Optimizing Fetal Aneuploidy Screening in an Austere Military Clinical Environment: A Prenatal Cost Comparison.

INTRODUCTION: Austere clinical settings, including remote military installations, face unique challenges in screening pregnant women for aneuploidy. The objective of this study was to compare the direct and indirect prenatal costs of traditional 2-part serum-based screening to cell-free DNA (cfDNA) for detection of trisomies 18 and 21 for a military treatment facility with limited in-house perinatal resources. MATERIALS AND METHODS: We identified Naval Hospital Guantanamo Bay as a surrogate for an austere clinical environment. A prenatal cost of care analysis incorporating direct and indirect expenses was performed to compare the 2 aneuploidy screening strategies for a theoretical cohort of 100 patients for detection of trisomies 18 and 21. The baseline aneuploidy uptake rate was determined using a historical cohort. Test performance characteristics were obtained from the contracting laboratory. Aneuploidy rates and costs were calculated using previously published data. RESULTS: Assuming a baseline screen uptake rate of 87%, initial screening using the traditional approach would directly cost $8,285.01 versus $44,140.32 with cfDNA. Considering indirect costs such as travel, consultative services, evaluation and follow-up testing of an abnormal screen result, and lost productivity, the cost difference narrows to $14,458.25 over a 5- to 6-year period. Cost equivalence is achieved when cfDNA is priced at $341.17 per test. CONCLUSION: Cell-free DNA as an initial screening strategy offers enhanced detection rates for trisomies 18 and 21 but remains more costly than traditional screening when incorporating direct and indirect expenses. In a low volume setting with limited resources, the added cost may be justified given the implications of unrecognized aneuploidy.

A Sensitive and Cost-Effective Chemiluminescence ELISA for Measurement of Amyloid-ß 1-42 Peptide in Human Plasma.

BACKGROUND: Amyloid-ß42 (Aß42) is associated with plaque formation in the brain of patients with Alzheimer's disease (AD). Studies have suggested the potential utility of plasma Aß42 levels in the diagnosis, and in longitudinal study of AD pathology. Conventional ELISAs are used to measure Aß42 levels in plasma but are not sensitive enough to quantitate low levels. Although ultrasensitive assays like single molecule array or immunoprecipitation-mass spectrometry have been developed to quantitate plasma Aß42 levels, the high cost of instruments and reagents limit their use. OBJECTIVE: We hypothesized that a sensitive and cost-effective chemiluminescence (CL) immunoassay could be developed to detect low Aß42 levels in human plasma. METHODS: We developed a sandwich ELISA using high affinity rabbit monoclonal antibody specific to Aß42. The sensitivity of the assay was increased using CL substrate to quantitate low levels of Aß42 in plasma. We examined the levels in plasma from 13 AD, 25 Down syndrome (DS), and 50 elderly controls. RESULTS: The measurement range of the assay was 0.25 to 500 pg/ml. The limit of detection was 1 pg/ml. All AD, DS, and 45 of 50 control plasma showed measurable Aß42 levels. CONCLUSION: This assay detects low levels of Aß42 in plasma and does not need any expensive equipment or reagents. It offers a preferred alternative to ultrasensitive assays. Since the antibodies, peptide, and substrate are commercially available, the assay is well suited for academic or diagnostic laboratories, and has a potential for the diagnosis of AD or in clinical trials.

The value of non-invasive prenatal testing: preferences of Canadian pregnant women, their partners, and health professionals regarding NIPT use and access.

BACKGROUND: Canadian policies regarding the implementation and public coverage of non-invasive prenatal testing (NIPT) are heterogeneous and shifting, with NIPT being publicly covered for high-risk pregnancies in some provinces, but not others. Such a diverse and evolving policy landscape provides fertile ground for examining the preferences of pregnant women, their partners, and health professionals regarding the implementation and coverage of NIPT by the public healthcare system, as well as the factors influencing their preferences, which is what the present study does. METHODS: In this paper, we report the results of three-large scale Canadian surveys, in which 882 pregnant women, 395 partners of pregnant women, and 184 healthcare professionals participated. RESULTS: The paper focuses on preferences regarding how and when NIPT should be used, as well as the factors influencing these preferences, and how coverage for NIPT should be provided. These are correlated with respondents' levels of knowledge about Down syndrome and testing technologies and with their stated intended use of NIPT results. CONCLUSION: Salient is the marked difference between the preferences of prospective parents and those of healthcare professionals, which has potential implications for Canadian policy regarding NIPT implementation and insurance coverage.

