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#1

General Discussion / An open letter to the HFEA abo...

Last post by mensfe_admin - 2025-06-30 20:53

Comment
The following letter has been sent to Peter Thompson, chief executive of the Human Fertilisation and Embryology Authority (HFEA).

Dear Peter,

Thank you for your recent communication and the interim publication of Choose a Fertility Clinic (CaFC) metrics on 29 May. We acknowledge the challenge of presenting meaningful outcome data in a rapidly evolving clinical landscape, and we appreciate the HFEA's intent to offer patients more timely information.

That said, we must raise serious concerns about the continued use of live birth per embryo transferred as the headline measure.

Focusing on live births per embryo transferred, rather than per cycle started or per patient, omits key aspects of the treatment journey.

This metric can unintentionally:

Favour clinics that selectively transfer only high-quality embryos, often after multiple freeze-all cycles where embryos of average quality are not even given chance and discarded, thereby inflating apparent success rates.
Allow exclusion of patients with poorer prognoses, including those whose cycles are cancelled or result in no embryos for transfer – particularly common in low ovarian reserve.
Create space for clinics to implicitly attribute success to adjunctive treatments or add-ons (such as PGT-A, IVIG, or immune testing), when in fact their reported outcomes benefit from methodological artefacts rather than evidence-based efficacy.
The statement on the HFEA website that differences are due to 'chance' is misleading in this context.

The data being published from highly heterogeneous populations and practices.

Clinics do not all treat the same mix of patients; they can (and do) differ in their:

Patient age profiles.
Use of donor gametes.
Use of PGT-A.
Patient selection (poorer prognosis patients may be shifted into 'natural IVF' category allowing to remove this group of patients from denominator).
Clinical protocols (multiple cycle banking for patients with poor reserve).
Inclusion or exclusion of certain types of cycles in reported denominators.
To suggest that differences of a significant percentage points are simply 'chance' without mentioning that systematic biases in patient selection and reporting drive these differences is non-scientific and risks misleading patients.

The mixing of different subpopulations into one 'success rate' is a serious methodological flaw.

Reporting an aggregate 'live birth per embryo transfer' without appropriate stratification:

Rewards clinics who heavily filter patients pre-transfer.
Hides poor performance in the stimulation, fertilisation, or embryo development phases.
Fails to account for the fact that many patients (especially older or poorer prognosis) never reach embryo transfer.
The current system ignores the fundamental problem of:

Denominator manipulation – by excluding failed cycles and those who never reach embryo transfer, a clinic can appear to outperform others simply by being more selective.
The PGT-A disclaimer is insufficient and misleading.

While the website does mention that PGT-A may influence success rates, the current wording is not enough to prevent patients from perceiving that PGT-A clinics are 'better'.

Critically, it fails to mention that:

Many patients are excluded from reported success rates entirely if their embryos are deemed 'abnormal' and no transfer occurs.
PGT-A outcomes should be reported separately and transparently (as per latest good practice recommendations), with success rates per cycle started or per patient, not just per embryo transfer.
Without full transparency on how many cycles never result in transfer, the success rates can appear artificially high.

We urge the HFEA to consider the following immediate steps.

The presentation of data in current format needs to be suspended.
Live birth rate needs to be reported per cycle started (multiple pregnancy rate still can be assessed in this setting).
Clearly separate PGT-A cycles and donor egg treatments in all outcome data, with transparent labelling by age group.
Aim to develop reporting on cumulative live birth rate per cycle started. While we understand that cumulative live birth rate per cycle started is a more complex metric to present, it remains the internationally accepted gold standard – already adopted by SART/CDC (USA), CARTR+ (Canada), ANZARD (Australia/New Zealand), and endorsed by ICMART. These systems recognise that the patient journey begins with a cycle start, not with an embryo transfer, and that fair reporting must reflect the full scope of that journey.
These concerns are not new. For well over a decade, clinicians and academics have pointed out that current reporting frameworks – including the continued reliance on embryo-based metrics – allow for distortion, selective exclusion, and confusion. Multiple studies and professional commentaries, including from members of our own team, have outlined how such practices undermine the original goals of the HFE Act: to inform, protect, and empower patients. Yet despite these repeated calls, meaningful reform has lagged behind international best practices. With the current update to CaFC, the Authority has a rare opportunity to address long-standing weaknesses and restore confidence in how outcomes are reported and understood.

