications of Britain’s largest ever study of egg freezing which was published this month in RBMO, adding substantial weight to the success rates and reliability of the procedure.

Our article highlights this month include papers on the effects of alcohol on gametogenesis, conception, embryogenesis and placentation; the latest report from the African Network and Registry for ART; pharmacological and non-pharmacological interventions for improving endometrial receptivity in infertile PCOS patients, among several other very strong pieces of work in the journal.

This issue also features the latest Laboratory Diagnostic Andrology UK Guidelines for Good Practice from the Association of Reproductive and Clinical Scientists, a profile of our Clinical Embryology section, with Section Editor Marcos Meseguer, and last but by no means least, a preview of our next RBMO Live journal webinar coming up in September.

If you enjoy this newsletter and would like to receive future issues and news directly from RBMO,?subscribe to our mailing list?– and please consider sharing with your colleagues who might find it of interest too.

We hope you enjoy the issue, and wish you an enjoyable Summer.

Africa’s latest registry data continue to reflect limited resources for treating infertility

Monitoring fertility treatment by registry has changed dramatically over the past ten years. Early global reports as provided by ICMART could do nothing more than present a patchy picture at best, a snapshot of world activity based on national registries plus a large helping of estimate. The deep black holes in the global numbers were China and Africa, where registry data ranged from scarce to non-existent.

But in 2023, when ICMART presented its global IVF data for 2019 and calculated a total of ‘at least 12 million’ IVF births since the first in 1978, registry data from China were finally included in the estimates, and for the first time to provide a reasonably comprehensive world picture. Before 2020, IVF activity in China was known to be prolific, but there was no clue to understanding the extent. But then in 2020 came a registry report from the China CDC recording over 900,000 cycles from 2016, which in 2019, according to ICMART, had become more than 1 million cycles a year. Overnight, China became the world’s largest provider ART.

But what about Africa? Now, published by Paversan Archary et al (pictured below) in RBM Online as an article in press is the fourth registry report from the African Network and Registry for ART, which provides a snapshot of activity (for 2020) and an idea of developments on most of the continent. However, the picture remains cloudy at best, both in terms of full data reporting and the huge burden of infertility born by the people, especially in sub-Saharan Africa.

‘Our results continue to document low ART utilization in Africa,’ the authors ruefully write, adding that ‘the sociocultural burden of involuntary childlessness is disproportionally high in the developing South’. Apart from the high utilisation rates reported from Egypt (103 centres, more than 13,000 fresh cycles), services in sub-Saharan Africa were few and far between, with just 67 centres reporting data from 37,063 cycles. Almost two-thirds of those transfers were with fresh embryos, while almost all fertilisations were achieved by ICSI.

With an emphasis on achieving pregnancy at the expense of safety, 84% of all fresh cycles involved the transfer of two or more embryos (and 7.2% for four or more embryos), with an SET rate of just 16% and a multiple delivery rate of 37%. The majority of patients were aged 34 or under. These features, say the authors, ‘remain the key characteristics of ART practice’ in Africa.

With access to ART necessarily correlated with cost, there have been many initiatives to introduce low-cost programmes to Africa, often through the philanthropic initiatives of clinics in Europe. Yet the numbers with undiagnosed infertility and the social stigmas incurred remain enormous. Proposals to lower cost have included one-stop diagnosis, mild stimulation, and simplified laboratory and culture systems. Yet, as many have argued, there seems something of a paradox in prioritising fertility treatment in regions where resources have traditionally been allocated to preventing pregnancy and ‘overpopulation’ or reducing perinatal mortality. Yet as demographic data now unequivocally show, the decline in fertility rate now seems as great in Africa as in the rest of the world, and, as the monumental report from the IFFS recently emphasised, the treatment of infertility presents as great a need in Africa - for personal as well as demographic reasons - as elsewhere in the world.

Study underlines advice to avoid alcohol not just during pregnancy but in the periconception phase too

Avoiding alcohol during pregnancy is now unequivocally and universally advised. ‘There is no known safe level of alcohol consumption during pregnancy,’ advised the NICE guidelines of 2022 in highlighting the risks of fetal alcohol spectrum disorder, with low birth weight, preterm birth and small for gestational age. However, according to a new report in RBM Online, the risks of drinking alcohol may not be confined to the time of pregnancy but may even be evident in the earliest developmental phases - gametogenesis, conception, embryogenesis and placentation. In support of the contention, researchers from the Rotterdam Periconception Cohort found that even ‘moderate’ maternal alcohol consumption during the periconception period was negatively associated with adverse fetal growth parameters.

