IVF News

An in vitro gametogenesis (IVG) breakthrough has been achieved as mouse stem cells have been used to create egg cells that have successfully developed into live mice when used in IVF. 

A team led by Professor Katsuhiko Hayashi and Dr Takashi Yoshino at Kyushu University in Fukuoka, Japan, conducted the research which has allowed the development of mouse egg cells entirely in vitro. Previously the team had developed a process by which they could develop mouse egg cells from embryonic stem cells and induced pluripotent stem (iPS) cells by incubating them in ovarian follicular tissue taken from mice. This research represents the next step towards developing entirely in vitro-derived gametes. Their results, along with commentary, have been published in the journal Science. 

'It's a very serious piece of work,' Professor Richard Anderson, chair of clinical reproductive science at the University of Edinburgh, who was not involved in the study told STAT News. 'This group has done a lot of impressive things leading up to this, but this latest paper really completes the in vitro gametogenesis story by doing it in a completely stem-cell-derived way.'

In mammals, the ovarian follicle is essential for the differentiation of an initial germ cell that develops inside a female fetus into a mature egg in an adult female capable of being fertilised and developing into an embryo. The initial germ cell must undergo meiosis, which is made possible by the cell signalling induced by the environment found in the ovarian follicle. It has proved particularly difficult to achieve this process in vitro, but it is essential if gametes are to be produced in the lab outside of the body. 

To overcome this limitation the team placed mouse stem-cell-derived egg cells into conditions that mimicked those found in the ovarian follicle. Researchers observed that follicle-like structures were formed they named rOvaroids, in which meiosis was observed to take place in the oocyte, and when these mature eggs were used to create embryos with sperm using IVF, live births were observed for 5.2 percent of the embryos. All the live births resulted in mice that grew to adulthood. 

The team is currently looking at repeating the process in marmoset monkeys. Professor Hayashi told STAT News: 'The issue is the quality of the in-vitro oocyte. That could take a long, long time to verify.'

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Tuesday 20th July, 2021. 3PM EST/ 8PM GMT / 9PM CET  

Pride is more than a rainbow.

Moderators:
Dr. Dawn Kelk
Terry Schlenker 

Presenters:
“Whose Child Is This Anyway?” Bill Singer 
"No Such Thing as a Normal Family...Family Formations in Fertility Treatment" Venessa Smith 
"Pride is More Than a Flag, a Parade or a Campaign" Dr. Cindy Duke 
"Global Access To Surrogacy For Gay Couples " Francesca Steyn

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29 June 2020: Studies indicate that the optimal and safe number of oocytes needed for achieving an ongoing pregnancy is between six and 15. However, the use of egg freezing, frozen embryo replacement (FER) cycles and aggressive stimulation regimes has increased this number in order to boost success rates in older women and in poor responders who produce fewer eggs. What is not known is the impact of numbers of eggs retrieved and of over-stimulation practices on the health of patients, and on their emotional and financial well-being. 

Now, a retrospective observational study suggests that IVF clinics in the UK may be retrieving “far too many oocytes” and that most of them “may never be used and are probably discarded”. Details of the analysis are presented today online at the virtual Annual Meeting of ESHRE by Dr Gulam Bahadur from North Middlesex University Hospital, London, who said the results may well reflect global practices too.

The findings based on number of eggs extracted versus IVF cycles show that a total of more than 1.625 million eggs in the UK were retrieved from 147,274 women between 2015 and 2018. Although an average of 11 eggs was collected per patient, 16% of cycles were associated with 16-49 oocytes retrieved (per cycle) and 58 women each had over 50 eggs collected in a single egg retrieval procedure. 

“Our observations suggests that the high oocyte number per retrieval procedure needs re-evaluation,” says Bahadur. “In particular, this needs to focus on the side effects, including ovarian hyperstimulation syndrome and procedure-related complications, and on the fate of unused frozen oocytes and the costs associated with freezing them. 

“Patients should be advised that it’s better to collect fewer eggs leading to good quality embryos which may go to term and result in a healthy baby.”

This report is based on all UK IVF clinics and relates to non-donor fertility treatment carried out between 2015 and 2018 during which 172,341 fresh oocyte retrieval cycles took place. All outcomes and patterns remained uniform over the four years. 

