Realising the promise of non-invasive prenatal testing

BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h1792 (Published 10 April 2015) Cite this as: BMJ 2015;350:h1792
  1. Lyn S Chitty, professor of genetics and fetal medicine1,
  2. Mark Kroese, consultant in public health medicine and programme director2
  1. 1UCL Institute of Child Health and Great Ormond Street NHS Foundation Trust, London WC1N 3BH, UK
  2. 2PHG Foundation, Cambridge CB1 8RN, UK
  1. Correspondence to: L S Chitty l.chitty{at}ucl.ac.uk

It should transform the quality of antenatal care

The presence in maternal plasma of cell-free fetal DNA, which is pregnancy specific1 and represents the whole of the fetal genome,2 offers enormous promise for the development of a wide range of prenatal genetic tests. Such tests require only a maternal blood sample rather than an invasive procedure that carries a risk of miscarriage. Several applications have already been approved for clinical use in the NHS. These have largely been based on the detection or exclusion of genetic changes in the fetus but not present in the mother (because they have been inherited from the father or arisen de novo at conception). Analysis of fetal sex from cell-free DNA can be used to guide invasive testing when the fetus is at risk of sex linked disorders,3 and several other tests are available for definitive prenatal diagnosis of some monogenic disorders.4 In parts of Europe, and hopefully soon in the United Kingdom, fetal RHD genotyping is routinely offered to Rhesus negative mothers to inform anti-D administration.5 However, it is the development of non-invasive testing for aneuploidy that stands to have the greatest impact on maternity care.

The first proof of principle studies, using next generation sequencing to detect Down’s syndrome by analysis of cell-free DNA in maternal blood, were published by academic units in 2008. Larger demonstration projects, led by industry, reported high sensitivities and specificities (98% and 99%, respectively) for detecting Down’s syndrome in high risk pregnancies and were followed by the commercial launch of non-invasive testing in Asia and the United States in 2011, and the UK in 2012. After unprecedented commercial development, non-invasive testing is now available in more than 60 countries,6 with the global market estimated to grow from around $0.22bn in 2012 to $3.62bn (£2.44bn; €3.3bn) by 2019.7 In the UK, outside of two research studies, non-invasive testing is available only in the private sector, the samples being sent to America or China for analysis. As in the US,8 there are reports of rates of invasive testing falling as those that can afford it opt for non-invasive testing. This includes women who would decline current screening and diagnosis because of the risk of miscarriage but will use non-invasive testing to prepare for the birth of an affected child.9 10

Barriers to NHS implementation

We are part of the UK team (www.rapid.nhs.uk) that is evaluating the requirements for implementing non-invasive testing as part of the NHS Down’s syndrome screening programme. Here, we highlight some of the challenges.

Non-invasive testing for aneuploidy is based on analysis of total cell-free DNA in maternal plasma, most of which comes from the mother, with fetal DNA emanating from the placenta. False positive results can therefore occur as a result of detection of abnormalities confined to the placenta or in the mother’s DNA. Furthermore, most evaluation studies have involved pregnancies at high risk based on screening using combinations of maternal age, serum biomarkers, and ultrasonography. National and international bodies therefore recommend that non-invasive testing for Down’s syndrome should be restricted to the high risk population and considered a highly sensitive screening test, with invasive testing required to confirmation an abnormal result.11 However, these views may change, because recently published results from the Ariosa group12 have shown non-invasive testing to have a positive predictive value of 80% in a large unselected population compared with 3.5% for the standard combined Down’s syndrome screening test.

Women and health professionals welcome non-invasive testing,9 13 but concerns have been raised that informed consent may be undermined if it is seen as “just a blood test” and becomes routine. Furthermore, women may face societal pressure to have a test that is safe and easy to do.10 These concerns may largely be overcome by careful pre-test and post-test counselling, but this will require education of health professionals and adequate provision for counselling.

Implementation in the NHS also has substantial implications for service provision. Should the test be developed in NHS laboratories or be outsourced to the commercial sector? As the requirement for invasive testing falls, will fetal medicine services need to be reconfigured to maintain skills, quality of care, and provide appropriate training? How should we manage the 1-6% of pregnancies in which non-invasive testing fails to give a result? The current cost of non-invasive testing is likely to prohibit it being used as a replacement for traditional screening in the NHS. Should we therefore offer it to high risk women as an intermediate test between traditional screening and invasive testing? If so, should we maintain the current risk cut-off of 1:150 and thus also maintain the current detection rate at around 85-90% of trisomy 21 cases or should we use a lower cut-off, which would mean we would offer non-invasive testing to more women but increase detection of Down’s syndrome?14 The National Screening Committee is responsible for decisions regarding the screening programme, and its recommendations are likely to depend on the optimum balance between reducing invasive tests and iatrogenic miscarriages, increasing detection, and the cost implications of the different implementation scenarios.

These are exciting times as technological advances enable transformation of prenatal diagnosis and screening based on cell-free fetal DNA. The challenges now are no longer technological but how to redesign maternity services to implement this innovative care. There is little doubt that we should encourage timely and clinically appropriate implementation for Down’s syndrome and other monogenic disorders. However, this must be accompanied by careful consideration of the developments needed in the care pathways and adequate education of both women and health professionals.


Cite this as: BMJ 2015;350:h1792


  • Competing interests: We have read and understood BMJ policy on declaration of interests and declare both authors are members of the RAPID research team funded by the NIHR through the Programme Grants for Applied Research (RP-PG-0707-10107). MK is vice-chair of NICE diagnostics advisory committee and is a public health adviser for the UK Genetics Testing Network. LSC has received funding for research from the International Society for Congenital Adrenal Hyperplasia and Oxford Gene Technology, and sequencing support from Illumina/Verinata for developing non-invasive prenatal tests and has received travel expenses from Ferris and Illumina to give lectures on the technology at educational meetings. The research funded is independent, and the views expressed in the paper are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

  • Provenance and peer review: Commissioned; not externally peer reviewed.


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