The study by Melissa van der Windt (pictured, below) and colleagues, drawn from a large prospective periconception cohort investigating (epi)genetic and environmental factors related to pregnancy, included 1744 female and 987 male participants all recruited before ten weeks’ gestation in both natural and ART pregnancies. Embryo development and gestational age was assessed by crown-rump length and other measurements from 3D ultrasound. Alcohol consumption in the periconception phase and first trimester was measured from a food frequency questionnaire, with quantities calculated as low, moderate and high.

The reported study results were derived from complicated models controlling for under-reporting and lifestyle variables (notably smoking) and defined alcohol consumption as a ‘continuous’ or ‘categorical’ variable. Results first showed that moderate alcohol consumption in the periconception period was negatively associated with fetal head circumference and fetal weight at 20 weeks, findings which remained significant after excluding women who smoked. By contrast, paternal alcohol consumption in the periconception period and during pregnancy showed ‘positive’ associations with fetal development.

Although some of the negative associations were not statistically significant (for example, in models where alcohol was included as a continuous variable), the findings were strong enough for the investigators to make public health recommendations - that not drinking alcohol before and during pregnancy ‘should be strongly advised’.

The advice, they added, should be louder in countries with a high prevalence of drinking, notably Denmark and UK. Indeed, despite the well known teratogenic effects of alcohol in pregnancy, other studies have still continued to show evident levels of consumption at this time. A recent Dutch study cited by the investigators found that one in nineteen women continued to drink alcohol during early pregnancy, although almost all kept quiet about it to their doctors.

Egg freezers returning to use their stored eggs have a similar chance of success as routine IVF couples

The UK’s largest ever study of egg freezing shows that success rates are comparable to those achieved by routine IVF and subject to the same variables of female age and embryo quality. The study, now published as an article in press in RBM Online, analysed the outcomes of treatment for 299 patients who had frozen their eggs at the London Women’s Clinic between 2008 and 2022 and had then returned to thaw them for fertilisation and pregnancy. The results of this 15-year study found an overall LBR per ET of 26%, which varied according to the age at which the eggs were frozen: a lower rate in over-35s but only 5% in over-40s. The overall cumulative LBR in freeze-all embryos was 34%, rising to 45% in those who had frozen their eggs before the age of 36.

The authors, who included Professor Nick Macklon, one of co-editors-in-chief of RBM Online (pictured below), described the results as ‘consistent and predictable’ when compared with other similar studies, and comparable to those achieved in routine IVF, as reported in studies by Blakemore et al, and Kawwass et al. The consistency of results, explained Macklon in a press statement, suggest ‘that the doubts still commonly expressed about the reliability of egg freezing are misplaced’.

Among several conclusions drawn by the authors is that the number of women returning to use their cryopreserved eggs remains low, and far below the numbers opting to freeze them.

Only 299 of 2171 patients freezing their eggs returned to complete 332 thaw treatment cycles, a return rate of 14%, and comparable to that found by other studies. Results also showed that LBR in freeze-all cycles was considerably improved when embryos were screened by PGT-A. Indeed, across all ages PGT-A was associated with a LBR double that of untested embryos (40% vs 21%). Indeed, all live births in women aged 40 or over were from an embryo which had been screened as chromosomally normal.

The paper was published in the same week that the UK’s regulator, the HFEA, released its data report for 2022 showing a continuing steep climb in egg storage cycles, rising 82% since 2019 and described as the UK’s ‘fastest growing treatment’. The HFEA attributed the trend partly to improved freezing techniques and survival rates, allowing greater patient confidence in freezing eggs and a realistic choice between egg and embryo storage.

ime-lapse visualisation of first mitotic divisions may hold clue to an embryo’s ploidy status

Errors in chromosome segregation during the mitotic divisions of preimplantation development are frequent in human embryos, and are largely the explanation for the presence of mosaic embryos detected during PGT-A. However, the underlying defects in the cell division which results in mosaic aneuploidy remain a subject of research and resistant to any explanation by visual assessment. Although testing by PGT-A allows distinction between euploid an aneuploid cells, such distinction has not yet been achieved visually through time-lapse incubation and data interpretation.

Now, a new study available in the September issue of RBMO concludes that observation of the patterns of embryo development during the first mitotic division may actually hold clues to the ploidy status of the embryo and future potential for pregnancy. The pattern which the study investigated during this first division was the angle of the first plane of division relative to the axis of the pronucleus - and described in three possible patterns: where the first plane of division was formed parallel to the axis of the pronucleus; of oblique formation; and of perpendicular formation. All 762 embryos in the study, which would later go on to form blastocysts, were allocated to one of these three patterns from time-lapse observation in respective groups.