The study showed that a sizable number (n = 10,148) of cycles did not yield any oocytes. 

More than half (53%) of all IVF cycles were in the desired egg yield range of 6-15. In addition, a quarter of cycles (n = 42,574) yielded 1-5 eggs; 14% (n = 23,794) produced 16-25; and a minority (2% or 3,970) resulted in 26-49 oocytes. The authors point out that multiple birth rates increase significantly from 6-15 oocytes onwards, which presents a risk to patients and babies such as birth complications and low birth weight. 

A total of 931,265 embryos resulted from all eggs retrieved – a fertilisation rate of 57%. Of the embryos created, more than one in five (22% or 209,080) were transferred into the uterus, while a slightly higher proportion (24% or 219, 563) were frozen. 

The fate of the unfertilised oocytes (43%) is unknown, but they are likely to have been discarded, as is normal practice. The authors say that most of the embryos not transferred (54%) will likely be discarded after patients have paid for several years of maintaining them in storage.

“This comes with a financial and emotional cost,” says Bahadur. “Patients build an attachment with this frozen material and there’s insufficient counselling to support them. They should be given more information about the implications of freezing eggs and embryos.”

Presentation 0-106, Tuesday 29 June 2021 
Non-donor IVF treatment cycles in the UK need to be re-evaluated against the 1.625 million oocytes retrieved 

Notes
1. All UK fertility clinics are legally obliged to provide IVF data as part of their licence agreement. 
2. Data used in this study was obtained from UK HFEA under the Freedom of Information Act 2000.
3. In the case of fresh oocytes, data was acquired for the number of cycles retrieving 1-5, 6-15, 16-25, 26-49, 50-59, and 60+ oocytes. 
4. Data on the maximum number of oocytes collected (50 and above) was not provided by the HFEA for technical reasons.

Tuesday 6th July, 2021. 3PM EST/ 8PM GMT / 9PM CET 

A mock quality management meeting from the fictitious fertility clinic "Awesome IVF".
A lively interactive session with a blend of recordings, discussion, and live "Q and A" with Giles Palmer, Dr.Kelly Tilleman, Dr. Alison Campbell, Jeanette MacKenzie, Debbie Venier, and Dr. Tony Anderson.

On the agenda:
Minutes of the Last Meeting
Non-Conformities, Incidents, and Root Cause Analysis
Document Control
Audit Schedule
New Staff Training
Regulatory/Inspections
Laboratory News

*Awesome IVF Staff: Giles Palmer (Chair), Dr. Kelly Tilleman, Venessa Smith, Shaista Sadruddin, Jeanette MacKenzie, Dr. Bill Venier, Debbie Venier, Dr. Marlane Angle, Dr. Denny Sakkas, Dr. Alex Varghese, Dr. Thomas (Rusty) Pool, Dr. Tony Anderson, Dr. Dean Morbeck, Dr. Alison Campbell, Anna McLaughlin, and Dr. Serena H Chen.

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Children born as a result of fertility treatment are no more likely to develop cancer than naturally conceived children, according to a new study.

Research from the Netherlands presented at the meeting of the European Society of Human Reproduction and Embryology 2021 showed no difference in cancer risk between children conceived by IVF, children conceived naturally by women with fertility issues and the general population. 

Dr Mandy Spaan from the Amsterdam University Medical Centre and Netherlands Cancer Institute described the findings as 'quite reassuring, especially for children conceived by IVF'.

The research looked at almost 100,000 children born to women who had been treated at IVF clinics in the Netherlands between 1983-2012. Roughly half of the children were born as a result of IVF, and the rest were conceived in vivo, either with or without ovarian stimulation. The children's health was followed for 17 years on average.

The children born following IVF did not have increased overall cancer risk compared to the group conceived naturally by subfertile women, nor compared to the general population. Of the participants followed into adulthood, no differences in cancer prevalence were observed.

The proportion of IVF cycles where ICSI and/or frozen embryo transfers take place has risen rapidly over the past few years, so when breaking down the data further, the researchers wanted to look at cancer risk in these two groups. They found no discernible differences in cancer risk between children born from fresh or frozen embryo transfers.

There was a small increase in the likelihood of cancer for children conceived using ICSI, but the authors warn that this was mostly due to four cases of melanoma, and that further research would be necessary to understand if this was a true association or down to chance.  

