Making Pregnancy Safer
Non-Invasive Pre-Natal Testing (NIPT) is a screening blood test that uses next-generation sequencing to evaluate whether a pregnancy has a high chance of certain fetal chromosomal conditions. Until recently, the test has only been offered in the private sector in the UK, but there are now moves towards introducing it into the NHS. That’s why we have got together a panel of experts, to discuss the potential impact of this test, as well as explore some of the ethical considerations involved.
FLG: What is Non-Invasive Pre-Natal Testing (NIPT), and what benefits does it offer pregnant women?
Baskaran Thilaganathan: Cell-free DNA (cfDNA) in the maternal circulation is derived from both maternal and fetal (placental) cells. Where a fetus has a chromosomal condition such as an aneuploidy like Down’s syndrome, the fetal component of cfDNA in maternal blood will reflect the genetic diagnosis. NIPT is a screening blood test which uses NGS to evaluate cfDNA in the maternal circulation with enough accuracy (sensitivity and specificity both >99%) as to be able to determine whether a pregnancy has a high chance of certain fetal chromosomal conditions. Currently, women considered to be at a higher chance of having a baby with an aneuploidy are offered invasive prenatal diagnosis – which carries a procedure-related risk of miscarriage of about 1%. From later this year, these women will also have the option of a safe blood test to more precisely determine the risk in their pregnancy.
Catherine Joynson: NIPT can be used to test fetuses for genetic conditions from around nine weeks of pregnancy. The test involves taking a blood sample from a pregnant woman and analysing the placental cell-free DNA that is circulating. So far NIPT has mostly been used as a screening test for Down’s, Edwards’ and Patau’s syndromes. NIPT is more accurate than other screening tests for these conditions, such as the combined test. Some false positive results still occur, so an invasive test, such as amniocentesis, is required to obtain a definitive diagnosis. NIPT has a number of other advantages. Compared to invasive diagnostic tests, NIPT carries no risk of miscarriage, and it can provide earlier results than other screening and diagnostic tests.
Brenda Kelly: NIPT encompasses a number of different methods for analysis of cell-free DNA fragments in the plasma of pregnant women for the non-invasive detection of fetal genetic abnormalities. The development of NIPT for aneuploidy represents a paradigm shift in prenatal screening. In pregnancy, most of circulating cell-free DNA is maternal in origin but around 10%-20% of it comes from the placenta, which is, in the majority of cases, representative of the unborn baby (cell-free fetal DNA). The development of NIPT for aneuploidy represents a paradigm shift in prenatal screening. In pregnancy, most of circulating cell-free DNA is maternal in origin but around 10%-20% of it comes from the placenta, which is, in the majority of cases, representative of the unborn baby (cell-free fetal DNA). NIPT can be reliably performed on a maternal blood sample from around 10 weeks in pregnancy. DNA sequencing and counting allow the very precise determination of the proportion of chromosome 21 derived DNA fragments in maternal plasma as compared to a reference value. Signiﬁcantly more fragments than expected would suggest fetal aneuploidy.
FLG: What is the potential impact of NIPT technology being rolled out across the NHS?
BK: NIPT has until recently in the UK been only available in the private sector with women paying for testing themselves. Following prospective clinical trials such as RAPID (UK) and greater worldwide experience with NIPT, there are now moves towards introducing it into the NHS. At present, it is likely that NIPT will only be offered on the NHS to those women with a screen-positive result using conventional screening methods though this may yet change as the costs of sequencing continue to fall. Using the strategy of offering NIPT to screen-positive women, it is estimated that there would be 4,870 fewer invasive tests per year compared to current conventional screening alone. This represents improved patient safety and a reduction in iatrogenic miscarriage rate without excessive cost to the NHS (full cost-benefit analysis can be found on RAPID website).
Although the decline in invasive testing is one of the major successes of NIPT, there are some unintended consequences for service organisation, service delivery and training. Complication rates are inversely proportional to operator experience and procedural volume at any institution. Wider implementation of NIPT in the NHS may mandate centralisation of services to maintain operator expertise as well as competency and quality assurance in cytogenetic and molecular diagnostic laboratories. This may have implications for configuration of fetal medicine and clinical genetics services. Innovation in training will be also be required to ensure the next generation of specialists can obtain competencies in invasive techniques despite falling numbers of procedures.