Analysis showed that the euploidy rate was significantly higher in groups A (parallel formation) and B (oblique formation) than in group C (perpendicular formation), whereas the aneuploidy rate was significantly higher in group C than in groups A and B. The authors thus propose that the first plane of division relative to the pronuclear axis is an indicator of embryonic euploidy (as later determined by NGS in this study), and that, when the first dividing plane is formed perpendicular to the pronuclear axis, the rate of a euploid embryo is reduced (with high probability of aneuploidy).

Mizobe (pictured below) and co-authors report that other studies have focused on the first mitotic division as an embryonic assessment measure, but these have concentrated on speed of development and cleavage. Now the present authors propose that theirs is the first study to report that ‘the formation pattern of the first plane of division relative to the pronuclear axis is a predictor of embryonic ploidy’ - and indeed an ‘indicator’ for the non-invasive indentification of euploid embryos.

Pharmacological and non-pharmacological interventions for improving endometrial receptivity in infertile patients with polycystic ovary syndrome: a comprehensive review of the available evidence

Stefano Palomba, Flavia Costanzi, Donatella Caserta , Amerigo Vitagliano

This review aids in providing comprehensive counselling regarding the effects of available strategies on endometrial receptivity to infertile women with PCOS. Since reproductive failure in women with PCOS appears to be also influenced by impaired endometrial receptivity, the authors advocate further studies to enhance the care of women with PCOS beyond the management of ovulatory disorders and weight/metabolic aspects.

Luteal phase support with oral progesterone improves the live birth rate in patients undergoing IUI cycles using letrozole with or without HMG

Qianwen Xi, Maokun Liao, Yingjie Wang, Bian Wang,?Yun Wang, Yanping Kuang

This retrospective study of patients with all infertility diagnoses demonstrated that luteal phase support with oral progesterone improved the live birth rate in IUI cycles using LE with or without HMG, although it did not significantly affect neonatal outcomes. 1199 IUI cycles with letrozole was included after PSM to evaluate the effect of oral progesterone for luteal phase support. Oral progesterone was proved to improve LBR without affecting neonatal outcomes. Taking letrozole paired with oral progesterone for luteal support appears to be beneficial in clinical practice.

Is HyFosy the new gold standard for assessing tubal patency? A systematic review and meta-analysis Elisabeth Gerard Cassiman, Sophie Harter, Romane Mougel, Cécile Mezan De Malartic, Charline Bertholdt, Olivier Morel, Mika?l Agopiantz

The results of this study show that hysterosalpingo-foam sonography (HyFosy) is at least as efficient as hysterosalpingography, has significantly better results than HyCosy and the agreement with laparoscopy is high. HyFosy is an efficient, well-tolerated and safe exam. The authors recommend new guidelines include HyFosy in first-line tubal patency assessment.

Potential anatomical determinants of retrograde menstruation: a comprehensive narrative review

Paolo Vercellini, Martina Piccini , Francesca Caprara, Giulia Emily Cetera , Paola Viganò , Edgardo Somigliana

The review addresses a topic of great significance and complexity, addressing a classic theory of endometriosis, providing a comprehensive overview of the various theories currently at play and discussing both their strengths and limitations. Building from the three uterine anatomical structures identified in Sampson’s mechanistic model over a century ago that may determine the amount of retrograde menstruation and the likelihood of endometriosis development, the authors critically appraised the available data published over the last 40 years, introduce new perspectives and raise pertinent questions to guide future research in this field.

A brief look back at ESHRE 2024

We have now successfully recuperated from the week of intensive presentations, discussions and meetings of the 2024 edition of the ESHRE conference. We were delighted to host an evening dinner with our Editors and Section Editors, and Publisher, taking the opportunity for some welcome editorial team socialising that the conference presents (with just a little journal strategizing for good measure).

Our booth was also busy with conversation over the week, and it was a pleasure to meet with so many of our authors, editorial board members and new faces.

Here our Elsevier Marketing manager Jayne Dawkins, Publisher Morgane Dagot and Editor Nick Macklon are ?in full flow debating the intricacies of journal publishing between sessions!

Our Editor Nick Macklon featured in two journal club sessions over the conference, with one discussing articles on ChatGPT and LLM text generators, and the other debating clinical add-on services. As an editor dealing with papers produced with text generating technologies, and as a Medical Director of an IVF clinic, Professor Macklon is well placed to offer some experienced and expert insights into both of these areas.

We were pleased to see many of our authors taking to the stages to speak about their work, and reference their RBMO papers – particularly those of our award winning authors. In this picture, Francesca Farlie , author of runner up RGE Prize paper, spoke about the range of environmental issues and sustainable laboratory practices that the paper was based on.

We also attended several other sessions featuring RBMO authors over the week.

Caroline Roelens presented work on the comparable rates of pregnancy at 12 weeks’ gestation between patients using oral dydrogesterone and micronized vaginal progesterone that builds on research from her team published in RBMO recently, on?reproductive outcomes in patients with low serum progesterone concentrations.