The authors were motivated to undertake the study by theories that early embryonic development could be influenced by the embryo's environment prior to implanting in the womb. The precise effects of freezing and thawing, different culture media and interventions such as ICSI could all potentially have an impact.

Dr Spaan has previously published results about ovarian cancer risk in women who have had IVF.

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Pre-eclampsia and high blood pressure in pregnancy may be linked to the way the uterus is prepared before frozen embryos are transferred.

Research presented at the meeting of the European Society of Human Reproduction and Embryology 2021 showed that pregnancies, where the uterus is primed with hormone therapy before a frozen embryo is transferred, have higher rates of hospitalisation from vascular problems. 

Dr Sylvie Epelboin from the Hôpital Bichat-Claude Bernard in Paris, France presented the research which was carried out on behalf of the French Biomedicine Agency.

This was the first large-scale trial to look into the correlation between the method of endometrial preparation and high blood pressure in pregnancy, although other studies have reported that rates of pre-eclampsia are higher in pregnancies resulting from frozen embryo transfers compared to fresh embryo transfers or natural conception. 

The study looked at records of almost 70,000 single-baby IVF pregnancies between 2013 and 2018, of which around 20,000 were from frozen embryo transfers. None of the pregnant women had a history of high blood pressure. 

The researchers further stratified the patients into those who had received hormone stimulation to prepare the uterus for the embryo to implant (AC-FET: artificial cycle frozen embryo transfer) and those whose natural cycle was used (OC-FET: ovulatory cycle frozen embryo transfer). There were around 10,000 pregnancies in each group.

The study showed that risk of pre-eclampsia and other blood pressure related problems was very similar in the fresh embryo transfer and the OC-FET groups, but significantly higher in the AC-FET group. 

According to Dr Epelboin, there are two possible reasons for this discrepancy: one is that the high and prolonged doses of artificial hormones administered in AC-FET could have a role in increasing the risk of high blood pressure. The other possibility she discussed is that the corpus luteum suggested that it could have a protective effect against vascular problems in pregnancy. The corpus luteum is a group of cells left behind after each ovulation that produce hormones that naturally help establish and maintain pregnancy, and would be present in natural conception, fresh embryo transfers and OC-FET.

Dr Epelboin recommended that OC-FET should be preferred as a first-line protocol where possible as there does not appear to be a difference in pregnancy rates in frozen embryo transfers using the natural ovulatory cycle or hormone replacement.

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A mouse embryo has been developed artificially in a lab from embryonic stem cells that represents the most sophisticated in vitro mammalian model ever created.

Using embryonic stem cells collected from mice, scientists from the University of Virginia have been able to produce a mouse embryo with a beating heart. Muscles, blood vessels, the digestive tract and the nervous system, with the formation of a neural tube, also starting to develop. They achieved this by discovering a way to instruct a group of cells to begin embryonic development. In response to this instruction the cells have developed into embryo-like structures in a process that mirrors embryo growth.

Professor Christine Thisse, who created the model alongside Professor Bernard Thisse, explained: 'We found a way to instruct aggregates of stem cells to initiate embryonic development. In response to this controlled instruction, the aggregates develop into embryo-like entities in a process that recapitulate the embryonic steps one-by-one.' Professor Bernard Thisse added: 'The only way to have all the variety of cells necessary to the formation of functional organs is to develop systems in which all precursor cells are present. The embryo-like entities we have engineered using stem cells are providing just this.'

It is the first in vitro model of a mammalian embryo with so many tissues to be built from stem cells, the researchers claim. Most importantly, those tissues are organised as they should be, around the notochord – the precursor of the vertebral column (spine) – a defining trait of vertebrate animals.

There has been a significant effort in recent years to replicate mammalian embryonic development in the lab. So far, scientists have only been able to produce multicellular structures which mimic parts of organs, known as organoids, from stem cells.

While these organoids are able to mimic the microanatomy of organs, they lack the organisation and full variety of cell types of genuine organs. To obtain this higher level of organisation the organ requires blood vessels and nerves, and needs to contain the full spectrum of cells and tissues.

