RBMO Insights Issue 22: March 2024
Reproductive BioMedicine Online
An international journal dedicated to biomedical research on human conception and the welfare of the human embryo
Welcome to our March issue of RBMO Insights. The year is picking up pace now, with a little more warmth and sunlight to cheer us (at least in the Northern Hemisphere) as the days start to get longer.
This month we have a bumper edition of Talking Points for you which includes three features addressing frozen embryo selection, PGT-A at younger ages, and a new review into stimulation protocols primed by progestins which we have accompanied with a video interview with Baris Ata on our recently launched YouTube channel. Watch that interview here, and read the Talking Points article below.
Prof Ata also features in our next big event this month, as we are pleased to announce a new Affiliated Society partnership with the Turkish Society of Reproductive Medicine, of which he is the current President.
And speaking of events, our RBMO Live webinar returns this month – 12th March. Read our preview in this newsletter, or jump straight to the registration form!
This issue also includes our regular article highlights, community news and a Section Profile with our Periconception, Pregnancy and Child Outcomes Section, Catherine Aiken.
We hope you enjoy the issue.
New review reflects greater confidence in stimulation protocols primed by progestins
A review of progestin-primed ovarian stimulation (PPOS) published in the February issue of RBM Online describes the approach as a ‘patient-friendly’ and cost-effective choice if a fresh embryo transfer is not intended. The authors, Baris Ata and Erkan Kalafat , report that PPOS ‘is being increasingly used’ in ovarian stimulation as an alternative to GnRH analogues for pituitary suppression in ART cycles whose first intention is embryo freezing - such as for freeze-all, PGT-A, planned segmentation in those at risk of OHSS and egg donation via egg banking. Fresh transfers would be contraindicated in PPOS cycles because of the progestin’s effect on the estrogen-primed endometrium and its window of receptivity. Because progestogens are inexpensive and can be taken in tablet form, the benefits of PPOS lie primarily with the patient - hence its more patient-friendly character than GnRH agonists or anatagonists. But for those benefits to be realised, clinics - and patients - must be reassured that the outcome with one must be as reliably effective as the other.
And already, there’s a plethora of data to consider, generated since the first report in 2015. Even by 2020, when Ata and colleagues reported the first meta-analysis of PPOS, there were ten studies comparing progestogens with antagonists, six with agonists and six with different progestogens and doses. And from that analysis the authors concluded that the duration of stimulation, gonadotrophin consumption and oocyte yield were comparable with both progestogens and GnRH analogues. Moreover, there appeared no variations depending on the type of progestogen used - medroxyprogesterone acetate, dydrogesterone and micronised progesterone all ‘suggested similar ovarian response and pregnancy outcomes’, reported Ata and colleagues. The euploidy status of embryos from PPOS cycles was similarly comparable to that of embryos from conventional stimulation cycles. And those conclusions remain roughly the same in this latest RBMO review. There is, however, now more data on ‘controversies’ - a conventional vs a shorter more flexible protocol (beginning on day 7 of the FSH course, as in am antagonist protocol), the developmental potential of oocytes (blastulation, euploidy rate) and clinical outcome (particularly cumulative LBR).
The latter, say the authors, is of concern, with at least one study reporting lower rates in PPOS cycles. However, Ata et al question these results - for an ‘arbitrarily defined’ cumulative period, and apparent biases in embryo transfer numbers in the two groups. Otherwise, as other studies have shown, the ‘number of oocytes obtained, fertilization rate, cleavage rate, blastocyst formation rate, number of good quality embryos, and number of transferable embryos’ were similar in the two groups.
This latest study thus presents a ‘reassuring’ picture of PPOS, consistent reports from retrospective studies and RCTs, though as Bata said in an interview with RBM Online, the caution still evident today may well benefit from more RCTs. He recognised a similar response to PPOS today as to the introduction of GnRH antagonists in 1999 - caution from a suspicion of reduced efficacy until better quality data increased confidence.
