IVF News

Pregnancies resulting from frozen embryo transfers are at greater risk of complications related to high blood pressure, according to new research.

High blood pressure (hypertension) in pregnancy can have serious consequences for both the mother and the fetus and complications such as pre-eclampsia. Dr Sindre Petersen from the Norwegian University of Science and Technology, Trondheim, Norway presented the findings at the annual meeting of the European Society of Human Reproduction and Embryology.

'This study was by far the largest sibling analysis to date investigating the association between assisted reproduction treatments and hypertensive disorders in pregnancy,' said Dr Petersen. 'Our findings are important because the number of [frozen embryo transfers] is rapidly increasing throughout the world.'

The study, by the Committee of Nordic Assisted Reproductive Technology and Safety, used data from more than 4.5 million pregnancies across three Nordic countries between 1988 and 2015. Pregnancies that resulted from frozen embryo transfers had almost double the chance of hypertensive disorders compared to those resulting from natural conception or fresh embryo transfers.

To exclude parental factors, the researchers were able to repeat the finding in a smaller group of 33,000 women who had two or more pregnancies – comparing pregnancies from frozen embryo transfers with those from fresh transfers or natural conception in the same woman. Researchers have not yet addressed the potential impact of maternal age, as a frozen embryo transfer would be likely to follow a fresh or natural embryo transfer at a later date.

Dr Peterson pointed out that the findings must be balanced against the fact that frozen embryo transfers facilitate transferring one embryo at a time, reducing the number of multiple pregnancies which are associated with greater risk for mothers and babies.

'I am confident that a well-grounded and individualised decision of whether to go for a fresh or a frozen cycle can be made after dialogue between the clinician and the couple, just as in all clinical decision making,' he said.

Professor Abha Maheshwari, clinical director of the Aberdeen Fertility Centre and lead clinician at Fertility Scotland told BioNews: 'Hypertensive disorders in pregnancy don't just affect outcomes for mother and baby in that pregnancy but have long-term implications for the mother. Hence, we as a community, have to do everything to minimise the risks.'

Sources and References

• 6 July 2022. 38th annual meeting of the European Society of Human Reproduction and Embryology
  Frozen embryo transfers in IVF linked to greater risk of maternal hypertension in pregnancy

A large-scale study comparing two protocols for stimulating the ovaries in IVF has found that one has a lower risk of ovarian hyperstimulation syndrome (OHSS), a potentially serious complication of IVF treatment.

Ovarian stimulation is part of an IVF cycle – it allows multiple eggs to mature and be collected at once, rather than a single egg which is normally released during a natural cycle. In order to accomplish this, the natural ovulation cycle needs to be paused and two different protocols can be used – the 'long agonist protocol' or the newer 'short antagonist protocol'.

Dr Pedro Melo from the Tommy's National Centre for Miscarriage Research at the University of Birmingham presented results at the annual meeting of the European Society of Human Reproduction and Embryology comparing the protocols in terms of live birth rates achieved as well as risk of OHSS.

'We can now say with a good level of confidence that in patients with predicted high or normal response [to ovarian stimulation], using long protocols is unlikely to improve their live birth rates but will probably increase their risk of OHSS', he said.

OHSS is a common complication of IVF, affecting up to a third of patients. Symptoms include enlarged ovaries, abdominal pain and bloating, but in around one percent this condition can progress to a more severe form which can affect the circulation, lungs and kidneys and can occasionally be life threatening.

OHSS is known to be more likely in women who are predicted to have a normal or high response to ovarian stimulation, based on hormone levels and an ultrasound of the ovaries. For these women, the risk of OHSS was reduced by 52 percent, when the short protocol was used.

The findings come from a meta-analysis of 171 randomised trials, incorporating almost 37,000 patients carried out by the Cochrane group.

'This meta-analysis confirms what we have known for some time - the GnRH antagonist protocol is safer for women undergoing IVF, while being equally effective and more convenient for patients than the GnRH agonist protocol,' Dr Raj Mathur, chair of the British Fertility Society and consultant gynaecologist at Saint Mary's Hospital, Manchester told BioNews. He was not involved in the study. 'UK clinicians have been prompt in adopting this innovation, which combined with an altered trigger can significantly reduce the risk of OHSS.'

Sources and References

• 4 July 2022. 38th annual meeting of the European Society of Human Reproduction and Embryology
  Reducing the risk of ovarian hyperstimulation syndrome in IVF

Changes that occur to DNA that could cause IVF embryos to stop dividing have been identified.

