Counselling that enables couples and donors to make informed decisions should underpin any genetic screening programme, both before and after testing. This was a central theme to emerge from this year’s annual conference of UK-based charity Progress Educational Trust (PET) which explored the impact of genomics on assisted conception and IVF.
Expanded carrier screening, PGT-A as an IVF add-on, polygenic testing, and genomics in relation to donor conception were the among themes discussed at the one-day event in London. The PET conference coincided with news of a controversy involving a donor with a cancer-causing gene. This case, where sperm from a man with a TP53 mutation had been used to conceive almost 200 children, was referenced by several speakers to illustrate the need for guidance on best practice around screening (1).
The rapid growth of genetic testing is creating new challenges for clinics and patients, and the programme began with the implications of expanded carrier screening (ECS). In her presentation, Heidi Mertes argued that just because you can do something, it does not mean you should.
A former chair of ESHRE’s ethics committee, Dr Mertes said the possibility of avoiding serious health conditions should not create a moral duty to rule out all genetic ‘defects’ in future offspring. Instead, a balance must be struck between reducing risk and accepting proportionate risk. If this is not achieved, screening can create needless worry, lead to discrimination, and steer couples towards IVF and PGT when they could have had healthy children naturally.
Dr Mertes added that difficult choices need to be made over gene panel size and type to avoid creating value judgements, especially around disability. Responsible implementation of ECS should involve patient counselling to allow would-be parents to make informed decisions and understand relative and absolute risk.
The next session focused on the ongoing controversy around PGT-A as an IVF add-on. ESHRE’s good practice recommendations discourage routine use of PGT-A because randomised controlled trials (RCTs) demonstrate a low evidence base for its effectiveness, as outlined by Professor Karen Sermon from the Vrije Universiteit Brussel (2).
An RCT for PGT-A is needed which is large and adequately powered with a broad patient population, she said. So far, RCTs based on PGT-A with trophectoderm biopsy have excluded mosaic embryos, an omission which Professor Sermon said a ‘good’ RCT should address with PGT-A on all embryos in the test population and transfer of not only euploid but also low/medium mosaic embryos.
Reasonable limits on screening were debated in the final session, sponsored by ESHRE, on donor conception and genomics. Stéphane Viville, from the University of Strasbourg, explained that clinics already screen donors for genetic conditions, although testing for recessive hereditary diseases varies widely.
Among the potential benefits of ECS is a reduction in the burden on healthcare of long-term conditions. Moreover, data from Australia shows testing is largely acceptable based on results from an ongoing research project where both couples and anonymous donors are offered free ECS (3). However, no test is perfect said Professor Viville who suggested that extensive screening would not have detected the cancer-causing gene in the case of the European sperm donor. Although essential, screening also raises ethical considerations, and goes too far when the aim is to achieve the perfect donor or where coercion is involved, according to Professor Viville. As such, his take-home message was that genetic counselling should be mandatory both pre and post testing.
The ethics of genetic screening was the focus for a talk by Michael Parker, Professor of Bioethics at the University of Oxford. He outlined a case where an egg donor had ticked a box not to be notified if it was discovered that she had a previously unsuspected genetic disease, or was a carrier of a harmful inherited condition. The child resulting from the donation was born with health problems, and the clinic involved was granted the right to contact the donor, many years after the donation, to seek her agreement to undergo genetic testing.
Professor Parker used this and other examples to underline the need for clinicians to develop ‘moral craft’ where they take responsibility for handling complex ethical situations. Communication and sharing of good practice are essential to develop the tools to assist in ethical and clinical judgements, he added.
Egg donation is central to mitochondrial replacement therapies (MRT) to prevent disorders that cause severe disability or death. A pioneering IVF technique, MRT is still novel and only legal in the UK and Australia. Dagan Wells presented evidence that suggests that the key methods – maternal spindle transfer (MST) and pronuclear transfer – successfully produce embryos with very low levels of the mother’s mitochondrial DNA, then implant and sustain a pregnancy to term. Reversal of disease risk remains a concern although all children born from MST have been shown to be healthy up to age 4 years.
What about using MRT to treat infertility? Pilot studies have been conducted into improving oocyte competence and Professor Wells said that carefully controlled trials are now needed to define the clinical value of MST for this application.
Privacy and informed consent may be the cornerstones of donor conception, but consumer DNA testing has effectively bypassed laws on confidentiality. Genetic genealogist Debbie Kennett said the ‘DNA’ in ‘DNA testing’ now meant ‘donors are not anonymous’ because children can identify donors on ancestry databases, even when the donor has not shared their details. All the child needs to do is identify a cousin or half-sibling to identify their biological parent said Ms Kennett, an honorary research associate at University College London.
This raises questions about the right to a private life. In her view, Ms Kennett said children born through donation did not consent to not knowing about their father. But they have the right to knowledge, not a relationship, and should not arrive on their donor’s doorstep ‘to cause trouble.’
The PET conference raised many profound questions such as what sort of society do people want to live in, how much information to give to patients, and what limits should be imposed on screening. What emerged is that experts are at a crossroads – as yet, they do not have many of the answers. This is where ESHRE and other societies have an important role to play in providing guidance including for policymakers, especially when the evidence does not back routine use.
Key messages on genetic testing
- The possibility of avoiding serious health conditions should not create a moral duty to rule out all genetic ‘defects’ in future offspring. A balance must be struck between reducing risk and accepting proportionate risk
- ESHRE’s good practice recommendations discourage routine use of PGT-A. Randomised controlled trials (RCTs) demonstrate a low evidence base for its effectiveness
- Coercion or achieving the ‘perfect’ donor are examples of when extended carrier screening (ECS) goes too far
- Genetic counselling should be mandatory both pre and post ECS
- Communication and sharing of good practice are essential to develop the tools to assist in ethical and clinical judgements in genetic screening
- Consumer DNA testing has effectively bypassed laws on confidentiality. Children can now identify their donors on ancestry databases, even when the donor has not shared their details.
References:
1 https://www.bbc.co.uk/news/articles/ckgmy90z991o
2 ESHRE Add-ons working group, K Lundin, J G Bentzen, G Bozdag, T Ebner, J Harper, N Le Clef, A Moffett, S Norcross, N P Polyzos, S Rautakallio-Hokkanen, I Sfontouris, K Sermon, N Vermeulen, A Pinborg, Good practice recommendations on add-ons in reproductive medicine, Human Reproduction, Volume 38, Issue 11, November 2023, Pages 2062–2104, https://doi.org/10.1093/humrep/dead184
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