Rebecca Daley

Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate, and comprehensive approach

Accurate prenatal diagnosis of genetic conditions can be challenging and usually requires invasive testing. Here, we demonstrate the potential of next‐generation sequencing (NGS) for the analysis of cell‐free DNA in maternal blood to transform prenatal diagnosis of monogenic disorders.

Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol

BackgroundNon-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK’s National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials.Methods/DesignNIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down’s syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7–10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals.DiscussionThe results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice.NIHR Portfolio Number13865

Non-invasive prenatal testing for trisomy 21: a cross-sectional survey of service users' views and likely uptake

To assess the views and likely uptake of non‐invasive prenatal testing (NIPT) for trisomy 21 among potential service users in the UK.

Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down's syndrome into NHS maternity care: prospective cohort study in eight diverse maternity units.

Objective To investigate the benefits and costs of implementing non-invasive prenatal testing (NIPT) for Down’s syndrome into the NHS maternity care pathway. Design Prospective cohort study. Setting Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. Participants All pregnant women with a current Down’s syndrome risk on screening of at least 1/1000. Main outcome measures Outcomes were uptake of NIPT, number of cases of Down’s syndrome detected, invasive tests performed, and miscarriages avoided. Pregnancy outcomes and costs associated with implementation of NIPT, compared with current screening, were determined using study data on NIPT uptake and invasive testing in combination with national datasets. Results NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down’s syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. Of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. Of 71 pregnancies with a confirmed diagnosis of Down’s syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. In an annual screening population of 698 500, offering NIPT as a contingent test to women with a Down’s syndrome screening risk of at least 1/150 would increase detection by 195 (95% uncertainty interval −34 to 480) cases with 3368 (2279 to 4027) fewer invasive tests and 17 (7 to 30) fewer procedure related miscarriages, for a non-significant difference in total costs (£−46 000, £−1 802 000 to £2 661 000). The marginal cost of NIPT testing strategies versus current screening is very sensitive to NIPT costs; at a screening threshold of 1/150, NIPT would be cheaper than current screening if it cost less than £256. Lowering the risk threshold increases the number of Down’s syndrome cases detected and overall costs, while maintaining the reduction in invasive tests and procedure related miscarriages. Conclusions Implementation of NIPT as a contingent test within a public sector Down’s syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down’s syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting.

Non-invasive prenatal testing for Down syndrome

Prenatal screening and diagnosis of Down syndrome and other major aneuploidies may be transformed following the identification of cell-free fetal DNA in maternal plasma at the end of the last millennium. Next generation sequencing has enabled the development of tests that accurately predict the presence of fetal trisomies by analysis of cell-free DNA in maternal blood from as early as 10 weeks of gestation. These tests are now widely available in the commercial sector but are yet to be implemented in publicly led health services. In this article we discuss the technical, social, and ethical challenges that these new tests bring.

Non-invasive prenatal diagnosis: progress and potential

Non-invasive prenatal diagnosis and testing by analysis of cell-free DNA in the maternal circulation is a rapidly evolving field. Current clinical applications include fetal sex determination, fetal rhesus D determination, the diagnosis of some single gene disorders, and a highly accurate screening test for aneuploidies. In the future it is likely to be used for the diagnosis of an increasing range of monogenic disorders, and may even be used to profile entire fetal genomes. The introduction of these tests into clinical practice brings clear benefits but also poses several ethical, social and service delivery challenges. Here, we discuss the current clinical applications, discuss some of the technical and ethical challenges, and look to what the future might bring as technology continues to evolve.

