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Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non-invasive prenatal testing
Abstract
Background:
Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21.
Aim:
To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective.
Methods:
Using a hypothetical cohort of 300?000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1?>?300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis.
Results:
The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51?876 compared to the contingent models which varied from $49?309-66?686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing.
Conclusion:
Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.
... Autosomal aneuploidies Y b NIPT is currently being used as both a first-tier test (offered to all pregnant women) and second-tier test (offered to those already identified as high chance 1 ) (53), and there is ongoing uncertainty over where it should sit in the antenatal screening pathway. The efficacy of both options has been demonstrated in audit and modeling studies (19,85,97,98) and is recognized in professional guidelines (126). NIPT's increasing prevalence correlates with a decrease in invasive prenatal tests (72,75,85,136). ...
... NIPT's increasing prevalence correlates with a decrease in invasive prenatal tests (72,75,85,136). This has reduced costs to the healthcare system but has increased the costs to pregnant people, raising concerns over equity (47,97). ...
Since its introduction in 2011, noninvasive prenatal testing (NIPT) has spread rapidly around the world. It carries numerous benefits but also raises challenges, often related to sociocultural, legal, and economic contexts. This article describes the implementation of NIPT in nine countries, each with its own unique characteristics: Australia, Canada, China and Hong Kong, India, Israel, Lebanon, the Netherlands, the United Kingdom, and the United States. Themes covered for each country include the structure of the healthcare system, how NIPT is offered, counseling needs and resources, and cultural and legal context regarding disability and pregnancy termination. Some common issues emerge, including cost as a barrier to equitable access, the complexity of decision-making about public funding, and a shortage of appropriate resources that promote informed choice. Conversely, sociocultural values that underlie the use of NIPT vary greatly among countries. The issues described will become even more challenging as NIPT evolves from a second-tier to a first-tier screening test with expanded use.
Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Previously published analyses from other multiple marker or contingent cfDNA screening programs are limited by a lack of population-level data linking prenatal screening results with cytogenetic records or birth outcomes. 3,[14][15][16][17] Our primary objective for this study was to report on the overall and modality-specific performance of Ontario's prenatal screening program, wherein the offer of cfDNA screening is contingent on specific criteria that increase the likelihood of T21 or T18 (Figure 1). Our secondary objective was to report on the impact of this screening approach on test utilization by pregnant individuals. ...
Background:
The emergence of cell-free fetal DNA (cfDNA) testing technology has disrupted the landscape of prenatal screening for trisomies 21 (T21) and 18 (T18). Publicly funded systems around the world are grappling with how to best integrate this more accurate but costly technology, as there is limited evidence about its incremental value in real-world conditions. The objectives of this study were to describe the population-based performance of Ontario's prenatal screening program, which incorporates publicly funded cfDNA screening for specific indications, and the effect of cfDNA testing on the screening and diagnostic choices made by pregnant people.
Methods:
We conducted a retrospective, descriptive cohort study using routinely collected data from Better Outcomes & Registry Network (BORN) Ontario, which captures linked population data for prenatal and neonatal health encounters across Ontario. We included all singleton pregnancies with an estimated due date between Sept. 1, 2016, and Mar. 31, 2019, that underwent publicly funded prenatal screening in Ontario, and a comparison cohort from Apr. 1, 2012, and Mar. 31, 2013. We assessed performance of the screening program for the detection of T21 or T18 by calculating sensitivity, specificity, positive predictive value and negative predictive value against diagnostic cytogenetic results or birth outcomes. We assessed the impact of the program by calculating the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing.
Results:
The study cohort included 373 682 pregnancies. The prenatal screening program had an uptake of 69.9%, a screen-positive rate and sensitivity of 1.6% and 89.9% for T21, and 0.2% and 80.5% for T18, respectively. The test failure rate for cfDNA screening was 2.2%. Invasive prenatal diagnostic testing decreased from 4.4% in 2012-2013 to 2.4% over the study period; 65.2% of pregnant people who received a screen-positive result from cfDNA testing went on to have invasive prenatal diagnostic testing.
Interpretation:
This publicly funded screening program, incorporating cfDNA analysis for common aneuploidies, showed robust performance, a substantial reduction in invasive prenatal diagnostic testing and that pregnant people exercise autonomy in their choices about prenatal screening and diagnosis.
