Polygenic embryo screening – Patient perspectives and concerns

In order to select against specific genetic abnormalities in embryos, preimplantation genetic testing (PGT) can be used alongside IVF. Embryos can be genetically tested for a single-gene/monogenic disorder (with PGT-M) or structural chromosomal rearrangement (with PGT-SR), so as to avoid transferring an affected embryo into a womb. PGT has been possible for the last three decades, though laws and regulation surrounding embryo selection differ from country to country.

Unlike monogenic conditions, many health problems that people can face in their lives – such as type 1 or type 2 diabetes, or various cardiovascular diseases – are not the result of a mutation in a single gene. Rather, many genes can each have a small effect on the risk of developing these conditions. Likewise, many traits – for example, intelligence – are influenced by a large number of genetic variants. Using whole genome sequencing and genome-wide association studies, it is possible to calculate a polygenic risk score to reflect the chance that a person will develop a particular condition or trait compared to a reference population, based on a combination of small genetic effects.

Recently, the option of using polygenic risk scores to screen embryos for polygenic conditions – and possibly traits more broadly – has been introduced by some companies. This has been referred to as polygenic embryo screening, or PGT-P. Compared to PGT-M and PGT-SR, PGT-P cannot provide any certainty about avoiding a specific inherited genetic condition. Instead, PGT-P can only provide risk scores, in principle, for various conditions at once.

The development of PGT-P has led to many concerns (see BioNews 1130, 1137 and 1249). Various scientific organisations have indicated that PGT-P is not ready for clinical implementation. Furthermore, development of polygenic conditions depends not just on genetic, but also environmental factors, which polygenic risk scores do not capture.

Concerns have been raised about PGT-P's limited clinical utility and validity, and the relatively low potential for (absolute) risk reduction when selecting embryos based on polygenic risk scores. Furthermore, polygenic risk scores are calculated using genome-wide association studies consisting largely of people of European ancestry, meaning that the reliability of these scores may be (further) reduced when applied to people of other ancestries. There is also limited genetic variability among IVF embryos from the same parents, and a limited number of IVF embryos to choose from, and so PGT-P potentially complicates decision-making in relation to embryo selection.

Next to these scientific concerns, it is crucial to consider what the clinical implementation of PGT-P could mean for reproduction and for (prospective) parents. Polygenic embryo screening could impact perspectives and paths regarding reproductive decision-making, and these potential consequences need to be considered when discussing the ethics of PGT-P.

In light of this, we wanted to gather insights from how those with experience of IVF and PGT would feel about PGT-P, and we therefore performed a qualitative study interviewing 28 patients who opted for PGT-M or PGT-SR in Belgium (where PGT-P is not currently available). We recently published our findings in Reproductive Biomedicine Online.

These patients highlighted the difficulties of their experience with IVF plus PGT, describing medical, psychological as well as more practical complexities of undergoing both. They did not think it would be worth what they had gone through, solely for risk score information about embryos. Furthermore, concerns were raised about the probabilistic nature of PGT-P, and the fact that it cannot provide certainty to prospective parents.

Participants also indicated that having PGT-P as an 'add-on' to IVF could make the process and choices more complicated, and could limit the chances of success, if people are too scared to transfer an embryo with a certain risk score.

Participants were also worried that knowing the risk scores of one's future child could lead to anxiety and overprotection of the child's health, or to a false sense of security. Knowing such information 'doesn't necessarily make you happier,' as one participant said, and is associated with wanting to control the child's health. This control was largely seen as an illusion, and participants said that it is important to accept a certain sense of 'naturalness' in reproduction. They also expressed worries that knowing such information could have consequences for the future child, for example in relation to the parent-child relationship or with regard to insurance possibilities.

Another element to consider is what PGT-P would be offered for. In our study, participants were of the view that, if it were to be offered, it should only be offered for conditions deemed serious enough and it should not be used to screen for non-medical traits. Non-medical selection, and also broad genetic screening, were perceived as linked to a search for perfection and as being superficial. A participant expressed the view that such aspects should not matter if you want a child.

In that sense, patients who had used PGT-M or PGT-SR generally thought that if PGT-P were offered, it should only be offered to those who have a concrete reason to use it (for example, a family history of a specific polygenic condition) and with sufficiently large risk reductions possible, rather than used for the population at large or as an IVF 'add-on'.

Our results point to several ethical considerations and consequences of PGT-P, that should not be overlooked. In promoting technologies such as PGT-P, the real-life impact of undergoing fertility treatment and of genetic testing of embryos could be underestimated. The possibility of PGT-P could lead to prospective parents experiencing an additional sense of responsibility to do what is 'best' for their future child and to be a 'good parent', despite scientific concerns and the limitations of the technology.

Knowledge about polygenic risk scores might lead not only to information about the future child's health, but also to an illusion of control of this health, complicating dynamics within parent-child relationships and potentially leading to (insurance) discrimination against the future child.

Lastly, the aim of PGT-P may differ depending on what it is offered for and to whom, with broad and/or perfectionist screening on one side of the spectrum and more concrete familial screening on the other side.

While the described viewpoints are context-specific, and interest in PGT-P has been reported among IVF patients and broader populations, these patient perspectives and reflections are important to acknowledge. It is crucial to focus not just on scientific concerns about PGT-P, but also on potential consequences for those who could be impacted by the technology. The impact that PGT-P could have on ideas about key aspects of life – such as reproduction, parenthood and health – needs to be recognised and examined.