New study finds marked benefits of PGT-A for embryo selection in ‘younger’ subjects
After more than 30 years since the first PGD reports, one might think that the big debates in PGT-A (does it work? add-on or routine?) are now consigned to history. Certainly, there now seems to be some consensus (at least in Europe and Australia) that PGT-A is beneficially appropriate only in specific groups - for those with previous pregnancy loss or of an older maternal age, for example. The latter position seems upheld by the landmark report of Munné et al in 1995 showing that cleavage-stage aneuploidy significantly increases with maternal age, with implantation failure in ‘older women’ largely explained by aneuploidy.
But what about younger women? Have they been forgotten and neglected in PGT-A? Santiago Munné’s group (pictured) reported in RBM Online in 2007 that from an analysis of more than 6000 embryos those with the best morphology and development were 44% euploid in patients younger than 35, but only 21% in patients 41 and older. But, as ever in PGT-A, studies aiming to translate this chromosomal observation into a treatment benefit in the clinic have been largely inconclusive in finding a true treatment benefit in younger subjects
The STAR trial, for example, found PGT-A offered no significant improvement in pregnancy rates in the full cohort of all-aged subjects - although a significant 14% improvement for women aged 35–40. Indeed, a retrospective cohort study from the SART reporting system in the USA found that PGT-A among all patients with blastocysts available was even associated with a lower cumulative LBR than routine IVF. This negative association of PGT-A was especially pronounced in patients under the age of 35. At age 35 cumulative LBR per cycle was 70.1% for untested embryos and 57.4% for those tested by PGT-A. What all these RCT results and reviews appear to have in common is an apparent inability of PGT-A to improve IVF outcomes in a routine population which includes 35s and under.
But now a new study reported in RBM Online by Mandy Katz-Jaffe et al. (pictured below) shows that PGT-A may well be offered beneficially to these younger women, with 72% of a small PGT-A group (n=100, mean age 32.6 years) achieving a live birth at their first IVF attempt. Indeed, the Colorado authors conclude, even for these younger neglected subjects, PGT-A as an embryo selection method resulted in the ‘fastest path’ to the healthiest singleton baby. This confidence was derived from a small retrospective study of 200 age-matched IVF patients having either PGT-A or morphology for their embryo selection. While the overall mean patient age was 32.6 years, with an age range of 25-43 years, results for the headline ‘younger patients’ (<35 years) were derived from separate data analyses in 73 age matched subjects (age range 25-34 years. As with the full cohort, first-cycle outcomes in the PGT-A group proved significantly better than in the morphology group: 78.9% LBR vs 54.9% per ET.
The study, which recruited its 200 subjects between 2016 and 2021, was designed as an intention to treat exercise, taking as its starting point the very first patient consultation. However, we are not told how the consultation decided on PGT-A or morphology for its embryo selection, other than that it was ‘physician directed’. The authors claimed that the ITT model added a real-life scenario to the analysis. The report also fails to explain nine sets of twins in the PGT-A group and five in the morphology group, with no mention of patient selection or embryo transfer policy - other than to note that in the PGT-A group all patients had at least one euploid blastocyst available for transfer, with 65.9% euploid, 31.5% aneuploid and just 2.6% mosaic.
The results here from the Colorado group run contrary to those of several big RCTs and registry studies of PGT-A in younger subjects. For example, a widely reported study from China in 2021, which had randomised its younger patients (all aged between 20 and 37 years) to PGT-A and routine IVF, failed to find any benefit in cumulative LBR in the PGT-A patients. Yet, as an editorial accompanying this report in the NEJM noted, PGT-A continues to be widely offered, despite lukewarm advice and results elsewhere. This latest Colorado study recognises its own somewhat anomalous conclusions, suggesting that the variability in results may be explained by differences in study populations - but continues to insist that ‘upfront embryo selection’ with PGT-A can indeed maximise live birth potential.
Growth in numbers freezing eggs far outstrips numbers thawing for use
Most national registries, although inevitably a year or so behind the real trend, describe elective oocyte cryopreservation as their fastest growing fertility treatment. The baseline numbers are still small, but the trend remains. These small baseline numbers, however, are even smaller in those returning to warm and use their oocytes for fertilisation and pregnancy, which is one reason why comments in our social and mass media urge caution in their readers: we just don’t know enough about egg freezing.