During IVF only around 30 percent of human embryos make it to the blastocyst stage, meaning only a fraction of the eggs collected become viable embryos that can be transferred to the uterus. Some other species, such as mice, have much higher success rates and so it hasn't been clear what makes human embryos different. Scientists have now shown that DNA changes affecting gene expression and metabolism underlie in vitro embryo arrest.

Dr Andrew Hutchins of Southern University of Science and Technology, Shenzhen, China and corresponding author of the study said: 'Human embryos are surprisingly difficult to grow in vitro, which is a major problem for the treatment of human fertility. Our study indicates that several biological processes are causing the arrest; including epigenetic and metabolic problems in the embryos.'

The team, publishing their work in PLOS Biology, categorised arrested embryos in to three groups depending on which stage they stopped developing at. Type one embryos were those which exhibited problems with the expression of genes around the two to four-cell stages, and types two and three were marked by dysregulation of genes usually expressed at the eight-cell stage and beyond.

Type one embryos were unable to switch on their own gene expression and convert from gene expression usually found in an egg cell to that found in a zygote. Levels of chromosomal aneuploidy were not significantly different between arrested and non-arrested embryos, so the authors looked for other changes which could be behind this.

The paper describes how the scientists analysed histone methylation, the addition of a small chemical group to the proteins which fold and regulate chromosomes, in the embryos. They looked at the mechanisms of methylation and found that the process was dysregulated in the arrested embryos, providing an explanation for their disrupted gene expression.

Type two and three embryos appeared to arrest mostly due to changes in metabolism, which is important considering that, after implantation and before they receive a blood supply, embryos start off in a low oxygen environment. To see if they could correct this, the team treated some of the embryos with drugs which affect cells' metabolic balance. This partially rescued some of the embryos but authors said this required further investigation.

Dr Hutchins remarked: 'Our results indicate that many IVF embryos enter a senescent-like state, in which changes in metabolism and gene expression prevent developmental progression. It appears to be possible to overcome this arrested state for some embryos, but much more work will be needed to determine the best strategy for doing so.'

Sources and References

• 30 June 2022. PLOS Biology
  Metabolic and epigenetic dysfunctions underlie the arrest of in vitro fertilized human embryos in a senescent-like state

• 30 June 2022. Science Daily
  Developmentally arrested IVF embryos can be coaxed to divide

• 30 June 2022. New Scientist
  Why two-thirds of IVF embryos suddenly stop developing

The US Supreme Court has overturned the landmark Roe v Wade decision, which could affect the provision of IVF in some states.

The court's decision allows individual states to enact their own legislation regulating abortion before 22 weeks, raising questions about whether fertility treatments such as IVF will be impacted.

'IVF did not exist before Roe v Wade, so we are entering uncharted waters,' said Dr Kara Goldman, associate professor of obstetrics and gynaecology at Northwestern University, Illinois. 'In states where bills are being introduced defining a fetus as a person, or defining life as beginning at fertilisation, this could dramatically change the way in vitro fertilisation is practised.'

A cycle of IVF typically involves the creation of multiple embryos that will not all be used, and any legislation defining life at conception will impact the creation, storage, or destruction of these embryos. Concerns include whether physicians could be prosecuted when embryos fail to implant successfully, or if patients will be forced to pay to store unused embryos indefinitely rather than discarding them.

'We're hearing a lot of concern from patients,'  said David Stern, CEO of Boston IVF, who told Bloomberg that his clinic has received numerous calls in the last week from patients asking if they should move their frozen embryos to a 'safer' location.

Others argue that the impact on IVF will be minimal following the reversal of Roe. The authors of a Washington Post analysis outline that historically, many states have specifically exempted IVF in legislation restricting abortion; that there is little state regulation of the fertility industry as a whole; and that there is far more public support for IVF than for abortion in the USA, therefore they argue that is unlikely for IVF to banned or restricted.

However, even if it is unlikely that new legislation would specifically target IVF, the language in which laws are hurriedly written may not clearly exclude IVF, potentially leaving the fertility industry in a legal grey area, leaving patients and clinicians to navigate uncertainty.

The International Federation of Gynecology and Obstetrics (FIGO) and the European Society of Human Reproduction and Embryology (ESHRE) have both issued statements condemning the decision, with ESHRE specifically calling attention to how there could be a restrictive impact on IVF.