Marte Saupstad presented results from her group’s latest research on blastocyst transfer day in FET, showing potential for more flexibility in timing that builds on the work published in RBMO in July,?progesterone concentrations on blastocyst transfer day in modified natural cycle frozen embryo transfer cycles.

Shari Mackens presents her work on the effects of ovarian stimulation on microbiota composition, showing estrogen rise during OS has a pivotal role in the LRT microbiota variation, and the LRT microbiota pre-OS, although associated, may not accurately predict ART success.

Association of Reproductive and Clinical Scientists

Laboratory Diagnostic Andrology UK Guidelines for Good Practice (2024)

Meurig Gallagher , Emily Roxburgh , @Gwen Bennett, @Susan Parker, Jackson Kirkman-Brown MBE

https://doi.org/10.1016/j.rbmo.2024.104373

Affiliated Society Communication from ARCS

These guidelines update and clarify items relating to diagnostic andrology in the 2012 Association of Biomedical Andrologists Laboratory Andrology Guidelines for Good Practice Version 3 (Tomlinson et al., 2012).

The main change separates diagnostic and therapeutic andrology into individual documents; post-vasectomy semen analysis still references the 2016 guideline (Hancock et al., 2016).

These guidelines seek to incorporate and clarify internationally agreed methodology following the World Health Organisation laboratory manual for the examination and processing of human semen 6th edition (World Health Organization, 2021), and publication of ISO 23162:2021 (International Organization for Standardization (ISO), 2021). Significant updates include: requiring four-category grading for motility (A: rapidly progressive; B: slowly progressive; C: non-progressive; D: immotile); 4-part morphology assessment (head, midpiece, tail, cytoplasmic droplets) as essential for quality assurance (even if only the percentage ‘normal’ are reported); and specifying sperm toxicity testing procedures for diagnostic andrology, and include a section on haematospermia; an observation requiring rapid onward referral.

A working group of the The Association of Reproductive and Clinical Scientists wrote these guidelines, with review from ARCS members. Their aim is to guide good practice in laboratories, but are not intended as a tool to judge the practice of centres within the UK or beyond.

RBMO LIVE Episode 9

Registration is open for our next webinar, Tuesday September 10, 3pm EST / 8pm UK / 9pm CET

RBMO Editor Signe Altm?e will join Nick Macklon to host the ninth edition of our quarterly webinar in September. ?

This session will put a spotlight on our Periconception, Pregnancy, Children Outcomes section, with Section Editor Catherine Aiken.

We are also pleased to feature Munevver Serdarogullari , Scientific Director at Ventus IVF Centre, Cyprus, presenting her recent review paper?Revitalising female fertility: platelet-rich plasma (PRP) - hype or hope?,?which featured in a Talking Points article in the February issue of Insights - plus more speakers to be confirmed!

Registration is open now.

Our webinars are hosted in collaboration with International IVF Initiative, so please do give them a follow to stay updated on RBMO Live and other webinars broadcast by i3.

This issue we showcase our Clinical Embryology section, with comments from one of our Section Editors, Professor Marcos Meseguer, and a selection of article highlights.

'Clinical Embryology is the main responsible of the success of any unit of Assisted Reproduction, embryologist must be differentiated not only by a high skills close to be microsurgical but also by its comprehensive knowledge of the laboratory performance and the continuous efforts in increase the efficiency of the procedures and the outcomes.

You can find in our journal, RBMOnline, manuscripts that could inspire your future challenges like embryologist but also improve your knowledge and become a better embryologist.'

Papers specially selected to showcase the Clinical Embryology section:

A compact, high-throughput semi-automated embryo vitrification system based on hydrogel Shanshan Wang et al.

Developing a novel device, Eggcell, to improve temperature stability during oocyte collection for IVF Nilendran Prathalingam et al.

Can the combination of time-lapse parameters and clinical features predict embryonic ploidy status or implantation? Yaoyu Zou et al.

Chromosomal mosaicism in human?blastocysts: a cytogenetic comparison?of trophectoderm and inner cell mass after NGS Effrosyni Chavli et al.

Altered morphokinetics and differential reproductive outcomes associated with cell exclusion events in human embryos Radhika Kakulavarapu et al.

Oocyte rescue-in vitro maturation does not adversely affect chromosome segregation during the first meiotic division Marga Esbert et al.

The clinical use of progesterone in human sperm preparation media for increasing in vitro fertilisation success Nicole McPherson et al.

Use of artificial intelligence (AI) embryo selection based on static images to predict first trimester pregnancy loss Alejandro Chavez-Badiola et al.

That brings us to the end of another Insights Newsletter.

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The RBMO Editorial Team