But a pattern is beginning to emerge which seems clear enough to inform predictable opinion, and which may offer a bit more public confidence in those for whom the technique seems of interest. A new study allocated to the April issue of RBM Online from Molly Johnson and colleagues at seven Monash clinics in Australia seems to reflect the trends seen elsewhere - that the numbers freezing their eggs are rapidly growing, while the numbers returning to warm/freeze their eggs remain consistently low. The study analysed treatments in patients freezing their eggs between 2012 and 2022 for both medical and non-medical reasons. As found elsewhere, the practice grew rapidly within the study period - from 63 cycles in 2012 to 603 cycles in 2021, with a commensurate rise in the number of patients. Most treatments (69%) were for medical indications, but many (21%) were for elective personal reasons.
What is also evident - and likely to increase in most jurisdictions as storage limits are extended - is that the number of eggs remaining in storage grew rapidly: from 1457 in 2012 to 21,809 in 2022 (a 1210% increase). By September 2022, 73% of the Monash eggs had been in storage for more than five years.
Of course, many of these eggs had been and would be thawed/warmed for future use, especially those originally cryopreserved for medical indications (46%). The majority of eggs thawed for use had been frozen for more than five years, although the study showed that over time this proportion slowly declined. From the overall 645 thaw cycles over the study period there were 377 embryo transfers resulting in 102 clinical pregnancies and 76 live born babies (12% LBR/thaw cycle, 20% LBR/ET). However, it was notable that these rates were higher in the cohort of elective oocyte freezers (18% LBR vs 10%).
The other scenario troubling clinics and regulators is the disposition of frozen eggs. How will cryostorage cope with the numbers? This study found that over the ten-year study period only 2800 eggs from 286 patients were discarded, donated or exported. Only 23 patients chose to donate their eggs, while 1132 eggs from 128 patients were discarded.
The authors report that their data trend is roughly the same as that reported by the Australia/New Zealand registry, with the majority of their freezing cycles for medical indications. However, they note that elective freezing treatments may be proportionally greater in some jurisdictions (while in others, particularly where state funding is in place, elective egg freezing might be non-existent). A retrospective 10-15 year follow-up report from a New York clinic found that the oocytes of 38% of elective egg freezers had been thawed/warmed, while 47% remained in storage, and 11% had been discarded.(2) What this and the latest RBMO study suggest is that the number of patients who return to use their frozen eggs remains low, and while this may indicate that freezing eggs has helped them find the right reproductive partner as a result, many will likely be faced with big decisions about their surplus eggs. It also seems that many seem disinclined to donate.
Clara Gadenne, Laura Miquel, Cindy Faust , Julie Berbis, Jeanne Perrin, Blandine Courbiere
There is little data on the impact of Chlamydia trachomatis serology on IVF outcomes, although the serology is often performed in reproductive medicine centers. In this matched cohort study, we found no impact on IVF results, which raises the question of the value of systematic screening for Chlamydia before IVF.
David Klein, Ivy van Dijke , Irene van Langen, Wybo Dondorp , Phillis Lakeman , Lidewij Henneman , Martina Cornel
While agreeing that the field of medically assisted reproduction provides an unique opportunity for offering expanded genetic carrier screening, reproductive healthcare workers in the Netherlands currently feel a lack of capability and limited motivation to offer this screening in their clinic. Professionals’ perspectives are important for responsible implementation in fertility clinics.
Siun Gallagher, Sara Attinger , Angie Sassano , Elizabeth Sutton, Ian Kerridge, Ainsley Newson FRSN , Bobbie Farsides , Karin Hammarberg, Roger Hart, Emily Jackson, William Ledger, Christopher Mayes, Catherine Mills, Sarah Norcross , Robert Norman AO , Luk Rombauts , Professor Catherine Waldby , Anusch Yazdani , Wendy Lipworth
Expert and patient participants considered that commercial forces influence provision of ART in a number of positive and negative ways. While competitive forces can support quality of care, the authors suggest that in Australia where the study was performed regulatory reforms, as well as organisational cultural initiatives, may ?needed as means to ensure the primacy of patient wellbeing.