... Some are missing birth outcomes for all screened pregnancies [9] [10], such that that specificity analyses cannot be performed. Other studies used fully modelled data [11], were enhanced with modeled data by extrapolating cohort findings into projected population performance [12], or used a screening and diagnostic testing cohort with unlinked estimated total births [13]. Performance of cfDNA screening has been published for numerous populations, but almost all are industry funded in part or in whole [14][15][16][17]. ...
Objectives: To measure the population-based performance and impact of Ontario, Canada's modified-contingent prenatal screening system for the detection of trisomies 21 (T21) and 18 (T18).
Design: A retrospective, descriptive cohort study examining routinely collected data from BORN Ontario, which captures linkable population data for prenatal and neonatal health encounters across a variety of settings (e.g., laboratories, birthing hospitals and midwifery practice groups).
Setting: A province-wide and publicly funded prenatal screening program in Ontario, Canada offering cfDNA screening for those at increased risk of having a pregnancy with T21 or T18.
Participants: 373,682 singleton pregnancies with an estimated due date between September 1 2016 and March 31, 2019 who were offered publicly funded prenatal screening.
Main outcome measures: Prenatal detection of T21 or T18, ascertained by cytogenetic results. Performance was assessed by calculating sensitivity, specificity, positive predictive value and negative predictive value against confirmatory diagnostic cytogenetic results and birth outcomes. The secondary objective was to determine the impact of contingent cfDNA screening by measuring uptake and the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing (PND).
Results: 69% of pregnancies in Ontario underwent prenatal screening for T21/T18. The modified-contingent screen sensitivity was 89.9% for T21 and 80.5% for T18. The modified-contingent screen-positive rate was 1.6% for T21 and 0.2% for T18. The cfDNA screening test failure rate was 2.2% (final result including multiple attempts). The PND rate among pregnancies screened was 2.4%.
Conclusions: This study is the largest evaluation of population-based performance of a publicly funded cfDNA prenatal screening system. We demonstrated a robust screening system with high sensitivity and low PND consistent with smaller validation studies.
... While NIPS as first-line screening has been suggested, but it was too expensive to be popularized in developing countries. Recent studies show that a contingent strategy was more cost-effective, in which a high risk group is identified through traditional screening methods and only pregnancies in this group are offered NIPS screening [11][12][13][14][15][16][17] . Contingent screening has the potential to reduce invasive diagnostic test and to increase the detection rate of fetal Down syndrome, depending on the different traditional screening risk cut-offs 18-20 . ...
To discuss combinations of traditional screening and noninvasive prenatal screening (NIPS) and to compare which traditional screening is the most suitable first-line screening approach to NIPS, pregnant women were recruited in this retrospective observational study. Pregnant women underwent one of four traditional screening tests. The 9 contingent models were combined by high risk cut-offs of 1:50, 1:100, 1:270 and intermediate risk cut-offs of 1:1000, 1:1500, 1:2000. We analyzed cost and performance of various screening models with contingent screening of different risk cut-offs. Compared with other screening tests, combined first-trimester screening (CFTS) had the lowest proportion of high risk (≥1:270) with the highest detection rate (DR) (78.79%) and the lowest proportion of intermediate risk (1:271~1:1000). When intermediate risk was 1:51 ~1:1500, CFTS as first-line screening had the lowest cost with DR of 93.94%. Other screening tests as the first-line screening with intermediate risk of 1:51~1:1000 had the lowest cost, there DR were 90.91%, 84.62%, 91.67%, respectively. Our study demonstrated if only one traditional screening was allowed to screen pregnant women, CFTS was recommended as the first choice. According to local health and economic conditions, adopting appropriate traditional screening with suitable cut-offs as first-line screening will contributed to a cost-effective screening model.
... They reported that if the NHS cost was at the lower end of the range of cfDNA price (£400-£900) in the private sector then at a selected population (cut-off of !1/150) cfDNA testing as contingent testing would be cost neutral or cost saving compared with current screening. Other Australian population cohort studies found that contingent cfDNA testing or cfDNA testing for selected high-risk patients (>40 years) was the most cost-effective strategy [16,17]. ...
Objective:
To estimate cost efficacy of first-trimester screening strategies based on nuchal translucency (NT) and maternal blood cell-free DNA (cfDNA) testing in women with advanced maternal age (AMA).