Sources and References

• 29/6/2022. FIGO

  As the US Supreme Court overturns Roe v Wade, global health care organisations call on all governments to defend access to safe and quality abortion care

• 25/6/2022. Washington Post

  Roe is gone. How will state abortion restrictions affect IVF and more?

• 30/6/2022. Northwestern University Feinberg School of Medicine 

  'I'm afraid for my IVF patients' after Roe v. Wade dismantling, fertility doctor says

• 29/6/2022. Bloomberg

  Abortion ruling clouds future for in vitro fertility patients

• 29/6/2022. CNN

  How could the Roe v. Wade reversal impact IVF embryos?

• 28/6/2022. European Society of Human Reproduction and Embryology

  ESHRE condemns US supreme court ruling on termination of pregnancy

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A UK widower has won the legal right to use the last remaining embryo that he made with his late wife in a landmark legal case.

Between 2013 and 2018, Ted Jennings and his wife Fern-Maria Choya underwent four rounds of IVF, producing embryos at a fertility clinic in London. After Choya's death in 2019, Jennings wished to use their last remaining frozen embryo to have a child via surrogacy, but because Choya had not provided written consent for posthumous surrogacy before her death, the Human Fertilisation and Embryology Authority (HFEA) could not approve the use of the embryo.

Mrs Justice Theis, ruling in the High Court of Justice, Family division, said that Choya '…had not been given relevant information and/or a sufficient opportunity to discuss it with the clinic,' with regards to posthumous surrogacy, and '…that if that opportunity had been given, that consent by that person would have been provided in writing'.

Due to the couples' experience with infertility, Jennings' and Choya's family both agreed that the outcome is what Choya would have wanted in the event of her death.

Jennings' lawyer, James Lawford Davies, a partner at Hill Dickinson law firm, said: 'I am delighted that the court has found in Ted's favour and that he can now proceed with surrogacy treatment. It was clear that this is what Fern would have wanted and this very thorough judgment allows her wishes to be respected'.

Justice Theis further concluded that the HFEA should review its consent forms with regards to a death of a partner and should clarify what the outcome would be for any remaining embryos.

This is the first case of posthumous surrogacy in the UK where the father has been granted legal permission to use any embryos made with his deceased partner's egg.

New research carried out by Ipsos and commissioned by the Progress Educational Trust (PET), the charity that publishes BioNews, investigated the opinion of UK adults on issues including posthumous conception. Sixty percent of respondents agreed that it should be permissible for a deceased person's frozen egg or sperm to be used by their partner to establish a pregnancy. Overall, the responses varied significantly in terms of age, gender or region but the '…support for posthumous conception was strongest when the person wishing to conceive was the husband, wife or partner of the deceased.'

Sources and References

• 22 June 2022. Guardian
  Widower wins right to have baby using embryo created with his late wife

• 23 June 2022. Metro
  Widower wins right to use embryo created with late wife to have a baby

• 23 June 2022. Independent
  Widower wins right to use embryo of late wife to have baby using surrogate

• 23 June 2022. Hill Dickenson
  High Court rules in favour of widower Ted Jennings in novel surrogacy application case

• 22 June 2022. Courts and Tribunals Judiciary
  Jennings -v- HFEA

• 22 June 2022. Progress Educational Trust
  Fertility, Genomics and Embryo Research: Public Attitudes and Understanding

• 22 June 2022. Ipsos
  Two-thirds of people believe the NHS should provide fertility treatment

Ovarian ageing in mice has been shown to be reversible using compounds that target fibrosis and promote mitochondrial health.

Scientists in Australia have discovered that as mice age they show increased levels of ovarian fibrosis, caused by mitochondrial dysfunction, inflammation, and excess collagen accumulation. In turn, these changes stiffen the architecture of the ovaries and impair ovulation – leading to reduced fertility. They suggest that this mechanism may explain why fertility in women can decline in their 30s, long before menopause.

'One challenge we faced was convincing our clinical colleagues that ovarian fibrosis (the excess inflammation and collagen) could actually be preventing egg release from ovaries' said study leader Professor Rebecca Robker from the University of Adelaide, Australia. 'Currently, clinical treatments for triggering ovulation in women involve administering very high doses of hormones to make the egg-containing follicles grow and mature, and the search for new therapies has been all about finding new hormones or treatment protocols to stimulate these follicles.'