Alyssa Hochberg, Michael Dahan , Hakan Yarali, Lan Vuong, Sandro Esteves
In women with good ovarian reserve markers undergoing IVF, various potentially modifiable clinical predictors are associated with an "unexpected" poor/suboptimal response. This finding, combined with the higher-than-expected threshold values for AMH and AFC indicating such a response, may influence decisions regarding ovarian stimulation protocols and dose adjustments for IVF cycles.
A comment from Section Editor Ioannis Messinis on Random-start ovarian stimulation in an oocyte donation programme: a large, single- centre, experience Jaime Guerrero et al.
领英推荐
This article confirms that ovarian stimulation for elective freezing in an oocyte donation program can be successfully initiated on any day of the menstrual cycle. This view has been a matter of debate among fertility specialists for some years. The rationale behind this idea is derived from the physiology of the menstrual cycle. It is known that the ovaries in reproductive years contain follicles at various stages of development. Especially, during the normal menstrual cycle, small antral follicles belonging to class 5 according to Gougeon are recruited under the inter-cyclic rise of FSH, which is also called the FSH window.
Only one of these follicles will be selected to become dominant and ovulatory. Normally, the recruitment/selection takes place during the luteal-follicular transition. Ovarian stimulation is achieved by widening the FSH window. Nevertheless, it is evident now that the ovaries can respond to exogenous FSH administration with follicle maturation at any stage of the cycle. Initially, this was observed in the so-called double ovarian stimulation protocol. This study confirms that freezing embryos and transferring them to subsequent thawing cycles achieves a similar clinical outcome regardless of when stimulation began in the cycle. From a physiological point of view, this means that oocyte maturation is not adversely affected by the hormonal environment in the different phases of the cycle even if it is markedly altered by the administration of FSH. It is obvious that the beginning of stimulation on any day of the menstrual cycle facilitates the earliest possible initiation of the special treatment of women with a malignant disease.
Diana Tain has produced a new infographic to illustrate RBMO paper Prospective reproductive outcomes according to sperm parameters, including DNA fragmentation in recurrent pregnancy loss, by Maria Christine Krog and team.
This study investigates whether measures of sperm parameters of SCSA, morphology and concentration can be used as a predictor to pregnancy loss.
The results indicate a high prevalence of increased DNA fragmentation index (DFI) measured by SCSA in men from recurrent pregnancy loss (RPL) couples, but high DFI was not associated with an increased risk of another pregnancy loss. Instead, the study showed a high DFI significantly increased the likelihood that an RPL couple did not conceive after referral. ?In addition, besides the high DFI, these couples often had sperm concentration and morphology within the normal range, which suggests an unrecognized male factor contributing to reproductive failure.
The article is published open access, available free to read from our in-press section now.
Register for RBMO Live!
The seventh edition of our free quarterly webinar will be held on Tuesday, 12th March, 3 pm EST / 7 pm UK / 8pm CET, in partnership with the International IVF initiative.
RBMO Chief Editors Nick Macklon and Juan Garcia Velasco will host this episode, featuring presentations from RBMO authors Greta Cermisoni and Dagan Wells, and a publishing tips session from Duncan Nicholas, giving behind the scenes insights and advice into journal submission.
From our Male Reproductive Health and Fertility section, Cermisoni Greta will discuss her group’s paper on the effect of ejaculatory abstinence period on fertilisation and clinical outcomes from an analysis of 6,919 cycles. This paper put concepts around abstinence time-frames to the test, and shows the importance of challenging long-established practices.
From the journal’s Clinical Embryology section, Dagan Wells will present on his group’s recent paper on chromosome segregation and IVF, investigating the effect of rescue-in vitro maturation in presence or absence of cumulus cells on meiosis I progress. From a cytogenetic perspective, this study's results argue that immature oocytes should not be discarded, particularly when few metaphase II oocytes have been retrieved, and we look forward to Dagan unpacking the implications of this interesting work.