Materials and methods:
This was a retrospective population-based analysis of all pregnant women with AMA booked for combined first-trimester screening (cFTS) in China over a 3-year period. The assumed screening strategies were the following: cFTS (Strategy 1), cfDNA testing as a first-tier investigation replacing biomarkers after NT measurement (Strategy 2), and cfDNA testing combined with dating ultrasound for all women (Strategy 3). The direct costs were compared between strategies.
Results:
Strategy 1 was completed in 6443 women with AMA. The respective detection rates were 94.5% and 90.9% for trisomies 21 and 18, with a total screen-positive rate of 13.5%. Such a policy resulted in 871 invasive tests and a total cost of $747,870 or a cost of $116 per person tested. Strategy 2 would result in a total cost of $1,812,570, or a cost of $281 per person tested, with increased detection rates for trisomies 21 and 18, and a decreased number of invasive tests compared with strategy 1. The total cost of Strategy 3 would be $1,675,430, or a cost of $260 per person tested with the least number of invasive tests.
Conclusion:
The cfDNA modalities have the advantages of higher detection rate for common trisomies and lower screening-positive rate. However, the cost of cfDNA testing needs to decrease significantly if it is to replace the current cFTS practice in a population of AMA on a purely cost effectiveness basis.
Routine maternal serum screening for multiple markers, together with the determination of one or more ultrasound markers, enabled a four‐ to fivefold increase in the proportion of affected pregnancies detected antenatally and a decrease in the extent of invasive testing. This chapter examines the underlying principles and explains the terminology and outlines the relative efficiency of different screening policies. The relationship between the new approach and the established screening modalities is reviewed. A number of developments have changed the simple paradigm of AFP screening: primary prevention has led to a fall in neural tube defect (NTD) prevalence and advances in detailed ultrasound has limited the need for invasive prenatal diagnosis. Health planners now consider both chromosomal abnormalities and NTDs in program design. The chapter provides information on the more common forms of aneuploidy which are sufficiently viable to survive to term in relatively large numbers and are amenable to screening.
Introduction:
Analysis of cell-free DNA (cfDNA) from maternal blood has showed a great potential as a screening method for fetal aneuploidies. cfDNA can be used as a first line screening tool or in a contingent model, after the combined test.
Methods:
Prospective study of women attending for first trimester combined screening in our Hospital, in the first year of contingent cfDNA screening. According to the combined screening test result patients were divided in high-risk (offered invasive test or routine follow-up), intermediate-risk (counselled for cfDNA, invasive or routine follow-up) or low-risk (routine ultrasound follow-up). Pregnancy outcomes and performance of screening were evaluated. A cost-effectiveness analysis was also done.
Results:
The majority of the 1272 enrolled participants were Caucasian (82,6%), multiparous (51,7%) and the median maternal age was 30 years old. Thirty women screened high-risk and 83,3% of them opted for an invasive test. Forty-nine patients had an intermediate risk and 75,5% of them choose cfDNA testing. Our rate of invasive tests decreased from 3.5% to 2.4%.
Discussion:
The cut-offs used to determine high and intermediate-risk are based on a compromise between detection rate, pregnancy lost rate and cost. Above a determined cut-off in the intermediate-risk group, the cost for each additional detected trisomy case is very high. One major benefit of this contingent model was the decrease in invasive testing.
Conclusion:
The contingent cfDNA screening model can be easily implemented in a public hospital with a low-risk population. Since cost/benefit is an important issue, further studies are needed to determine the ideal cut-off for our country.
Background:
Pregnant people have a risk of carrying a fetus affected by a chromosomal anomaly. Prenatal screening is offered to pregnant people to assess their risk. Noninvasive prenatal testing (NIPT) has been introduced clinically, which uses the presence of circulating cell-free fetal DNA in the maternal blood to quantify the risk of a chromosomal anomaly. At the time of writing, NIPT is publicly funded in Ontario for pregnancies at high risk of a chromosomal anomaly.
Methods:
We completed a health technology assessment, which included an evaluation of clinical benefits and harms, value for money, budget impact, and patient preferences related to NIPT. We performed a systematic literature search for studies on NIPT for trisomies 21, 18, and 13, sex chromosome aneuploidies, and microdeletions in the average-risk or general population. We evaluated the cost-effectiveness of traditional prenatal screening, NIPT as a second-tier test (performed after traditional prenatal screening), and NIPT as a first-tier test (performed instead of traditional prenatal screening). We also conducted a budget impact analysis to estimate the additional costs of funding first-tier NIPT. We interviewed people who had lived experience with NIPT and people living with the conditions NIPT screens for, or their families.