'Having all the variety of tissues made allows us to hope that the scientific community will be able to build organs with a proper vascularisation, innervation and interactions with other tissues,' said Professor Christine Thisse. 'This is essential to be able one day to produce functional human replacement organs in a dish. This would overcome the shortage of organs for transplants.'

However, this new model is unable to develop into a complete mouse. 'The embryoids we are currently producing lack the anterior brain domains,' Professor Bernard Thisse explained. The development stops at a time corresponding to the middle period of gestation of a mouse embryo. He continued: '... with the techniques we have developed, we should be able, at some point, to manipulate molecular signals that control embryo formation, and this should lead to generating embryo-like entities containing all tissues and organs including the anterior brain.'

The researchers hope that their breakthrough will assist researchers to further understand mammalian development.

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Fertility patients who have recovered from COVID-19 have the same chance of conceiving that they did before they were infected, according to a small study. 

The research, presented at the meeting of the European Society of Human Reproduction and Embryology 2021 looked at levels of anti-Mullerian hormone (AMH) as a marker for ovarian reserve. AMH is widely used to predict how patients are likely to respond to ovarian stimulation as part of IVF treatment. Patients who had recovered from COVID-19 had their AMH levels re-measured and compared to their results from before they became infected.

'The data showed no variation in AMH levels before and after SARS-CoV-2 infection, and we could assume that the chances of success in their fertility treatment remained intact,' said Dr Maria Cruz Palomino from IVI Madrid in Spain, who presented the research.

The study classified the 36 patients according to their AMH levels as likely to be low responders (AMH levels of 1ng/ml of blood or less) to ovarian stimulation or normal responders (greater than 1ng/ml). In samples taken less than six months later – after the patients had COVID-19 – those in the normal responder group showed on average a decrease in AMH levels, but not enough to reclassify any individuals as low responders. In the low responder group, the values before and after infection were very similar.

Dr Palomino cautioned that the decrease in AMH levels in the normal responders could not necessarily be attributed to coronavirus infection and that for all the patients involved 'we could assume that the chances of success of fertility treatment remain intact.'

The researchers wanted to investigate the effect of COVID-19 on ovarian reserve because the ACE2 receptor, which the SARS-CoV-2 virus uses to invade host cells, is widely expressed in ovarian tissue, and throughout the female reproductive system. As such, there was concern that infection with the virus could disrupt fertility.

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Germline cells seem to reset their biological clocks around the time of embryo implantation, not when generating gametes, as previously thought.

Scientists measured an increase in genetic damage in embryonic cells during the early stages of embryogenesis in mice before undergoing a total reset within a 'rejuvenation period', reversing any cell damage.

'This study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal ageing,' wrote the researchers from Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts.

Previously, it was thought that, unlike the somatic cells which form our bodies, germline cells – which differentiate into either sperm or eggs – were ageless and did not inherit genetic damage from their parent organisms. However, recent research has shown that germline cells do age and display hallmarks of genetic damage. Yet, babies do not inherit their parents' age, and start again from zero.

The team employed machine-learning algorithms as 'ageing clocks' to calculate the ages of human and mouse embryonic tissue by measuring the prevalence of methylation – an epigenetic marker. These markers accumulate with age on certain sections of DNA and are influenced by environmental factors. Although these markers do not affect the DNA sequence, they can alter the way a gene is expressed and modify proteins produced.

Genetic data sets collected from mouse embryos during different stages of embryonic development were analysed by these epigenetic ageing clocks. Data sets recorded from mouse embryos following fertilisation showed increased epigenetic ageing with time during the first six days of cell division. But, during its implantation within the uterus wall, the embryonic cells displayed a decrease in epigenetic damage, characteristic of a reversal in ageing. 

The team were unable to perform the same experiment in human embryos but were able to compare methylation in human induced pluripotent stem cells and embryonic stem cell lines and datasets detailing methylation in human fetal tissue samples and see that a similar reset appeared to have occurred. 

The findings, published in the journal Science Advances, have wide-reaching implications for aiding the treatment of age-related illnesses such as Alzheimer's and Parkinson's disease. These diseases feature cells with accelerated epigenetic ageing and through a greater understanding of these biological reset mechanisms, it is thought that epigenetic damage to these cells could be reversed. However, achieving this in practice may be challenging since knowledge of other causes of cellular ageing is needed. 

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