IVF News

Tuesday 7th December, 2021. 3PM EST/ 8PM GMT / 9PM CET 

Moderators:
Dr. Dorte Egeberg 
Giles Palmer

Presenters:
"Anonymity, Genealogy and CSI" Debbie Kennett
"Crime Scene Investigations" Craig Huldie MCSFS, Cert Ed
"European Sperm Bank and Sperm Dogs" Dr Dorte Egeberg and Steen Stausholm
"Fundamentals of Forensic Sperm Assessment" Amanda Napp 
"Crime in the Cloud: An Intro to Cybersecurity" Mike Pool

VIEW HERE

Scientists have created a 'blastoid' model of the human embryo at early-stages that can successfully attach to uterine cells in vitro, mimicking the implantation of an embryo in the mother's uterus. 

In the first week of fertilisation human embryos form a ball of cells called a blastocyst, which must implant into the uterine wall for a pregnancy to continue. Models of the human blastocyst have previously been created by other labs from stem cells but had shortcomings as they contained cells not normally found in the human blastocyst and it was not known if they could implant into a human uterus. The new 'blastoid' model created in this study more faithfully imitated early embryo development spatially and temporally, and successfully attached to uterine cells in vitro, researchers said. 

Lead author Dr Nicolas Rivron, from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, said: 'These experiments clearly point out the fact that we are able to model in the dish the first touch between the embryo and the mother.'

In the study published in Nature, scientists used two types of human stem cells to create the blastoids: embryonic stem cells from previously established cell lines or pluripotent stem cells, reprogrammed from adult cells. 

The blastoids reliably replicated the key phases of early embryo development, in the correct sequence and time frame and with the correct cellular composition. When they were placed in contact with cells from the lining of the uterus that had been stimulated with hormones, about half of the blastoids attached to the uterine cells and started to grow in the same way blastocysts would, modelling implantation of an embryo to the uterus.

The researchers believe their model could advance our understanding of early development and be used to develop contraceptives or fertility treatments, being able to use the lab-grown blastoids in large numbers for drug discovery and screening. Dr Rivron's group is already using their blastoids to test an FDA-approved drug which could disrupt embryo implantation, and thus could be used as a non-hormonal contraceptive. 'Now that we have formed a reliable embryo model, we can uniquely understand the molecules at play, and I believe that these molecules will actually become tomorrow's medicines to enhance fertility or to be used as contraceptives,' said Dr Rivron. 

The study and the use of blastoids already have implications for IVF. Researchers identified the molecule lysophosphatidic acid increased the rate of blastoid formation from stem cells and implantation, and further research could clarify if this could be used by IVF clinics as a medium to culture embryos in to improve their chances of successful implantation.

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The Human Fertilisation and Embryology Authority (HFEA) has detailed potential updates to current laws regarding fertility treatment practices in the UK, including improved patient protection.

The announcement was made in a speech delivered by Julia Chain, chair of the HFEA, at the annual conference of the Progress Educational Trust (PET, the charity that publishes BioNews). She clarified that much of the Human Fertilisation and Embryology Act 1990, which established laws regarding fertility treatments and research (and was given a major update in 2008), remains suitable for purpose. However, she argued, the sector had become increasingly difficult to regulate, given substantial medical advances and changes in social attitudes.

'The fertility sector has really changed significantly since the Act was first brought into being', Chain told the Today programme on BBC Radio 4 prior to the conference. 'It's time we really had a look at what needs to be modernised.'

In her speech, Chain pointed out that the Act does not contain 'any words in it relating to patients, patient safety, or even outcomes of treatment'. As a regulator, she argued that it was the duty of the HFEA 'to keep all those three things at the front of our work'.

Sarah Norcross, director of PET, welcomed the call for modernisation. 'We decided to hold our "Reproducing Regulation" conference, with speakers including the HFEA and other regulators, because the law and regulation that govern fertility treatment and related research are showing their age', she said. 'This is a fantastic opportunity to clarify who regulates fertility, and how.'

In her speech, Chain highlighted several areas of the Act that require particular focus. The first concerned patient protection and maintaining the quality of care provided for them. This would include a broader range of methods for addressing poor performance, such as economic sanctions against non-compliant clinics. This would also include addressing the increasing commercialisation of the fertility sector, where 65 percent of treatments are self-funded and public funding is poorly distributed, resulting in a 'postcode lottery'.