First-trimester risk assessment based on ultrasound and cell-free DNA vs combined screening: a randomized controlled trial.

OBJECTIVE: This was a randomized controlled trial to compare risk assessment by first-trimester combined screening (FTCS) with an approach that combines a detailed ultrasound examination at 11-13 weeks' gestation and cell-free DNA (cfDNA) analysis. METHODS: Pregnant women with a normal first-trimester ultrasound examination at 11-13 weeks' gestation (fetal nuchal translucency (NT) ≤ 3.5 mm and no fetal defects) were randomized into one of two groups. In the first group, risk of aneuploidy was assessed using FTCS based on the most recent UK Fetal Medicine Foundation algorithm. In the second group, risk assessment was based on ultrasound findings and cfDNA analysis. An additional tube of blood was collected for FTCS in case the cfDNA analysis was uninformative. Primary outcome was false-positive rate in screening for trisomy 21. A case was considered false positive if the karyotype was not trisomy 21 and if the risk for trisomy 21 was >1:100, irrespective of the method of risk calculation. Results were compared using 95% CIs using the Clopper-Pearson method. RESULTS: Between October 2015 and December 2016, 1518 women with singleton pregnancy underwent first-trimester screening. Thirty-one (2.0%) pregnancies were not eligible for randomization due to increased NT (> 3.5 mm) and/or fetal defect. After exclusion of women who declined randomization (n = 87) and cases of fetal death and loss to follow-up (n = 24), 688 pregnancies were randomized into the FTCS arm and 688 into the ultrasound + cfDNA analysis arm. There were no differences in maternal and gestational age, maternal weight and BMI, ethnicity, use of assisted reproduction and cigarette smoking between the two arms. In the ultrasound + cfDNA analysis arm, median risk for trisomy 21 was 1 in 10 000. None of the cases had a risk above 1: 100 (95% CI, 0.0-0.5%). In the FTCS arm, the median risk for trisomy 21 was 1 in 3787 and in 17 cases, the risk was higher than 1:100, which corresponds to 2.5% (95% CI, 1.5-3.9%) of the FTCS study-arm population. CONCLUSION: Our study has shown that first-trimester risk assessment for trisomy 21 that includes a detailed ultrasound examination as well as NT measurement and is followed by cfDNA testing is associated with a significant reduction in the false-positive rate compared with FTCS. This approach obviates the need for maternal serum free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A in screening for fetal aneuploidy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal screening costs at a large military treatment facility.

OBJECTIVE: Prenatal screening with cell-free DNA (cfDNA) offers improved detection of Down syndrome (T21) compared to conventional screening. These tests are expensive and have fewer detectable anomalies. Our objective was to investigate potential costs and test performance of screening algorithms when accounting for detectable aneuploidies. METHODS: This is a cost analysis for a large military treatment facility. Using a theoretical delivery cohort and published performance data, universal screening with cfDNA was compared to sequential screening, comparing T21 to all detectable aneuploidies. Predicted test performance and costs were calculated. RESULTS: A cohort of 3000 deliveries was used. For T21, universal cfDNA is more expensive ($1,346,064) than sequential screening ($244,885), but has a lower false positive rate and avoids 101 invasive diagnostic tests. An additional case of T21 is detected with a marginal cost of $1,101,179. For all detectable aneuploidies, cfDNA is more expensive ($1,353,660) than sequential screening ($239,189), and 59 invasive diagnostic tests are avoided. Sequential screening detects an additional case of aneuploidy, with a cost savings of $1,114,471. CONCLUSIONS: Although cfDNA is superior in detecting T21 cases, sequential screening is superior when considering all aneuploidies detectable. The cost increase with universal cfDNA is significant, and is not justified with small improvements in the performance.

Factors associated with utilization of maternal serum screening for Down syndrome in mainland China: a cross-sectional study.