We also welcome clarity on the upcoming consultation process.

Will clinics, patients, and independent experts be able to contribute formally?
Will the consultation explicitly address the use and abuse of elective freeze-all cycles and multi-cycle commercial packages?
We note that the HFEA's 2025–2028 Strategic Plan includes strong commitments to transparent, patient-centred information and to reducing inequalities in treatment outcomes. We are concerned, however, that the current CaFC metrics – in particular the continued focus on embryo-based success rates – may not fully reflect those strategic priorities in practice. We hope the forthcoming consultation will be an opportunity to bridge this gap and bring CaFC into closer alignment with the Authority's vision.

We believe this is a critical moment. How the HFEA reports outcomes will influence not only patient choice, but also clinical practices and commercial models across the UK fertility sector. Inaccurate or overly simplified metrics carry real risk of harm and perpetuate inequity. Transparent, cycle-based reporting – underpinned by clear definitions and cumulative success data – is essential if CaFC is to become a truly trusted tool for patients.

We thank the Authority for recognising the weight of this responsibility and remain committed to supporting the development of a fairer, more clinically accurate system of reporting.

Professor Dusko ILIC, MD PhD
Professor of Stem Cell Science
King's College London Faculty of Life Sciences and Medicine
School of Life Course and Population Sciences
Department of Women and Children's Health
Person responsible for the HFEA clinical license 0102
Assisted Conception Unit, Guy's and St Thomas' NHS Foundation Trust

Dr Julia Kopeika, MD PhD, FRCOG
Consultant Gynaecologist
Head of Assisted Conception Unit, Guy's and St Thomas' NHS Foundation Trust
Lead For Fertility Preservation
Sub specialist in Reproductive Medicine and Surgery

Professor Yacoub Khalaf, MD, FRCOG
Professor of Reproductive Medicine and Surgery
King's College, London Consultant in Reproductive Medicine and Surgery
Guy's and St Thomas' NHS Foundation Trust Medical Director of the Assisted Conception Unit and Centre for PGD

Tarek El-Toukhy, MSc MD MRCOG
Consultant Gynaecologist
Senior Lecturer, King's College London
Subspecialist in Reproductive Medicine and Surgery
Assisted Conception Unit, Guy's and St Thomas' Hospital NHS Foundation Trust

Professor Caroline Mackie Ogilvie, BSc DPhil OBE
Guy's and St Thomas' NHS Foundation Trust

Professor Ying Cheong, MD, FRCOG
Professor of Reproductive Medicine
University of Southampton

Some of the issues discussed in this open letter will be explored at this year's PET Annual Conference, What Does Genomics Mean for Fertility Treatment?.

#2

General Discussion / Re: Genome sequencing every ne...

Last post by mensfe_admin - 2025-06-23 21:00

Films of all six events can be watched below. We believe that you will find them informative, as the UK Government considers rolling out this approach for all newborns. And the team at PET looks forward to holding further public discussions, as this work proceeds.

1. What Should Be Looked For? What Should Be Fed Back?

If you can't see the film embedded above, you can watch it on YouTube.

2. Consenting Adults, Sequencing Babies

If you can't see the film embedded above, you can watch it on YouTube.

3. What Research Can, and Should, Be Done with a Baby's Genome?

If you can't see the film embedded above, you can watch it on YouTube.

4. Genomic Data: A Resource from Cradle to Grave?

If you can't see the film embedded above, you can watch it on YouTube.

5. Workforce Implications for Healthcare Professionals and Beyond

If you can't see the film embedded above, you can watch it on YouTube.

6. Implementing the Generation Study

If you can't see the film embedded above, you can watch it on YouTube.

#3

General Discussion / Genome sequencing every new bo...