Under this heading, Chain also addressed fertility treatment 'add-ons', and the possibility that these may contribute to patient confusion or vulnerability to financial exploitation by clinics. She explained that as things currently stand, the HFEA has little power over this aspect of fertility treatment – hence the HFEA's recent collaboration with the Competition and Markets Authority, whose director of consumer protection spoke alongside Chain at PET's conference.

Chain touched on several other areas where she considered the Act to be out of step with modern families and medicine, including the definition of a mother as 'the woman who is carrying or has carried a child'. This effectively excludes some same-sex couples, trans parents and single parents.

Chain also singled out the 14-day rule, which requires human embryos used in research to be destroyed within 14 days of their creation, and the fact that information about fertility treatment has a special status of medical secrecy (over and above ordinary considerations of patient confidentiality).

Chain anticipated that quick progress would be made bringing about these changes, saying that 'we are not starting with a blank sheet of paper and much of the Act remains fit for purpose'. She added that her aim is 'to reach an outline agreement with the Department of Health and Social Care next year on what needs to change.'

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Many IVF embryos discarded due to chromosomal abnormalities could lead to viable pregnancies and healthy babies, a new non-selection clinical trial has suggested. 

Currently fewer than three percent of mosaic embryos, which have a mixture of normal and aneuploid cells, are transferred into the uterus during IVF due to a belief they are not viable. This practice limits IVF where few alternative embryos are available to a patient, although there is limited evidence to suggest that mosaic embryos are not viable as a few abnormal cells might not affect fetal development. 

'It was already known that putative mosaic embryos can develop to term and make healthy babies, but many of the previous studies that looked at this issue were affected by selection bias toward a population of patients that had a poor prognosis because they had previously failed implantations with euploid embryos,' said first author of the study Dr Antonio Capalbo, laboratory director at Igenomix, Marostica, Italy, which specialises in genomic testing services.

In the clinical trial, published in the journal American Journal of Human Genetics, embryos were tested with pre-implantation genetic testing that looked specifically for mosaic aneuploidy. In addition to euploid embryos (those with no aneuploidy), embryos with low-grade mosaicism (20 to 30 percent aneuploid cells) and medium-grade mosaicism (30 to 50 percent aneuploid cells) were blindly reported as euploid and implanted. This strategy avoided bias as any embryo that fitted the defined criteria could be used for implantation. 

The investigators found that across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos, the mosaic embryos were as likely to implant in the uterus as the normal embryos, and had the same likelihood of becoming a healthy baby carried to term. The obstetric and neonatal outcomes were also similar across the three groups. 

Miscarriage rates were similar across the three groups and of the pregnancies which resulted in miscarriage which were investigated, none were due to aneuploidy.

'This is an area that has created a lot of controversy over the last decade, with some who believe it blindly and some who believe it's wrong. It has divided the field' Dr Ippokratis Sarris, director of King's Fertility, who was not involved in the study, commented in the Telegraph. 'Clinicians and doctors are asking: "what should I do with mosaic embryos?" We're becoming more confident in putting back mosaic embryos and seeing what happens.'

The researchers expect the study to change current guidelines on the use and reporting of mosaic embryos prior to IVF treatment, thus allowing patients to make more informed decisions about the transfer of mosaic embryos, which can be deemed healthy and normal according to the trial. 

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A recent study found that preimplantation genetic testing for aneuploidy (PGT-A) may not improve live birth rate. 

PGT-A is an add-on that many fertility clinics offer, due to the belief that not transferring aneuploid embryos will help to reduce miscarriage rate and improve live birth rate. Previous research had suggested that it could help improve live birth rate for older women but there was little research into how it impacted outcomes for young, healthy women. PGT-A is also potentially undesirable as it involves discarding aneuploid embryos, which can leave intended parents with fewer to have transferred than conventional IVF treatment. 

Professor Richard Paulson director of USC Fertility in Los Angeles, California who was not involved in the research said: 'If you are someone who is in a good prognosis group ... and you have three blastocysts, it is in your best interest to not do the genetic testing.'

The research, detailed in the journal New England Journal of Medicine, was carried out across 14 fertility centres in China. The randomised, controlled trial involved 1212 subfertile women, ages 20-37, who had a good likelihood of having a live birth due to no history of recurring miscarriages or IVF cycles where the embryo had not implanted. 