BT: NIPT is a screening blood test which uses NGS to evaluate cfDNA in the maternal circulation with enough accuracy (sensitivity and specificity both >99%) as to be able to determine whether a pregnancy has a high chance of certain fetal chromosomal conditions. Currently, women considered to be at higher chance of having a baby with an aneuploidy are offered invasive prenatal diagnosis – which carries a procedure-related risk of miscarriage of about 1%. From later this year, these women will also have the option of NIPT to more precisely determine the chance of trisomy in their pregnancy, prior to deciding about invasive testing. The planned evaluative rollout of NIPT by Public Health England (PHE) has the potential of bringing safer pregnancy testing to the wider NHS with the clinical gain of reduced pregnancy losses from miscarriage and some cost-saving to the NHS at the same time. Infrequently do we see improved medical care being provided at cheaper cost – this is especially notable when considering that NIPT involves routinisation of NGS technology.
CJ: From late 2018, pregnant women who are found to have at least a 1 in 150 chance of their fetus having Down’s, Edwards’ or Patau’s syndrome after having the combined test will be offered NIPT in the NHS. Research suggests that this will increase prenatal diagnoses, giving more women the opportunity to prepare for a disabled child or have a termination. It is hoped it will also lower the number of invasive diagnostic tests, thereby reducing procedure-related miscarriages. Because NIPT is very accurate and involves only a blood test, there is a risk that women and couples will think it is equivalent to a diagnostic test, or that it is a routine part of prenatal care. It will be essential that women and couples are provided with accurate, balanced information to ensure they are able to make informed, genuine choices about screening. Public Health England is currently developing new patient information materials and specialist training for midwives as part of the roll-out.
FLG: The possible increase in terminations is a concern when dealing with this test. Do you think this concern is justified and what do you think could be done to mitigate it?
CJ: We don’t yet know whether offering NIPT in the NHS will lead to an increase in the number of women having terminations after a fetal diagnosis of Down’s, Edwards’ or Patau’s syndrome. If it does, some are worried there will be a reduction in the number of people born and living with these conditions in future, and that this will have negative consequences for those people and their families. Making NIPT available in the NHS also could be perceived as sending negative and harmful messages about the value of people with the syndromes being tested for. To help off-set these potential harms, the Government and others must ensure that disabled people are provided with high-quality specialist health and social care, and that discrimination and exclusion experienced by disabled people is properly tackled.
BK: I appreciate concerns from some rights groups that better sensitivity of prenatal screening will lead to more diagnoses and subsequent terminations of Down syndrome babies. The wider context of screening, however, also needs to be considered. Women who don’t want testing will continue not to have it, and those who want a test will be relieved to be offered an option which is safer, better, faster and carries no risk of miscarriage, unlike the existing CVS or amniocentesis tests. Additionally, it is important to look at the evidence to date relating to termination in the context of NIPT. Not all women with a confirmed positive NIPT result terminate their pregnancy. In the large study in the UK, approximately one-third of women in this situation chose to continue their pregnancy, suggesting that the high uptake of NIPT includes women who would like additional information to prepare and not necessarily for decision making about termination of pregnancy. Similar findings were reported in two regional US studies suggesting that NIPT has not affected the number of infants born with Down’s syndrome.
There are possible societal issues with greater uptake and further development of NIPT technology which I do think, as a profession, we ought to reflect on. Whilst pregnant women should be supported in their screening choices, improved prenatal screening and availability of termination for Trisomy 21 and other prenatally detected fetal anomalies may adversely influence attitudes to disability. With wider implementation of NIPT for T21, it is possible, counter to research findings above, that more terminations of affected babies do occur. I acknowledge concern that reduced numbers of individual’s with Down Syndrome in the community could lead to diminished social acceptance and fewer disability services- this is something we need to guard against.
BT: Women in the UK have full legal rights and freedoms’ relating to reproductive health – but that is not necessarily the case in other countries around the world. The Nuffield Council on Bioethics recently reviewed the role of NIPT and concluded that “women and couples should be able to access NIPT to enable them to find out, if they wish, whether their fetus has a significant medical condition or impairment” (http://nuffieldbioethics.org/project/non-invasive-prenatal-testing). The Nuffield report did raise the potential risk of increased number of terminations, but the proposed NHS clinical pathway is to only offer NIPT to women at higher chance of a fetal aneuploidy as an alternative to invasive prenatal diagnosis – not routine NIPT assessment to all women. As such, introduction of NIPT in this manner is very unlikely to result in increased terminations in the NHS – and this is our experience, as well as the finding of two other UK studies (Chitty LE et al. BMJ. 2016 and Gil MM et al. Ultrasound Obstet Gynecol. 2016).
FLG: However, there are independent bodies that have worked in conjunction with the healthcare community. What are the opportunities of working with these organisations, rather than against them?
BT: Women’s individual reproductive choices will necessarily revolve around accurate provision of information both about the diagnosis as well as the risks and benefits of various options. Here it is my personal opinion that no one organisation or community has the necessary experience or expertise to provide comprehensive support. I believe it is vital for these institutions and organisations to work together to help women make an informed choice for them and their families.