Last post by mensfe_admin - 2025-06-23 20:55

A Tale of Two Surrogates
Comment
Sequencing the genomes of newborn babies: What led to the UK Government's plans?
by Sarah Norcross

Genomics has been in the headlines in recent days, due to comments made by the UK's health secretary Wes Streeting that were published in the Telegraph. According to that newspaper and other reports, a ten-year health plan is due to be published imminently by the UK Government, and it will include an objective to make whole genome sequencing available for every newborn baby.

Research commissioned by PET (the Progress Educational Trust) in 2022 – conducted by Ipsos – showed that a majority of the UK public at that time (53 percent) supported the idea of whole genome sequencing at birth, as a way of screening for a larger number of rare genetic conditions than the nine that were being screened for by the 'heel *****' test (see BioNews 1148). The same research showed that just ten percent of the UK public were opposed to such an approach.

However, many practical and ethical challenges are involved in sequencing the genomes of newborns. These challenges are currently being investigated by the Generation Study, an NHS-embedded research study which is sequencing the whole genomes of 100,000 newborns. This study, in turn, forms part of the Newborn Genomes Programme (see BioNews 1172), one of several initiatives run by Genomics England.

Since 2014, PET has collaborated with Genomics England to produce public events that explore scientific, ethical and other aspects of whole genome sequencing. Speakers at these events have included experts, practitioners and advocates from a wide variety of backgrounds, including patients and their relatives. Discussion has ranged from lay-accessible explanations of the relevant technology to robust debate about the issues raised.

In recent years, six PET/Genomics England events have focused on the implications of sequencing the whole genomes of newborns. The most recent of these events took place shortly after the announcement that testing of newborns as part of the Generation Study had begun (see BioNews 1259 and 1261), while the preceding five events enabled ideas to be explored and considerations weighed up in public, ahead of the study's launch.

The focus of each event was as follows.

What Should Be Looked For? What Should Be Fed Back?
Consenting Adults, Sequencing Babies
What Research Can, and Should, Be Done with a Baby's Genome?
Genomic Data: A Resource from Cradle to Grave?
Workforce Implications for Healthcare Professionals and Beyond
Implementing the Generation Study
Films of all six events can be watched below. We believe that you will find them informative, as the UK Government considers rolling out this approach for all newborns. And the team at PET looks forward to holding further public discussions, as this work proceeds.

#4

General Discussion / Cumulative live birth rate and...

Last post by mensfe_admin - 2025-05-19 08:05

Yaping Jiang†, Lei Jin†, Bo Huang   , Li Wu, Xinling Ren, and Hui He 

ABSTRACT
STUDY QUESTION: Is early rescue ICSI (E-RICSI) an effective and safe technique compared to conventional ICSI?
SUMMARY ANSWER: Despite the higher multi-pronucleus (PN) rate compared to conventional ICSI, E-RICSI did not add extra risks to clinical and neonatal outcomes.

WHAT IS KNOWN ALREADY: Based on the finding that the second polar body was released in 80% of fertilised oocytes by 4h after exposure to spermatozoa and in 90% of fertilised oocytes by 6h, E-RICSI brings forward the timing of rescue ICSI to 6h after initial insemination and effectively prevents oocyte ageing and embryo-uterus asynchrony. However, some researchers still voice concerns about the efficacy and safety of E-RICSI, and comparative studies are limited.
STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was conducted on patients who underwent conventional ICSI or E-RICSI treatment between January 2015 and December 2020 at a university-affiliated hospital. Using 1:1 propensity score matching, 1496 cases entered each group.

PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1496 couples undergoing conventional ICSI oocyte retrieval cycles and 1496 undergoing E-RICSI oocyte retrieval cycles were enrolled in this study, and basic clinical characteristics, embryologic data, clinical outcomes and neonatal data were compared between groups. The embryos in the E-RICSI group were divided into two subgroups: those fertilised by IVF (IVF subgroup) and those fertilised by E-RICSI (E-RICSI subgroup). The embryologic data, clinical outcomes, and neonatal data for these subgroups were also compared with those of the conventional ICSI group. Logistic regression was used for statistical analysis with potential confounder adjustment.