BACKGROUND: Knowledge of the factors that influence maternal serum screening (MSS) service utilization can be used to develop health policies to promote equitable access to MSS and further diagnostic tests. The purpose of this study was to find the factors associated with utilization of MSS as well as the current status of service utilization in mainland China. METHODS: This was a hospital-based cross-sectional study with respondents interviewed with a questionnaire designed based on Andersen's behavioral model. Descriptive statistics, univariate analysis, and multilevel logistic regression analysis were used to identify the factors associated with MSS utilization, and to explore potential methods to improve screening uptake. RESULTS: A total of 8110 women who had given birth within the previous 7 days in one of 111 participating institutions from six provinces in mainland China were interviewed. Approximately 36% of the participants had used MSS. Women between 20 and 35 years, who resided in urban areas, were educated, were in a stable occupation, who had health knowledge, who attended maternal preparation classes, who had received eight or more prenatal checkups, who were from a region of higher social economic status, and who delivered in a tertiary healthcare institution were significantly more likely to use MSS than their counterparts. As compared with other factors, insufficient education is the single most important demographic factor for service underutilization. CONCLUSIONS: Efforts should not only be made to target the population that underuses MSS, but the overall organization of MSS service delivery should be assessed during policy development to make access to MSS equitable to the entire population of mainland China.

[Assessment of patients' knowledge of first-trimester combined Down syndrome screening at the time of their first trimester ultrasonographic evaluation: Results of a prospective study about 201 women]. / Évaluation des connaissances des patientes concernant le dépistage de la trisomie 21 lors de l'échographie du premier trimestre : résultats d'un sondage prospectif sur un échantillon de 201 femmes.

OBJECTIVE: Assess pregnant women's knowledge on first-trimester combined Down syndrome screening, at the time of their first trimester ultrasound scan. MATERIALS AND METHODS: A questionnaire was submitted to the patients coming for their 12-week pregnancy ultrasonographic evaluation in a University Hospital prenatal clinic between May 2012 and May 2013. Correct and incorrect statements on Down syndrome screening were proposed to the mothers who were asked to rate them. Each patient was questioned on her prior exposition to Down syndrome screening, the category of medical of professional she previously consulted, and the information she received. Patients' knowledge was evaluated according to these criteria. RESULTS: Two hundred and one patients were included in this study. The average correct answer rating was 4.6 (out of 8 questions). The average incorrect answer rating was 2.4 (out of 6 questions). No difference was found between the different social and demographic groups, nor according to the category of professional consulted before the first ultrasound scan. Higher correct answer ratings were observed when the patient had already been submitted to a Down syndrome screening (P=0.039), when they had previously received explanations about the screening (P=0.003); and when they stated that they had been sufficiently informed (P=0.042). CONCLUSION: These results show that patients' knowledge on Down syndrome screening is inadequate and depends on their experience of previous screening and information. It is deemed necessary to improve information especially to young women who are pregnant for the first time.

The impact of introducing combined first-trimester trisomy 21 screening in the French population.

BACKGROUND: French state health insurance has funded trisomy 21 prenatal screening for all pregnant women since decades. First-trimester combined screening was introduced nationally and funded in 2010. OBJECTIVE: To evaluate the impact of the introduction, of a national policy of prenatal trisomy 21 first-trimester screening on the reduction of invasive prenatal diagnostic procedures. METHODS: The results of all prenatal trisomy 21 screening and invasive diagnostic procedures were collected for the whole country over the period 2009-12. The screen-positive rates (risk cut-off 1 : 250, including isolated nuchal translucency ≥ 3.5 mm), positive predictive values and percentage of cases diagnosed prenatally were calculated. RESULTS: Over the study period the number of women undergoing serum screening (including first- and second-trimester screening tests) increased from 678 803 to 689 651 (83 to 85% of deliveries, P < 0.0001). By 2012, first-trimester combined screening accounted for 70% of all trisomy 21 screening. The screen-positive rate decreased from 9.5 to 4.8% (P < 0.001) resulting in a 37 478 (47%) drop (P < 0.001) in the number of invasive diagnostic procedures. The positive predictive value of screening increased from 2.6 to 6.1% from 2009 to 2012 (P < 0.001), due to the higher positive predictive value of first-trimester over second-trimester screening (9.1 vs. 1.8% over the period 2010-12, P < 0.001). The percentage of prenatally diagnosed cases remained high at around 80% between 2010 and 2012. CONCLUSIONS: The policy shift from second-trimester to first-trimester trisomy 21 screening allowed to reduce the number of invasive tests. The number of antenatal trisomy 21 diagnoses increased (+2.7%) over the study period.

A cost-effectiveness analysis of cell free DNA as a replacement for serum screening for Down syndrome.