And finally, RBMO Development Editor, Duncan Nicholas will deliver the first in a series of publishing tips that will cover topics such as submission, peer review and revision, open science, post-acceptance, post-publication and science communication skills for newer (and more experienced) researchers. The first set of tips will cover manuscript preparation and requirements for submission and acceptance at a high impact journal.
There will be time for panel discussion and audience questions on all topics presented during the webinar.
All six previous episodes of RBMO Live are available on our recently launched YouTube channel, along with author interviews and other videos.
RBMO Welcomes TSRM!
We are pleased to welcome the Turkish Society of Reproductive Medicine (TSRM) as a new Affiliated Society of Reproductive BioMedicine Online.
TSRM was established in 2003, and has become the largest academic reproductive medicine association in Türkiye, with a membership of over 1000 physicians, embryologists, geneticists and nurses working across the field. Though Turkish in name, the Association has built ?an international reputation and network of collaborators. Among its goals, TSRM aims to establish the country's first Reproductive Research Network, conduct multi-centre studies, and expand its programme of educational and ?Special Interest Group activities. RBMO Co-Chief Editor Prof. Nick Macklon says about the partnership, ‘Our colleagues in the TSRM continue to make a strong and ?significant contribution to the advancement of reproductive science, and are providing leadership in many areas of clinical practice. We are delighted to welcome the TSRM to the RBMO family of prestigious affiliated Societies.
TSRM President, Prof. Bar?? Ata says ‘RBMO offers one of the finest platforms for cutting-edge research and the exchange of ideas in reproductive medicine. The journal currently runs an outstandingly efficient publication process and provides high quality peer review and constructive editorial comments, which improve submissions until they reach publication. We have observed firsthand how the publication of abstracts from our annual meeting in RBMO has significantly enhanced both the quality and quantity of submissions to our subsequent meetings. We are deeply grateful for this opportunity and view our affiliation as an exciting chance to advance reproductive medicine research in Turkey, inspiring and motivating younger generations in particular.’
RBMO’s Co-Chief Editor Prof. Juan García-Velasco adds ‘TSRM captures the scientific advancements generated by the large community of gynaecologists, embryologists and scientists of its members. ?We are very pleased to welcome TSRM as one of our affiliated Societies. and look forward to building ?a strong relationship that will contribute to the development of both the Society and the journal.’
This month we put a spotlight on our Periconception, Pregnancy and Child Outcomes section (PPCO).
The PPCO section of RBMO focuses on laboratory studies or clinical research addressing pre-conception health, post-implantation phase and early pregnancy (including early pregnancy loss), pregnancy, maternal and offspring outcomes, and the developmental origins of health.
Catherine Aiken, University of Cambridge
Periconception, Pregnancy and Child Outcomes Section Editor
‘I am an academic clinician at the University of Cambridge. My clinical work focuses on high-risk maternal medicine, while my research interest in the long-term outcomes of suboptimal intrauterine environments complements this. As section editors at RBMO, we often have the opportunity to review some of the most interesting studies emerging in the field of maternal and offspring pregnancy outcomes. I’m particularly excited by studies that make innovative use of animal models or human cohorts to explore longer-term outcomes following complex pregnancies. This is an area that can be difficult to study, but is of critical importance in improving population health.
I would love to expand the number of studies we publish that elucidate the links between the intrauterine environment and health outcomes beyond the immediate pregnancy and neonatal period. While understanding these immediate outcomes is extremely important, I am really keen to emphasise the ‘child’ aspect of the section ‘Periconception, Pregnancy and Child Outcomes’. I’m very keen for Reproductive Biomedicine Online to become a leader in publishing research in this innovative and emerging area.’
Selected papers from our Periconception, Pregnancy and Child Outcomes section
That brings us to the end of another Insights Newsletter.
If you have any thoughts or ideas you’d like to share with us about the newsletter, please do leave us a comment, send us an email, or find us at any of the links below.
The RBMO Editorial Team