MAIN RESULTS AND THE ROLE OF CHANCE: The 2PN rate, blastocyst formation rate, and viable blastocyst formation rate of the E-RICSI group were significantly lower compared to the conventional ICSI group (2PN rate: P<0.001; blastocyst formation rate: P<0.001; viable blastocyst formation rate: P¼0.004), and the multi-PN rate in the E-RICSI group was significantly higher than the conventional ICSI group (P<0.001). However, the numbers of 2pn embryos, normal cleavage embryo rates, Day 3 high-quality cleavage embryo rates, and high-quality blastocyst rates were similar between groups. When considering the IVF embryos and E-RCSI embryos in the E-RICSI group independently, the 2PN rate of the conventional ICSI group was significantly lower than E-RICSI subgroup but higher than the IVF subgroup, whereas the blastocyst formation rate and viable blastocyst formation rate were higher than E-RICSI embryos but comparable to IVF embryos. Regarding the clinical and neonatal outcomes, the implantation rate in the E-RICSI subgroup was significantly lower than in the IVF subgroup but comparable to that in the conventional ICSI group. Conversely, the low birthweight (LBW) rate was significantly lower compared with the conventional ICSI group but similar to that in the IVF subgroup. No other differences were observed among the three groups for cumulative clinical pregnancy rate, cumulative live birth rate, and the pregnancy outcomes per transfer, including clinical pregnancy, ectopic pregnancy, miscarriage, and live birth, either in fresh or frozen embryo transfer cycles. Furthermore, neonatal outcomes, including cesarean section, sex ratio, LBW, preterm birth, and macrosomia, were similar among groups.

LIMITATIONS, REASONS FOR CAUTION: This study is limited by the retrospective design, limited sample size, and short follow-up period. However, our study underlies the need for large-scale, multi-center randomized controlled trials with long-term follow-up.

WIDER IMPLICATIONS OF THE FINDINGS: Short-term insemination (3h) combined with E-RICSI may be a safe and effective method to prevent the occurrence of total fertilisation failure, and patients with normal or borderline sperm could be encouraged to try IVF first.

#5

General Discussion / Epigenetic differences identif...

Last post by mensfe_admin - 2025-05-13 08:06

by Dr Marisa Flook

Methylation in the placentas of male and female fetuses has marked differences, according to a study by researchers at the National Institutes of Health, Bethesda, Maryland.

DNA methylation is an epigenetic mechanism that cells use to control gene expression. It occurs when a tag known as a methyl group is added to the DNA molecule without altering its underlying sequence. The addition of this tag allows the regulation of gene expression by turning genes 'on' or 'off'. Using multi-omics techniques, to determine the precise molecular changes which define cell types and their development, the researchers analysed the methylation patterns of 152 male and 149 female placental samples from a larger study. The placenta develops from cells that are part of the early embryo, and the researchers have identified differences between male and female placentas that may play a role in birthweight and adult diseases.

Publishing their findings in Nature Communications the authors wrote: 'This study offered several unique insights about the landscape of sex differences in the level and genetic regulation of methylation and gene expression in the human placenta... [The] findings suggest the potential role of placenta-mediated sex differences in developmental and later-life physiological traits and diseases.'

The researchers identified 6077 DNA sites with different methylation patterns between males and females, of which 2497 were previously unreported. Overall, 66.9 percent had higher methylation in DNA from male placentas, which were linked with greater neonatal size. The remaining 33.1 percent had higher methylation in DNA from female placentas and were linked to greater placental size.

Some increases in methylation were sex specific, such as DNA sites near the CCDC6 gene in males and the NIRF1 gene in females. Reduced expression of these genes has been previously linked to preterm deliveries and preeclampsia, respectively.

The authors found that higher methylation near the FNDC5 gene was associated with lower expression of the gene in male placentas but not in female placentas. FNDC5 is involved in the production of irisin, which protects the placenta from damage by reactive oxygen molecules and insulin resistance. Lower irisin levels have been associated with preeclampsia and lower placental weight.

Additionally, the researchers identified variations in the ATP5MG and FAM83A genes expressed in the female placenta that have been associated with asthma, hay fever, eczema and breast cancer.