Development and evaluation of training resources to prepare health professionals for counselling pregnant women about non-invasive prenatal testing for Down syndrome: a mixed methods study

BackgroundThe availability of non-invasive prenatal testing (NIPT) for aneuploidies is expanding rapidly throughout the world. Training health professionals to offer NIPT in a way that supports informed choice is essential for implementation. The aim of this study was to develop and evaluate a training package for health professionals to support the introduction of NIPT into clinical practice.MethodsTraining on NIPT was offered to health professionals, primarily midwives, involved in Down syndrome screening and testing in eight hospitals located in England and Scotland as part of a research study evaluating the implementation of NIPT in the UK National Health Service. Training was evaluated using a mixed methods approach that included quantitative questionnaires at three time points and post-training qualitative interviews. The questionnaires measured confidence, self-perceived knowledge and actual knowledge about NIPT for Down syndrome. Interviews explored opinions about the training and experiences of offering NIPT.ResultsThe training provided to the health professionals was found to positively impact on their confidence in discussing NIPT with women in their clinic, and both their perceived and actual knowledge and understanding of NIPT was improved. Knowledge remained weak in four areas; cell-free fetal DNA levels increase with gestation; turnaround time for NIPT results; cell-free fetal DNA is placental in origin; and NIPT false positive rate.ConclusionsTraining materials, including a lesson plan, PowerPoint presentation and written factsheet on NIPT, have been developed and evaluated for use in educating midwives and supporting the introduction of NIPT. Implementation of training should include a greater focus on the areas where knowledge remained low. Some groups of midwives will need additional training or support to optimise their confidence in discussing NIPT with women.

Time and travel costs incurred by women attending antenatal tests: A costing study

OBJECTIVE to estimate the costs to women, their friends and family for different antenatal tests in the Downs syndrome (DS) screening pathway. DESIGN questionnaire-based costing study. SETTING eight maternity clinics across the UK. PARTICIPANTS pregnant women (n=574) attending an appointment for DS screening, NIPT or invasive testing between December 2013 and September 2014. MEASUREMENTS using data collected from the questionnaires we calculated the total costs to women by multiplying the time spent at the hospital and travelling to and from it by the opportunity costs of the women and accompanying person and adding travel and childcare costs. Assumptions about the value of opportunity costs were tested in one-way sensitivity analyses. The main outcome measure was the mean cost to the women and friends/family for each test (DS screening, NIPT, and invasive testing). FINDINGS mean costs to women and their family/friend were £33.96 per visit, of which £22.47 were time costs, £9.15 were travel costs and £2.34 were childcare costs. Costs were lowest for NIPT (£22), £32 for DS screening (£44 if combined with NIPT), and highest for invasive testing (£60). Sensitivity analysis revealed that variations around the value of leisure time opportunity costs had the largest influence on the results. KEY CONCLUSIONS there are considerable costs to women, their friends and family when attending different tests in the DS screening pathway. IMPLICATIONS FOR PRACTICE when assessing the cost-effectiveness of changes to this pathway, costs to women should be considered.

Uptake, Outcomes, and Costs of Implementing Non-invasive Prenatal Testing for Down Syndrome Into NHS Maternity Care: Prospective Cohort Study in Eight Diverse Maternity Units EDITORIAL COMMENT