Split equally into two groups the trial looked at the live birth rate within a year and with up to three embryo transfers for women who had IVF with ICSI with PGT-A, and without PGT-A. They found similar rates between the two groups with a live birth rate of 85.3 percent for women whose embryos received PGT-A screening and 82.5 percent for women whose embryos did not.

A lower rate of miscarriage was found in the group who received PGT-A (8.7 percent compared to 12.6 percent), but more women in the conventional IVF group had second or third transfers of their embryos within a year, suggesting there were more embryos available for this group. 

The authors of the study conclude that while PGT-A is not supported for women with a good prognosis, their results are not necessarily applicable to older women or women who have experienced multiple pregnancy loss or implantation failure. They also note they used ICSI for all women in the study which is not used for all IVF patients.

In a commentary that accompanied the piece Dr Sebastiaan Mastenbroek an embryologist from University Medical Centres in Amsterdam, the Netherlands and others who were not involved in the research noted: 'According to the 2018 Fertility Clinic Success Rates Report of the Centres for Disease Control and Prevention, PGT was used in 37.7 percent of all IVF cycles that resulted in an embryo transfer,' in the USA. He went on to point out that although the FDA does not regulate some fertility clinic 'add-ons' in the USA now, the public is calling for increased regulation. He warned the sector must be careful to innovate 'responsibility 'to avoid potential class-action lawsuits in future. 

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Pioneering research seeks to preserve fertility in boys and young men who undergo childhood cancer treatment.

Treatment for cancer, including chemotherapy and radiotherapy, can compromise the ability to make sperm. While sperm can be collected and frozen prior to cancer treatment in males who have gone through adolescence, this is not an option for pre-pubescent boys, who do not yet make sperm. With childhood cancer on the rise in Scotland, finding an option to treat infertility later in life is increasingly becoming a priority. Now, a team at the MRC Centre for Reproductive Health at Edinburgh University led by Professor Rod Mitchell, hopes to get permission to start clinical trials for a treatment, named testicular cryopreservation, early next year.

'We are all very excited about it', said Professor Mitchell. 'The fact that we are about to embark on seeking approval to start trials is really positive news for the patients and their parents and carers involved in our research, who are generally very enthusiastic about the programme'.

Over the last five years, researchers at the MRC Centre for Reproductive Health at Edinburgh University have been focusing on freezing biopsies of healthy testicular tissue taken from children prior to cancer treatment, in the hope that the tissue can be re-implanted later in life to restore fertility. 

If successful, the resulting sperm could be extracted and used in assisted reproductive technologies. 

Preliminary studies in animals show promising results, with a trial of the technique on monkeys leading to the birth of a baby rhesus macaque called Grady in the USA in 2019.

In a talk at the recent Progress Educational Trust (PET) event 'Advances in Assisted Reproduction: What Can We Expect', Professor Mitchell highlighted how pubescent boys, whom he termed the 'inbetweeners' are somewhat in limbo between testicular cryopreservation and sperm cryopreservation. Patients of these ages are likely to become the focus of fertility preservation trials in the future.

Ovarian tissue cryopreservation has been used for over 25 years in pre-pubescent girls prior to cancer treatment and has proven successful as a treatment for infertility later in life. Data from this has been important in guiding the selection criteria for testicular cryopreservation in pre-pubescent boys.

Sarah Norcross, director of PET, the charity which publishes BioNews, said 'This is an ingenious method of seeking to restore male fertility, and could be of immense benefit to men whose fertility has been lost or compromised during childhood or adolescence, either by disease or by treatment for disease... Reproductive options for men in this predicament have been severely limited, but now there is real hope this situation could change. Careful work will now need to be done to assess and refine these new techniques but the fact that this work is now sufficiently advanced to embark on clinical trials is a remarkable achievement'.

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High-resolution single-cell gene expression analysis has been performed on a gastrulating human embryo, providing landmark insights.

Because human embryos cannot legally be cultured longer than 14 days in the UK, if scientists wish to study them the embryos must be conceived naturally and donated following a termination. As most potential donors do not know they are pregnant at this stage and so would not be seeking termination, studies on human embryos at and shortly beyond a phase known as gastrulation, which occurs around two weeks after fertilisation, are extremely rare.

Professor Shankar Srinivas of the University of Oxford and corresponding author of the study said: 'Our body is made up of hundreds of types of cells. It is at this stage that the foundation is laid for generating the huge variety of cells in our body – it's like an explosion of diversity of cell types.'