The authors noted that their study was unable to distinguish sex differences that emerged in early gestation from those that emerged in later gestation. For example, a previous methylation study on first trimester placentas found that ZNF300 was highly methylated in male but not female placentas (see BioNews 1262), which was similarly observed in the present study.

Dysfunction of the placenta underlies many pregnancy complications and is thought to determine male and female health differences that occur later in life. The differences in DNA methylation uncovered in this study could support future research on the higher risk for pregnancy complications involving male fetuses, such as stillbirth and prematurity.

Temperature controls mechanism in sperm linked to male fertility
by Dr Coco Newton

The mobility of sperm appears to be temperature-dependent due to the action of a single protein, according to research carried out in mice.

Researchers from Washington University School of Medicine, St Louis, Missouri used techniques originally developed to study brain cells to show that electrical discharges from a particular sperm protein, CatSper, increased when the temperature surrounding the cell surpassed 38 degrees Celsius. In parallel, sperm behaviour switched from a smooth swim-like motion used for navigation to hyperactive propellor movements needed for entry into the egg.

'That hyperactive state in sperm is key for successful fertilisation, and no one knew exactly how temperature triggers it,' said professor of cell biology and physiology Polina Lishko, corresponding author of the paper published in the journal Nature Communications.

Previous research suggested sperm mobility changes may be activated by environment pH or reproductive hormones like progesterone (see BioNews 1078, 1102 and 1121).

While the study was done in mice, the CatSper protein is common to all mammals, and previous research has linked mutations in the CatSper gene to human male infertility. The protein regulates calcium ion entry into sperm cells, thereby controlling the sperm tail motion.

Because most mammals – including humans – create and store sperm in testes around two to four degrees lower than the body temperature, the researchers hypothesised that reaching the warmer internal female reproductive tract might activate CatSper.

Professor Lishko suggested the findings may offer new approaches to male contraception and infertility treatments, with previous attempts to target the protein proving unsuccessful: 'Instead of creating inhibitors, it might be possible to activate CatSper with temperature, thus prematurely switching on this channel to drain the sperm of energy, so that by the time the sperm cell is ready to do its job and enter the egg cell, it is powerless.'

The study also revealed that the pH of the testes and an additional ejaculate molecule, spermine, both appear to shield CatSper from warmer temperatures to prevent sperm activating before reaching the egg.

The authors drew on evolutionary observations that species without the CatSper proteins, such as birds, have internal testes where temperature-activation is redundant. They also highlighted that men with varicocele – an overgrowth of blood vessels leading to increased testicular temperature – show impaired sperm motility which can lead to infertility. However, whether CatSper is the mechanism by which variocele affects fertility remains unknown

#6

General Discussion / Sperm cells carry past trauma ...

Last post by mensfe_admin - 2025-02-07 12:03

Story by Devika Rao,
Generational wounds may live in our genes. New research suggests that childhood trauma leads to a difference in the epigenetics of a sperm cell, which can impact a child's development and also be passed on by that child via epigenetic inheritance. According to the new study, a parent's particular experiences and behaviours may significantly affect future generations more than previously assumed.
 drinking or smoking behaviours. The study said these results "provide further evidence that early life stress influences the paternal germline epigenome and supports a possible effect in modulating the development of the central nervous system of the next generation. "
Generation after generation
While the study found epigenetic changes in the sperm cells of those who experienced distress as children, "the inheritance of these findings has not yet been proven, so further research is needed," University of Turku Professor Emeritus Hasse Karlsson, who worked on the study, said in a press release. "Next, we want to study childhood maltreatment, epigenome of sperm, and offspring characteristics together," added Tuulari in the press release. "Demonstrating epigenetic inheritance in humans would rewrite the rules of inheritance, which highlights the need for further research."
Scientists have long been interested in how the behaviour and experiences of parents genetically affect their children, especially when it comes to the sperm cell. "There must be a huge component of the pathogenesis which is not simply explained by genetic predisposition," Raffaele Teperino, a physiologist and pharmacologist at Helmholtz Munich, said to The Scientist. For example, a 2024 study found that paternal diet and weight can affect their offspring's metabolic health — even if the offspring has a healthy diet.

#7

Research / Reason for lower cancer risk i...