CJ: The Nuffield Council on Bioethics is an independent body that carried out an inquiry in 2016-2017 on the ethical issues raised by NIPT. The Council ran a number of consultation activities that provided opportunities to contribute. Valuable evidence and opinions were gathered from healthcare professionals, scientists, NIPT providers, interest groups and charities, people with genetic conditions and their families, and women who had recently undergone NIPT. We are always open to hearing from people with experience and views on the topics we are working on. We also have been contributing to the discussions of other organisations on these issues, such as the UK National Screening Committee, industry bodies, and religious organisations.
BK: Prenatal screening and diagnosis has focussed on Down syndrome largely because at the beginning of the prenatal screening era there was a recognised albeit crude, screening test (maternal age) and a diagnostic test (amniocentesis and karyotype). What sometimes gets overlooked in ethical discussions around NIPT for Trisomy 21 is that prenatal diagnosis did not set out to identify Down syndrome before birth because it was felt to be the most important condition rather that this was simply a condition for which prenatal screening and diagnosis was possible. I can understand the angst and anger from some quarters particularly disability rights groups that the continued emphasis and evolution of technologies to improve screening for T21 potentially adds to a public perception that T21 is a disease that must be awful if there is such comprehensive prenatal screening and ultimately, that must be “dealt with”. The reality, palatable or not, is that prenatal screening for T21 is set to continue and women considering NIPT screening must have access to balanced information to make an informed choice about whether or not to have the test and what to do in the event of if Trisomy 21 is subsequently confirmed.
I believe it is of utmost importance that national screening bodies and care providers continue to work closely with organisations such as the Down Syndrome Association to ensure that both health professionals offering the test and women considering T21 screening are fully informed about T21. I think it is fair to say that in the context of prenatal screening, pregnant women and their families are often presented with a medicalised discussion about T21 and the challenges a child and family might face without care providers necessarily offering information about the wider experience of what it is like to raise a child or live as an child or adult with T21. I think this omission represents a knowledge gap rather than intentional misleading of women. Working with such disability rights and other stakeholder groups to develop more balanced educational resources makes sense.
FLG: It has been reported that pregnant women haven’t received adequate support when having the test in a private setting. What needs to be done to ensure women are receiving the correct standard of care?
BK: I think there is an urgent need to develop more robust pretest education for all pregnant women and consistent post-test management recommendations for those with discordant test results. For the majority of women having NIPT for T21 screening, it will involve a single blood draw. I believe there is a risk of routinisation of NIPT, that it becomes “just another blood test” – where women have the test done simply because it is offered. Whether the test is offered in a private or public healthcare setting, women need to understand, amongst other things, what condition is being screened for, the nature of the test offered and importantly the limitations of the test (e.g. positive predictive value, test failures) to make an informed choice about screening in the first instance. Women and care providers alike need to appreciate the small but well-recognised false positive rate of NIPT- a screen-positive NIPT result does not equate to a diagnosis of T21, or other aneuploidy of interest, and that invasive testing should be offered.
As evident in other areas of medicine, it may prove difficult to create standards of care for private sector. With implementation planned in the public health care setting, robust guidance, audit of standards of care and education of care providers as well as users will be important.
BT: A common misconception is that paying for healthcare guarantees better healthcare. Whilst the majority of private practitioners provide an excellent level of medical care with the continuity of care that ensures good communication and trust, there is no doubt that they are sometimes let down by their colleagues. As in any walk of life where financial gain is bartered for services, unjustifiable compromises are made, where suboptimal provision of information and healthcare may result. Regulation of services has been proposed, but I believe that simpler recommendations for guidance may suffice – for example, only private clinics able to provide information on screening, invasive prenatal diagnostic tests and post-test counselling should be empowered to provide NIPT evaluations. Private clinics also can have little justification for ignoring ethical guidance provided by the Nuffield Council, especially with regards offering non-validated tests or routine fetal sexing.
CJ: Although there are examples of good practice, we think many NIPT manufacturers and clinics could do better in providing high quality information to their customers. We have produced guidance for providers of NIPT on the information they should provide on their websites and patient leaflets. This should include jargon-free information on the test performance, the possibility of a failed test, the need for follow-up testing to obtain a diagnosis, and the genetic conditions being tested for. We also recommend that private clinics should only offer NIPT as part of an inclusive package of care that should include pre- and post-test counselling and follow-up invasive diagnostic testing if required.
FLG: Right now, NIPT is used to test for Down’s syndrome, Edward’s syndrome and Patau’s syndrome. Could NIPT be used to test for a wider range of syndromes in the future?