The research, published in Science Advances, showed that fibrosis was already widespread in the ovaries of 12-month-old mice (corresponding to about 35 human years), which is considerably earlier than previously thought. Obese mice also had increased levels of ovarian fibrosis and exhibited a loss of fertility comparable to the aged mice.

The researchers found that using drugs to target ovarian fibrosis – including those that improve mitochondrial function and reduce inflammation – improved ovulation rates. This is the first study to identify non-hormonal methods to improve ovarian function, although the findings still need to be replicated in humans.

Reflecting on the results, Professor Robker said 'there is likely to be a treatment for ovarian fibrosis in the foreseeable future' but cautioned that a non-invasive way to diagnose ovarian fibrosis is needed to identify patients who could benefit.

'Women are increasingly wanting to have children later in their reproductive life, and enhancing the function of the ovaries at that time would be valuable,' commented Professor Richard Anderson from the MRC Centre for Reproductive Health at the University of Edinburgh, who was not involved in the study. 'There are lots of questions about whether this [research] might be relevant to women, but we do know that older human ovaries have more collagen, and that this can affect egg development in human ovaries as well as in mice.'

Sources and References

• 17 June 2022. Science Advances
  Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary

• 21 June 2022. Lifespan
  Targeting fibrosis reverses ovarian ageing in mice

• 21 June 2022. Bioworld
  Ovarian fibrosis-mediated ovulation failure is reversible: study

• 17 June 2022. Science
  Softening tough tissue in aging ovaries may help fight infertility

Discrepancies between public opinion and real-world access to fertility services in the UK have been highlighted by research commissioned by the Progress Educational Trust (PET).

Ipsos surveyed 2233 individuals and found that 67 percent of respondents supported access to fertility treatments, such as IVF, via the NHS. This is in contrast to the actual availability of these services, as many women under 40 are not offered the three cycles of IVF recommended by the National Institute for Care and Health Excellence. Often those seeking fertility treatments are instead subject to the 'postcode lottery', an economic and region-dependent barrier to access.

Speaking about the results of the survey, Sarah Norcross, director of PET, said: 'The commissioning of fertility services needs to catch up with public opinion. These survey results send a strong message to Government, NHS England and commissioning bodies to take action. Infertility is not a lifestyle choice nor a luxury, it is a recognised medical condition that impacts people's physical and mental well-being, affecting not just the individual or couple but their wider family.'

The research also provided more detailed insight into attitudes to fertility access, indicating that only 28 percent of respondents believed same-sex couples should have access to NHS-funded fertility treatment. This dropped to 19 percent when the prospective parent was transgender. Compared with support for access for infertile heterosexual couples (49 percent), this suggests a continuing bias towards traditional family structures.

The research discovered that 75 percent of respondents were willing to donate sperm or eggs in certain circumstances. Clare Ettinghausen, director of strategy and corporate affairs for the Human Fertilisation and Embryology Authority, said that 'whilst the use of donor eggs and sperm increased from 2019 to 2020, the number of donor registrations decreased during this period. It's therefore reassuring to see PET's findings which suggest that over half of men surveyed would consider donation.'

When it comes to editing the genomes of embryos in a treatment context, 53 percent of respondents agreed with this when the aim was to eliminate severe or life-threatening conditions (eg, cystic fibrosis). Although global outrage was sparked in 2018, by He Jiankui editing the genomes of babies in China, it is interesting to note that UK perceptions are still rather positive. However, PET says in its report that any future medical applications must be carried out 'in a scientifically and ethically rigorous way'.

The research comes at a time of likely policy reform in this area, with the upcoming Women's Health Strategy for England in the immediate term, and key pieces of UK legislation expected to be reviewed in the longer term.

The complete report is available online: Fertility, Genomics and Embryo Research: Public Attitudes and Understanding.

Sources and References

• 22 June 2022. Progress Educational Trust
  Not enough funding or sperm: the state of UK fertility treatment

• 22 June 2022. The Guardian
  Half in UK back genome editing to prevent severe diseases

• 22 June 2022. The Independent
  World's first IVF baby calls out 'postcode lottery' of care

• 22 June 2022. Medscape
  'Postcode Lottery' in NHS Infertility Treatment

• 22 June 2022. Progress Educational Trust
  Fertility, Genomics and Embryo Research: Public Attitudes and Understanding

• 22 June 2022. Ipsos
  Two-thirds of people believe the NHS should provide fertility treatment