Last post by mensfe_admin - 2024-12-10 13:35

by Dr Catherine Turnbull

How ageing induces iron insufficiency, reduces stem cell renewal and tumour formation has been discovered.

The risk of developing cancer increases until around 80 years of age. This is thought to be associated with the accumulation of mutations within different cells of the body, including stem cells and pluripotent cells. However, as we age, these cells lose their ability to regenerate and divide effectively which offsets any amassed tumour-promoting mutations. Now, researchers studied the effects of stem cells in the lungs of older mice that had lung cancer mutations introduced via an adenovirus.

'As with many types of cancer, lung cancer is diagnosed in most people around age 70... But once you get to 80 or 85, the incidence rate starts to come down again,' said Dr Xueqian Zhuang from Memorial Sloan Kettering Cancer Centre in New York, and first author of the study. 'Our research helps show why... Ageing cells lose their capacity for renewal and therefore for the runaway growth that happens in cancer.'

Mice at around two years old were used as they resembled the age of 65-70 year old people; the most common age that lung cancer is diagnosed. The lung stem cells were isolated from the mice to measure their self-renewal capacities and gene expression was analysed using single-cell RNA sequencing. DNA methylation patterns were also studied to determine any epigenetic changes linked to ageing.

Publishing their findings in Nature, the researchers have shown that ageing suppresses the ability of lung stem cells to form tumours. The aged mouse stem cells had increased gene expression of Nupr1, through age-accumulated epigenetic modifications to their DNA, resulting in high amounts of the NUPR1 protein, a specific transcription factor involved in iron insufficiency.

'The ageing cells actually have more iron, but for reasons we don't yet fully understand, they function like they don't have enough,' Dr Zhuang said.

NUPR1 makes the cells function as if they are iron deficient, and subsequently have a reduced ability for regeneration, which is directly linked to the older mice developing fewer tumours. However, this effect could be reversed, which the researchers achieved by giving the older mice additional iron or by reducing the amount of NUPR1 in their cells.

Furthermore, the researchers discovered that disrupting this pathway in young cells induced cell death caused by too much iron. Thus, reinforcing the age-specific role of Nupr1.

'What our data suggests in terms of cancer prevention is that the events that occur when we're young are probably much more dangerous than the events that occur later,' said Dr Tuomas Tammela from Memorial Sloan Kettering Cancer Centre, and senior author of the study. 'So, preventing young people from smoking, or from tanning, or from other obvious carcinogenic exposures are probably even more important than we thought.'

#8

General Discussion / Re: Friends' genetic traits ma...

Last post by mensfe_admin - 2024-11-02 10:52

On a genetic level, recent research shows that genes influencing brain behaviours operate within "contextually responsive regulatory networks," meaning that they adapt to environmental inputs. This adaptability is vital to brain development and social behaviour. However, conventional genome-wide association studies (GWAS) often miss this complexity, as they isolate genetic markers without factoring in environmental influences—especially in humans, where controlling for variables like upbringing and social context is difficult.
This gene-environment interplay is especially significant for donor-conceived individuals, who may inherit genetic traits from a donor they've never met but develop within their unique family environments.

A better understanding of these interactions could help address the developmental needs of these individuals more effectively.

PR

#9

General Discussion / Re: Stepingstones

Last post by mensfe_admin - 2024-10-10 10:14

We shall not cease from exploration
And at the end of all our exploring
Will be to arrive where we started
And know the place for the first time

(but heard, half heard, in the stillness
Between two waves of the sea.)
From TS Elliot  Four quartets

#10

General Discussion / Stepingstones

Last post by mensfe_admin - 2024-10-10 10:10

Travelling backwards
The train rolls on
And I continue my journey -backwards.
I am sitting here facing with my back to the direction of travel
(its meant to be safer in the event of a crash)
Ironic
I am travelling forward, facing the past

I've had to leave my mate
Somewhere in a port in Scotland
I've run out of time
And couldn't continue our adventure

Home summons me,
Sues embraces and the children's laughs and cuddles.
I resume the longer voyage; and as much as I love and accept that journey
I look forward to my next adventure