Lawfully running a red light: aneuploidy testing

In a recent press statement on the use of preimplantation genetic testing (PGT) of human embryos, the Human Fertilisation and Embryology Authority (HFEA) stated that 'Embryo selection is only legal in the UK to avoid serious inherited illnesses, usually by means of pre-implantation genetic diagnosis authorised by the HFEA, known as PGT-M or PGT-SR.' This drab, jargon-loaded declaration, which the HFEA has yet to clarify, is more remarkable than it seems, and may not be correct.

Here are four recognised types of PGT:

• PGT-A: testing for aneuploidy embryos (those with an abnormal number of chromosomes). Aneuploidy is a major cause of failed implantation for pregnancy, miscarriage and of birth defects in children, though the benefits of PGT-A are unknown and the focus of some debate (see BioNews 1123).

• PGT-M: testing for monogenic (single gene) conditions that one (or both) of the parents is known to carry.

• PGT-SR: testing for structural rearrangements of chromosomes, such as deleted, duplicated or inverted segments. Embryos affected by structural rearrangements are less likely to result in a live birth.

• PGT-P: calculating a polygenic risk score to predict the likelihood of the child resulting from the embryo being at risk of complex diseases. This is not permitted in the UK.

The HFEA's press statement came in response to widely reported warnings issued in relation to polygenic risk scores used for preimplantation testing (see BioNews 1130), by the European Society of Human Genetics (ESHG), which described them as unproven and unethical in a paper in the European Journal of Human Genetics last year. It is clear that this type of PGT, PGT-P, is unlawful in the UK but the implications of the HFEA's declaration for the three other types of PGT is ambiguous.

Legal background

The Human Fertilisation and Embryology Act 1990 (the 'Act') provides that embryos known to have a gene, chromosome or mitochondrion abnormality involving a significant risk that a person with the abnormality will have or develop a serious physical or mental disability, illness, or other serious medical condition, must not be selected in favour of embryos not known to have such abnormality. Selection therefore requires adequate and relative knowledge about candidate embryos, which requires reliable testing. According to the HFEA's statement, two tests are permitted – PGT-M and PGT-SR. The most recent edition of the HFEA's Code of Practice (the 'Code'), published last October, devotes a chapter to the licence conditions required for conducting PGT-M and PGT-SR. Single gene variants tested for by PGT-M are obviously heritable, and the structural rearrangements identified by PGT-SR may also be inherited. Notably, the HFEA's press release claims that their use is limited to the avoidance of 'serious illness', which it says must be hereditable.

This is quite an assertion, because the Act does not require illnesses to be 'inherited'. Indeed, the risk of 'serious illness' is not the only condition to be selected against. Embryos having a significant risk of developing into a person with a 'serious physical or mental disability' or other 'serious medical condition' must also not be preferred whether or not those disabilities, conditions or illnesses are heritable.

However, the HFEA has not modified its declaration despite a request for clarification at a recent Progress Educational Trust event and similar pleas from others about the third testing type – PGT-A, in which the polar body or one or more cells obtained from the embryo by biopsy are analysed for an abnormal number of chromosomes. The Code states that 'embryos with an abnormal number of chromosomes [...] have less chance of developing into a baby or, less commonly, may result in a baby being born with a genetic condition....' So, unless the HFEA statement is claiming that a 'genetic condition' arising from a change in chromosome number may be 'inherited', the inference of the HFEA's declaration is that PGT-A is now illegal, on the basis that, say, trisomy 21 is not a 'serious inherited illness'. Well, it isn't, but this is not the correct legal test.

Indeed, the Code explicitly permits PGT-A, stating that 'An embryo may be tested using [...] (PGT-A) [...] and [...] (PGT-M) and [...] (PGT-SR) [...] where the requirements for each have been satisfied before testing is carried out' and dedicates an entire chapter to PGT-A licence conditions. Plainly, PGT-A cannot be both legal and illegal so, in the absence of clarification from the Authority, which is it?

The likelihood is that the HFEA would justify its statement that 'embryo selection is only legal in the UK to avoid serious inherited illnesses' on the basis that, following the advice of its Scientific and Clinical Advances Advisory Committee, it put PGT-A on its 'red list' in October. This sits awkwardly with the fact that the PGT-A chapter of the Code was published in the same month, but it does raise a serious issue.

HFEA traffic light system and certification

The HFEA 'red lights' an add-on 'where there is no evidence [from randomised control trials] to show that it is effective.' The traffic light scheme, reflects a 2019 Consensus Statement by the HFEA and a number of important professional organisations.

First generation PGT‐A took cells and polar bodies from cleavage‐stage embryos, then analysed them genetically using FISH probes. Evidence published in a Cochrane Review in 2020 showed this to be ineffective, leading to more recent approaches that take biopsies at other stages of development and use different means of genetic analysis. Irrespective of any traffic light, tests put into service must be certified as conforming to applicable standards as an in vitro diagnostic medical device (IVD). Tests which could be used off-label, but are not marketed as such should be marked 'this kit is NOT intended to be used for the risk evaluation of trisomy 21'. Subject to the exception discussed below, a person putting into service a test that is not certified will be committing a criminal offence.

This should not come as a surprise to the HFEA, whose Code of Practice requires devices such as culture media to be certified as Class III medical devices. The rationale applicable to culture media, namely the need to protect the 'safety of the gamete, of the embryo, or of the mother-to-be' applies equally to embryo testing. This is reflected in the new EU IVD Regulation (IVDR), which classifies devices that are used to screen for congenital disorders as Class C IVDs. How this might be reflected in UK law in coming months and years remains unclear, but a radical departure from the IVDR seems unlikely.

If a PGT device is not certified for use, it cannot be placed on the market, and targeting an HFEA-approved and green-lit monogenic condition does not make marketing the device lawful. The specific exception to this is when a clinic chooses to put laboratory equipment to use as a test. In this case, the clinic will be deemed to be the manufacturer of the device. If only used in-house, marketing regulations become largely irrelevant, so it's not inappropriate for the HFEA to maintain standards using its powers as a licensing authority.

However, if a test has been certified, its manufacturer might challenge an HFEA decision to red light its use, given that the test has already been found compliant with applicable regulation and, in particular, that its claims to efficacy have been validated. The HFEA would be wise, therefore, to reflect standards applicable under the UK's two IVD regimes (the IVDR and forthcoming GB regulations), and to work with the Medicines and Healthcare products Regulatory Agency and the European Commission so as to develop such standards. A good starting point is the IVDR's requirement for those relying on the in-house exemption to declare their tests to have met agreed general safety and performance requirements and, if not, to justify the departure.

So, is the HFEA's statement correct? Not quite. The PGT-A red light is not an absolute prohibition. As the HFEA remarks, 'For specific patient groups there may be reasons for the use of a treatment add-on other than improving your chances of having a baby. In these situations, it may be appropriate for you to be offered a treatment add-on as part of your treatment and not in a research setting.' In other words, clinicians still have the discretion to use PGT-A where they deem it appropriate, with no obvious need to explain such use. In any event, many would find it helpful if the HFEA were to clarify its statement.