CJ: NIPT can be used to test fetuses for some rare single-gene conditions, such as cystic fibrosis, achondroplasia and Apert syndrome. NIPT is diagnostic for these conditions and removes the need for invasive testing altogether, which is why it is often called non-invasive prenatal diagnosis or NIPD in these cases. NIPD for more single-gene conditions are likely to be developed in future. Some private providers offer NIPT for a range of other kinds of genetic conditions, such as sex chromosome disorders and microdeletion conditions. In some cases, the performance of NIPT for these conditions has not been well tested, and the rate of false positives is very high or unknown. In addition, some of the conditions being tested for are not considered to be particularly serious, such as triple X syndrome, raising a number of ethical concerns.
BK: Screening based on cell-free DNA is a direct measure of chromosome dosage (as opposed to indirect measures of proteins or hormones that comprise conventional screening for aneuploidy). Such is the pace of development that it is possible in the not too distant future that the entire fetal genome could be analysed.
New horizons are already opening up including prenatal screening and non-invasive testing of conditions which have an identified subchromosomal microdeletion or microduplication but hitherto, have not been routinely screened for. Those in favour of widening scope of of prenatal genetic screening argue that microdeletion conditions such as Cri du chat, De George Syndrome are associated with a far more severe phenotype than conditions such as T21 and are in addition, more prevalent than T21 in the younger population of pregnant women. A number of companies have already added other chromosome abnormalities, primarily microdeletions and sex chromosome aneuploidies, to their cell free DNA prenatal genetic screening panels. This is despite the fact that very little has been published on the clinical utility and validity of screening for these conditions. Of concern, the positive predictive value of screening for such chromosomal disorders is low when applied to an unselected or low risk population (e.g. those women who have a normal prenatal ultrasound). Thus apparent advances (“one blood draw-many conditions screened”) comes at a cost. With increasing numbers of disorders added to the panels, the false‐positive rates increase and the positive predictive value (PPV) of the test, taken as a whole, decreases. Critically, the poorer test performance of screening for subchromosomal disorders compared to T21, risks reversing gains made in reducing unnecessary invasive testing achieved with implementation of NIPT for aneuploidy. Offering expanded cell-free DNA screening to all may undermine rather than expand choice and parental autonomy. It inevitably introduces complexity into counselling and raises unrealistic expectations of genomic technology. Internationally, professional bodies such as ACOG, ESHG are advising against routine cfDNA screening for microdeletions and microduplications.
BT: The NGS technology used for testing fetal aneuploidy may, in principle, be extended to other chromosomal and genetic disorders. For de-novo fetal genetic problems, all that remains is validation of test accuracy in larger cohorts so that rates of clinical misdiagnosis are minimised. For inherited conditions where the mother may be a carrier, the margin of error for abnormal fetal cfDNA detection is significant. Here, additional advances in enrichment of fetal fraction or alternative DNA analysis technologies may be required to facilitate clinical utility.
FLG: How do you see NIPT progressing over the next ten years, within the UK, and across the rest of the world?
BT: NIPT represents the first large-scale routinisation of NGS technology in population healthcare. The diagnostic possibilities are boundless and there are massive economies of scale to be made with more widespread testing. What will limit the exploitation of this technology will be the costs of testing set by industrial giants balanced against the clinical challenges of providing balanced information to pregnant women and our community’s tolerance for such wider testing.
CJ: Whole genome sequencing of fetuses using NIPT has been carried out in a research setting, and it could be available for clinical use in the future. This could help genetics professionals to obtain a diagnosis for a fetus with a suspected genetic mutation as a kind of ‘scatter gun’ approach, and all by means of a blood test. However, some are worried about whole genome sequencing using NIPT becoming available more widely. Revealing information about the fetus that is of unknown or uncertain clinical significance could create unnecessary anxiety for women and couples, and lead more women to have invasive diagnostic procedures. It could also provide information about less serious medical conditions, adult-onset conditions, and non-medical traits. The future person that the fetus will become would be deprived of the opportunity to make their own decision about whether to undergo testing. We recommend that whole genome sequencing of fetuses should only be offered if there is a specific clinical need.
BK: The pace of development and speed of dissemination of NIPT across the world is unprecedented. This has been largely due to the huge investment in research, development and marketing by private companies. I believe NIPT will become the screening modality of choice for Trisomies 13, 18 and 21 over the next 10 years in the UK. Whether it is offered widely in other public healthcare settings internationally remains to be seen.
As assessment of the whole fetal genome becomes possible, the boundaries of what will be possible to screen for will expand. But such advances in technology present ethical challenges as well as opportunities. Should we be offering screening for conditions of highly variable phenotype or heritable conditions such as Huntingdon’s Disease? What about cancer and neuro-susceptibility genes? Or put more simply, when it comes to expanding prenatal screening scope: just because it can be done, does it mean we should do it?