OBJECTIVE: The aim of this article is to determine the cost effectiveness of cell free DNA (cfDNA) as a replacement for integrated screening using a societal cost perspective. METHOD: This study used Monte-Carlo simulation with one-way and probabilistic sensitivity analysis. RESULTS: Cell free DNA is more effective and less costly than integrated screening. The incremental cost-effectiveness ratio for cfDNA relative to the integrated test was -$277 955 per case detected (95th percent confidence interval -$881 882 to $532 785). CONCLUSION: Cell free DNA screening is a cost-effective replacement for maternal serum screening when the lifetime costs of Down syndrome live births are considered. The adoption of cfDNA screening would save approximately $277 955 for each additional case detected over integrated screening.

A unified approach to risk assessment for fetal aneuploidies.

OBJECTIVE: To examine the potential impact of combining measures from cell-free DNA (cfDNA) testing with maternal age and first-trimester biomarkers in screening for fetal trisomies. METHODS: This was a theoretical study using Bayes' theorem to combine the a priori risk for fetal trisomy 21 derived from maternal age with likelihoods from nuchal translucency thickness, serum pregnancy-associated plasma protein-A, serum free ß-human chorionic gonadotropin and plasma cfDNA. We adopted a binomial counting model for the cfDNA likelihoods and developed a model to account for errors in estimating fetal fraction. RESULTS: When Bayes' theorem was used to combine the a priori risk for trisomy 21 derived from the first-trimester combined test with likelihoods from the cfDNA test, and when the true fetal fraction was known, the detection rate increased from 62% at a fetal fraction of 4% to 100% at a fetal fraction of ≥ 9%; the positive likelihood ratio (trisomic/euploid) increased from 620 to 1000 and the negative likelihood ratio (euploid/trisomic) increased from 3 to > 10 000. When the fetal fraction is < 4%, the cfDNA test has traditionally been considered to be a failure, but the cfDNA results can be used to improve the performance of screening by the combined test. CONCLUSIONS: In contingent policies that use the first-trimester combined test for first-line screening to select the subgroup for cfDNA testing, the data from the latter should be used to update the risk from the former. Individual patient results from cfDNA testing depend crucially on the fetal fraction and the precision of its measurement.

A new model for providing cell-free DNA and risk assessment for chromosome abnormalities in a public hospital setting.

OBJECTIVE: Cell-free DNA (cfDNA) offers highly accurate noninvasive screening for Down syndrome. Incorporating it into routine care is complicated. We present our experience implementing a novel program for cfDNA screening, emphasizing patient education, genetic counseling, and resource management. STUDY DESIGN: Beginning in January 2013, we initiated a new patient care model in which high-risk patients for aneuploidy received genetic counseling at 12 weeks of gestation. Patients were presented with four pathways for aneuploidy risk assessment and diagnosis: (1) cfDNA; (2) integrated screening; (3) direct-to-invasive testing (chorionic villus sampling or amniocentesis); or (4) no first trimester diagnostic testing/screening. Patients underwent follow-up genetic counseling and detailed ultrasound at 18-20 weeks to review first trimester testing and finalize decision for amniocentesis. RESULTS: Counseling and second trimester detailed ultrasound were provided to 163 women. Most selected cfDNA screening (69%) over integrated screening (0.6%), direct-to-invasive testing (14.1%), or no screening (16.6%). Amniocentesis rates decreased following implementation of cfDNA screening (19.0% versus 13.0%, P < 0.05). CONCLUSION: When counseled about screening options, women often chose cfDNA over integrated screening. This program is a model for patient-directed, efficient delivery of a newly available high-level technology in a public health setting. Genetic counseling is an integral part of patient education and determination of plan of care.

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

BACKGROUND: Non-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/DESIGN: NIPT 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. DISCUSSION: The 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 NUMBER: 13865.

Model-based analysis of costs and outcomes of non-invasive prenatal testing for Down's syndrome using cell free fetal DNA in the UK National Health Service.

BACKGROUND: Non-invasive prenatal testing (NIPT) for Down's syndrome (DS) using cell free fetal DNA in maternal blood has the potential to dramatically alter the way prenatal screening and diagnosis is delivered. Before NIPT can be implemented into routine practice, information is required on its costs and benefits. We investigated the costs and outcomes of NIPT for DS as contingent testing and as first-line testing compared with the current DS screening programme in the UK National Health Service. METHODS: We used a pre-existing model to evaluate the costs and outcomes associated with NIPT compared with the current DS screening programme. The analysis was based on a hypothetical screening population of 10,000 pregnant women. Model inputs were taken from published sources. The main outcome measures were number of DS cases detected, number of procedure-related miscarriages and total cost. RESULTS: At a screening risk cut-off of 1∶150 NIPT as contingent testing detects slightly fewer DS cases, has fewer procedure-related miscarriages, and costs the same as current DS screening (around UK£280,000) at a cost of £500 per NIPT. As first-line testing NIPT detects more DS cases, has fewer procedure-related miscarriages, and is more expensive than current screening at a cost of £50 per NIPT. When NIPT uptake increases, NIPT detects more DS cases with a small increase in procedure-related miscarriages and costs. CONCLUSIONS: NIPT is currently available in the private sector in the UK at a price of £400-£900. If the NHS cost was at the lower end of this range then at a screening risk cut-off of 1∶150 NIPT as contingent testing would be cost neutral or cost saving compared with current DS screening. As first-line testing NIPT is likely to produce more favourable outcomes but at greater cost. Further research is needed to evaluate NIPT under real world conditions.