The study, published in Nature and performed by researchers at the University of Oxford and the Helmholtz Zentrum München, Germany, focused on a single donated embryo staged at 16–19 days post-fertilisation. Researchers separated the embryo into its constituent cells, sequencing the messenger RNA of a total of 1195 individual cells to create a highly detailed map of gene expression across cell types.

Generation of high-resolution data of the molecular mechanisms governing this step of development is especially crucial. This is the point at which a cluster of relatively indeterminate cells begins to differentiate into different parts of the body.

Sarah Norcross, director of the Progress Educational Trust, said: 'It is extremely rare for specimens of human embryos at this 16–19 day stage to become available to researchers. The fact that this is unlikely to happen again in the foreseeable future makes this study all the more precious, and adds to the case for extending the 14-day rule, so that early human development can be better understood through the study of embryos that have been cultured in the laboratory beyond 14 days.'

The work has provided a fuller picture of the path from stem cell to tissue type specification in humans. This enhanced understanding could inform treatment and diagnosis of developmental diseases and efforts to grow human tissues and organs outside the body.

The results have also revealed similarities between humans and model research organisms at this stage of embryogenesis. Dr Richard Tyser of the University of Oxford and first author of the paper said: 'Reassuringly, we have now been able to show that the mouse does model how a human develops at the molecular level. Such models were already providing valuable insights, but now this research can be further enriched by the fact we're able to cast light into that black box and more closely see how it works in humans.'

However, many differences remain between the mechanisms revealed by this work and those which take place in other animals. The findings highlight the importance of studying this step of embryogenesis in humans and the effect barriers to this may have on scientific progress.

Norcross concluded: 'If and when the 14-day rule is extended, this study will provide an invaluable reference point, so that similarities and differences between embryos cultured in vitro and in vivo can be better understood and taken into account. We have an opportunity here to open the "black box" of human development, study gastrulation and related processes, improve our understanding and treatment of disease, and perhaps improve our understanding of miscarriage and infertility as well. We should seize this opportunity.'

Others were keen to emphasise the importance and significance of the study too. 'The new study provides a Rosetta Stone for developmental biologists,' Dr Peter Rugg-Gunn, of the Babraham Institute, in Cambridge said who was not involved in the study. 'The new study is already yielding important new insights into how the early cell lineages are formed and positioned in the developing embryo... This information provides new leads to understand why these processes sometimes go wrong during pregnancy, which can result in developmental defects in some babies.'

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A genome-wide association study has identified three genetic variants associated with increased risk of polycystic ovary syndrome (PCOS) in Finnish and Estonian women. 

Two of these variants identified affect the CHEK2 gene. CHEK2 is a gene known to play a key role in cell quality control and the repair of damaged DNA that has also been linked to ovarian reserve and differences at age of menopause.

'This technique compares the genetic material (DNA) sequence in women with PCOS, for instance, to women without the condition and allows the identification of sequence changes which are more frequent in the group with the trait of interest,' said Dr Triin Laisk, associate professor at the Institute of Genomics at the University of Tartu in Estonia. 

Conducted by researchers at University of Tartu and the University of Oulu in Finland, the study analysed the genetic data of over 233,000 women. A total of 3609 PCOS cases were identified from national registers with all other 229,788 women designated controls. First a genome wide association study was carried out using data on 141,355 women from the FinnGen study, and then these findings were validated using a separate dataset of 92,042 women from the Estonian biobank. 

Published in the journal Human Reproduction, the findings included two causal variants in the CHEK2 gene and one on the MYO10X gene.

Previous research has discovered other genes associated with PCOS. The authors of this study believe however that using population-specific data could help provide further insights.

The Finnish population has a high number of genetic variants that occur at a low frequency across the rest of Europe, the authors note. The Estonian population is thought to be genetically closest to the Finnish population. 

'Due to differences in demographic history, the enrichment of some variants in Finnish and Estonian populations provided a unique opportunity to capture novel rare genetic variants associated with PCOS when focusing only on these populations,' said Natàlia Pujol Gualdo, PhD student and co-first author of the study.

'Further research is needed to explore the role of CHEK2 variation in PCOS and we hope this study serves as a base for further experiments that can clarify their interplay,' said Dr Laisk. 'At the same time, this study highlights the importance of population-specific biobank initiatives as unique means to seek into the genetic landscape of complex diseases'. 

It is not yet known whether these genetic variants will be found in other ethnic groups, but they contribute to our overall understanding of the genetic control of PCOS.

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