The dos and don’ts of non-invasive prenatal testing

Dr Philippa BriceTuesday, 7 March 2017

Philippa provides strategic leadership and oversight for all external engagement and marketing, as well as insight and opinion on issues related to health policy.

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A new report from the Nuffield Council on Bioethics supports the use of a non-invasive prenatal testing (NIPT) technique recently approved for use as part of the NHS Fetal Anomaly Screening Programme in pregnancy, as well as setting out some concerns surrounding current commercial provision and potential future uses of testing.

The advantages of NIPT

Diagnostic testing for genetic and chromosomal conditions requires foetal DNA obtained via an invasive technique (amniocentesis or chorionic villus sampling) that carries a small risk of miscarriage. When screening suggests a foetus may have a genetic abnormality, many expectant mothers are reluctant to undergo testing because of the risk to the pregnancy. NIPT offers a much lower risk opportunity to obtain medical information from foetal DNA fragments in a maternal blood sample, notably abnormalities for which screening is normally offered to all pregnant women. These are forms of aneuploidy (abnormal chromosome number) of which Down’s Syndrome is the most common, and the least severe.

Trials have shown that NIPT performs better than standard screening tests on maternal blood samples, both among high-risk pregnant women and also in low-risk, unselected populations of pregnant women. Research (including an NHS pilot) has shown that offering NIPT in pregnancy is popular with women; produces modest increases in the number of cases of aneuploidy detected; produces significant decreases in the number of invasive tests performed; and small decreases in the numbers of miscarriages caused by invasive testing.

Ethical overview

The ethical, legal and social issues associated with NIPT were first reviewed by the PHG Foundation in 2009 as part of a wider report on the likely clinical impact of the technique. Now the Nuffield Council on Bioethics has conducted a fresh review of ethical, legal and regulatory issues surrounding NIPT with the aim not of impeding NIPT but to consider ‘how NIPT could change the way we view pregnancy, disability and difference, and what the wider consequences of its increasing use might be’.

Non-invasive prenatal testing: ethical issues has three broad conclusions:

1. Women and couples who wish to should be able to access NIPT to identify a significant medical condition or impairment in the fetus in an environment that enables them to make autonomous, informed choices, with steps taken to minimise the potential wider harms of NIPT.

2. NIPT should not normally be used to test whether a fetus has a ‘less significant’ medical condition or impairment or an adult-onset condition; to determine whether the fetus is the carrier of a gene for any kind of medical condition or impairment; or to reveal non-medical features of the fetus, including sex.

3. NIPT for whole genome or exome sequencing of fetuses normally should not be offered.

The majority view among pregnant women is that NIPT is a very good thing. In the current absence of widespread NHS availability, those that can afford commercial testing services are flocking to use them, and it is therefore reassuring that the report firmly recommends that women should continue to be able to access testing for ‘significant’ medical conditions in the foetus – which is, in fact, the purpose of the existing NHS foetal anomaly screening programme.

The spectre of genetic discrimination?

Concerns have been expressed that NIPT will lead to an increase in terminations of Down’s Syndrome pregnancies – not in fact observed in the NHS pilot, but a possibility given that around 95% of women currently opt for termination – and a decrease in support or even stigmatisation for patients and families. It is true that any decrease in the number of children born with Down’s syndrome could decrease the size and visibility of the Down’s syndrome community, in which case it would be important that the interests of those affected are not eroded.

Societal sticking points

Questions of what should and should not be tested for prenatally can easily lead to a form of displaced societal debate over what sort and severity of foetal impairment should be considered justification for termination, although there are valid personal and medical reasons for wishing to obtain information about foetal abnormalities ahead of birth other than the option to terminate a pregnancy. From a medical perspective the focus is always on causes of serious illness or disability, where early detection can help plan supportive medical care, prepare parents psychologically – or make termination of pregnancy feasible.

The report reflects that as NIPT can determine sex earlier in pregnancy than ultrasound screening, it makes it more feasible for parents to practice sex-selective termination of pregnancy, although illegal (except for in the case of sex-linked genetic disorders), and proposes a ban on the return of NIPT results for fetal sex on this basis.

Protecting informed and autonomous choice

The report outlines urgent concerns around whether women are able to make fully informed choices on the basis of accurate information about the reliability of NIPT. Whilst much more accurate than other forms of aneuploidy screening, NIPT is not perfect, and a definitive diagnosis continues to require invasive testing and analysis. The report says that not all commercial providers provide ‘accurate, balanced and nondirective information and support’ to an appropriate standard, leaving the NHS to ‘pick up the pieces’. Ensuring consistently good practice for NIPT in both the commercial and public sector will therefore be important.

The proposed ban on NIPT involving whole genome sequencing (WGS) or whole exome sequencing (WES) of foetuses is based around the capacity to predict medical outcomes on the basis of genomic information, which is highly variable. Sometimes, a clear prenatal medical diagnosis is feasible – though even then, the degree to which an individual would be affected cannot necessarily be predicted. The clinical impact of other genetic changes may not be known; geneticists generally take a very cautious approach (especially for prenatal testing) and feedback only results that are in their professional opinion definitely or highly likely to be associated with a significant medical condition.

The real problem here is not WGS or WES sequencing per se, but rather the analysis and interpretation of information produced by these mechanisms, and in determining which tests should be performed and which results should be returned. This issue just reinforces the need for consistent good practice from both NHS and commercial test providers, since the return of ambiguous information, the failure to make recipients aware of the limitations of testing, or the failure to provide suitable clinical and psychological support to clients could all have seriously adverse effects.