Alec McEwan

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.

HARVESTING FETAL CELLS FROM THE MATERNAL CIRCULATION

Schmorl is generally credited with being the first to report finding fetal cells in maternal blood. In 1893 he identified trophoblasts in the pulmonary circulation of women who had died of eclampsia. Years later, in 1969, Walnowska identified Y chromosomes in lymphocytes isolated from the blood of pregnant women carrying male fetuses and this was repeated by Herzenberg in 1979 in white blood cells recognised as fetal by their surface HLA-A2 expression. Other sporadic reports followed but not until the 1990s did investigation into harvesting fetal cells from maternal blood begin in earnest. The aim of this article is to review the progress made in isolating and analysing these cells for the purposes of prenatal diagnosis.

Pre-natal diagnosis of single gene disorders

Abstract More than 5000 human diseases are caused by mutations within single genes. In many cases, the genomic location of the affected gene is known and this usually allows some form of molecular testing to determine whether a disease-causing mutation has been inherited by a pregnancy. Indeed, the gene may have been studied in such detail that mutations may be relatively easy to recognize. There is no doubt that molecular biology has transformed pre-natal diagnosis. However, there remain a number of congenital abnormalities, syndromes and metabolic disorders where patterns of inheritance suggest a single gene defect but where identification of the gene responsible, or its mutations, has so far proved elusive. In these cases, alternative forms of pre-natal diagnosis are still required.

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.