Noninvasive prenatal testing, also known as cell-free DNA (cfDNA) screening, is an efficient screening test for Down syndrome with roughly 99% sensitivity and false-positive rates of less than 0.1% in both high-risk and general populations. This study aimed to examine the potential costs and consequences of introducing cfDNA screening in the public sector Down syndrome screening pathway as an additional screening test dependent on the risk generated by current screening. The RAPID (Reliable, Accurate Prenatal, non-Invasive Diagnosis) research program was conducted in 8 NHS hospitals in the United Kingdom between 2013 and 2015. Pregnant women older than 16 years who accepted combined or quadruple testing with a later risk of at least 1/1000 were included in the cohort study. The outcomes were cfDNA screening uptake, number of invasive tests performed, number of Down syndrome–positive cases detected, and number of miscarriages associated with invasive testing. The pregnancy outcomes and costs related to cfDNA screening implementation, compared with present screening, were determined by data on cfDNA screening uptake and invasive testing combined with national datasets. Of 3175 women with an existing screening risk, 2494 women (78.6%) accepted cfDNA screening. Among 934 women with a risk of at least 1/150, 695 (74.4%) and 1799 (80.3%) of 2241womenwith a risk between 1/151 and 1/1000 opted for noninvasive prenatal testing. Among 42 pregnancies with confirmed positive cfDNA screening results for Down syndrome, 13 (31%)were continued. Approximately 18% of women with a standard screening risk of at least 1/150 chose invasive testing directly, among which 3 invasive tests failed (2%). A total of 29 pregnancies with Down syndrome were reported in this group, of which 2 (7%) continued and resulted in live births, which was significantly lower than the 13 (31%) of 42 who continued after abnormal cfDNA screening results (P = 0.003). The uptake of invasive testing before cfDNA screening availability was 54% in women with a risk of at least 1/150, and uptake of follow-on (combined cfDNA screening and invasive) testing in these women at high risk was 92.5%. The cfDNA screening uptake was expected to be 70.5% in women with lower screening risk (1/151 to 1/1000). Cell-free DNA screening use as a contingent test with a risk threshold of 1/150 with the direct invasive testing option led to a nonsignificant increase in the number of Down syndrome cases detected by 195 (95% uncertainty interval −34 to 480) while needing 3368 (2279 to 4027) fewer invasive tests and resulting in 17 (7–30) fewer procedure-related miscarriages for a nonsignificant reduction in overall total costs (−£46,000, −£1,802,000 to £2,661,000). At a screening threshold of 1/150, cfDNA screening would be cost neutral compared with present screening if the cost was £256 with direct invasive testing option and £316 without this option. Cell-free DNA screening costs must be decreased progressively to remain cost neutral as the threshold is reduced. The study concluded that cfDNA screening can be provided successfully at reasonable costs as part of a public sector Down syndrome screening pathway.

Authors' reply: Noninvasive prenatal testing for trisomy 21: when counselling is needed before responding to a survey

Sir, In our recent publication we presented the results of a cross-sectional survey with 1301 women and partners and showed that service users are very positive towards the introduction of noninvasive prenatal testing (NIPT) for trisomy 21 and that uptake is likely to be high, although a small proportion would prefer invasive testing. Sala et al. 2 suggest that pre-test counselling for survey participants would have resulted in a more accurate indication of test uptake. Nondirective pretest counselling is indeed essential to ensure that women aremaking informed decisions regarding prenatal testing for Down syndrome. Pretest counselling allows for the provision of accurate information about testing and the opportunity to deliberate the possible impact of test results. While the provision of pretest counselling to study participants would perhaps have meant a more accurate reflection of clinical practice, it would not have been feasible for this study in which 1301 participants completed the questionnaire. To do so would require substantially reducing the sample size and a subsequent loss of the information afforded by such a large study population. The study questionnaire provided a summary of the key features of each of the tests assessed that was purposely succinct and clear to ensure understanding by participants. This included a description of the test accuracy as >99%, which is in line with the most recent data. 3,4 Sala et al. indicate that omissions from the information provided about NIPT, including a description of the test as screening tool, test failure rates, time for results and costs, may have impacted on the resulting indication of test uptake. Given the hypothetical nature of the test described we did not feel that it was appropriate to go into specific details around timings and test failure rates, which may alter across test providers. Although it is possible that these more detailed additions to the description of NIPT may have altered women’s preferences, research has shown that test safety is the key overriding factor in women’s decisions about prenatal testing for Down syndrome and that other test attributes may not play as significant a role. As such, it is not surprising that uptake of NIPT was high (88% for women with a high screening risk in our study). With regards to informing survey participants about test costs, this surveywas to inform implementation of NIPT in an NHS clinical service. Hence, all costs would be covered by the state. Ultimately, the only way of getting reliable information on actual uptake is to offer NIPT within a clinical setting. We are currently evaluating NIPT in an NHS setting through five maternity hospitals across London and the south of England as part of the NIHR-funded RAPID (Reliable Accurate Prenatal non-Invasive Diagnosis) programme. Our data so far show high uptake rates, particularly for high-risk women (>1:150). Of the 146 women with a high-risk screening result who have been offered NIPT, 84% have had NIPT, 13% have gone straight for invasive testing and 3% have declined.&