Prenatal screening for Down syndrome in Australia: costs and benefits of current and novel screening strategies.

OBJECTIVE: To analyse the cost-effectiveness and performance of noninvasive prenatal testing (NIPT) for high-risk pregnancies following first-trimester screening compared with current practice. METHODS: A decision tree analysis was used to compare the costs and benefits of current practice of first-trimester screening with a testing pathway incorporating NIPT. We applied the model to 32 478 singleton pregnancies screened between January 2005 and December 2006, adding Medicare rebate data as a measure of public health system costs. The analyses reflect the actual uptake of screening and diagnostic testing and pregnancy outcomes in this cohort. RESULTS: The introduction of NIPT would reduce the number of invasive diagnostic procedures and procedure-related fetal losses in high-risk women by 88%. If NIPT was adopted by all women identified as high risk by first-trimester combined screening, up to 7 additional Down syndrome fetuses could be confirmed. The cost per trisomy 21 case confirmed, including NIPT was 9.7% higher ($56,360) than the current prenatal testing strategy ($51,372) at a total cost of $3.91 million compared with $3.57 million over 2 years. CONCLUSION: Based on the uptake of screening and diagnostic testing in a retrospective cohort of first-trimester screening in Western Australia, the implementation of NIPT would reduce the number of invasive diagnostic tests and the number of procedure-related fetal losses and increase the cost by 9.7% over two years. Policy planning and guidelines are urgently required to manage the funding and demand for NIPT services in Australia.

A tradeoff analysis of risk cutoffs for the quadruple serum screen for Down syndrome.

OBJECTIVES: In maternal serum screening for Down syndrome, a cutoff of 1 : 270 is often used as a decision point to recommend invasive confirmatory testing. However, it has not been established how well this or any other cutoff relates to patient preferences, that is, the values that pregnant women attach to various screening outcomes. The purpose of this study was to examine the clinical and economic tradeoffs of a wide range of risk cutoffs for the quadruple screen. METHODS: Screening costs and outcomes for multiple risk cutoffs were modeled using a Monte Carlo simulation. RESULTS: The optimal cutoff for maternal serum screening depends on the relative values placed by the patient on different outcomes. Total societal costs were similar across the range of cutoffs. CONCLUSIONS: Given that different screening outcomes are optimized by different cutoff values, a one-size-fits-all approach may not be appropriate.

[Screening of trisomy 21 nowadays. Is maternal age so important?]. / A 21-es triszómia szurése napjainkban. Az anyai életkor valóban olyan fontos?

INTRODUCTION: Trisomy 21 is the most common chromosomal abnormality, therefore, screening and diagnosis of this disorder is in the centre of attention worldwide. An efficient screening method is the combined test based on maternal age, ultrasound signs, biochemical markers, and a risk ratio can be calculated based on these data. AIM: The aim of the authors was to determine the causes of missed prenatal diagnosis of Down's syndrome at the 2nd Department of Obstetrics and Gynecology, Semmelweis University. METHOD: A retrospective study was carried out by collecting data from medical records of mothers who had delivered a newborn with Down's syndrome in the Department between 2008 and 2012. Each medical record was analyzed individually. RESULTS: In most cases the missed diagnosis of Down's syndrome occurred when the expectant mother failed to attend the first trimester screening or did not take the risk of invasive diagnostic procedures needed for fetal kariotyping. CONCLUSIONS: Analysis of fetal DNA circulating in maternal plasma can be a solution for those who refuse invasive fetal diagnostics. This test has high sensitivity and very low false positive rate. It has become available since the end of 2011 in the United States and, since the autumn of 2012, in Hungary, too. The test, however, is not reimbursed by national health insurance.