Results:
The pooled clinical sensitivity of NIPT in the average-risk or general population was 99.5% (95% confidence interval [CI] 81.8%-99.9%) for trisomy 21, 93.1% (95% CI 75.9%-98.3%) for trisomy 18, and 92.7% (95% CI 81.6%-99.9%) for trisomy 13. The clinical specificity for any trisomy was 99.9% (95% CI 99.8%-99.9%). Compared with traditional prenatal screening, NIPT was more accurate in detecting trisomies 21, 18, and 13, and decreased the need for diagnostic testing. We found limited evidence on NIPT for sex chromosome aneuploidies or microdeletions in the average-risk or general population. Positive NIPT results should be confirmed by diagnostic testing.Compared with traditional prenatal screening, second-tier NIPT detected more affected fetuses, substantially reduced the number of diagnostic tests performed, and slightly reduced the total cost of prenatal screening. Compared with second-tier NIPT, first-tier NIPT detected more affected cases, but also led to more diagnostic tests and additional budget of $35 million per year for average-risk pregnant people in Ontario.People who had undergone NIPT were largely supportive of the test and the benefits of earlier, more accurate results. However, many discussed the need for improved pre- and post-test counselling and raised concerns about the quality of the information they received from health care providers about the conditions NIPT can screen for.
Conclusions:
NIPT is an effective and safe prenatal screening method for trisomies 21, 18, and 13 in the average-risk or general population. Compared with traditional prenatal screening, second-tier NIPT improved the overall performance of prenatal screening and slightly decreased costs. Compared with second-tier NIPT, first-tier NIPT detected more chromosomal anomalies, but resulted in a considerable increase in the total budget. Interviewees were generally positive about NIPT, but they raised concerns about the lack of good informed-choice conversations with primary care providers and the quality of the information they received from health care providers about chromosomal anomalies.
Cell-free DNA screening has quickly become established in Australia as an accurate
– albeit costly – prenatal screening test for trisomy 21, 18 and 13. It is also commonly used for the detection of sex chromosome abnormalities. The increasing number of prenatal screening pathways available to women has increased the complexity of pretest counselling. Concurrent advances in diagnostic testing with the widespread use of chromosomal microarrays create further challenges for the continuing education of clinicians and health consumers. This article aims to answer common clinical questions in this rapidly evolving field and complements the recently updated Royal Australian and New Zealand College of
Obstetricians and Gynaecologists Statement on Prenatal Screening for Fetal Chromosome and Genetic Conditions.
Background: Advances in technology can bring great benefits to human health, but their implementation may be influenced by socioeconomic factors, particularly in the field of prenatal screening for Down syndrome.
Aim: To analyze screening test indications for, and diagnostic yield of, prenatal diagnostic testing (PNDx) according to socioeconomic status.
Methods: Retrospective analysis of population-based data on PNDx and karyotype results for 2014-2015 in the Australian state of Victoria. Women having PNDx < 25 weeks due to combined first trimester screening (CFTS), second trimester serum screening (STSS), or noninvasive prenatal testing (NIPT) results were included. PNDx data were analysed by indication and maternal Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), the latter determined by postcode.
Results: There were 145,206 births in 2014-15; 1906 women underwent PNDx for the indication of CFTS (70.1%), NIPT (17.8%) or STSS (12.0%). Covariates positively associated with NIPT-indicated PNDx, compared with CFTS-indicated testing, were residence in a region of socioeconomic advantage, metropolitan status, and maternal age. Women from the most advantaged regions had higher adjusted odds of NIPT-indicated testing compared with women from disadvantaged regions (aOR 5.72, 95% CI 2.95-11.09). The diagnostic yield of PNDx increased with socioeconomic region, from 14% in the lowest IRSAD quintile to 31.2% in the highest (p < 0.0001).
Conclusion: Population-based data reveal significant disparities in screening indications for PNDx and hence, in diagnostic yield, according to socioeconomic region. This finding may have ethical and policy implications for prenatal screening in Australia.
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.
Background:
Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations.
Methods:
In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Down's syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13.
Results:
Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001).
Conclusions:
In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).
Background:
The first- and second-trimester screening for trisomy 21 (T21) are reimbursed for all pregnant women in Belgium. Using a cut-off risk of 1:300 for T21, about 5% of all pregnant women are referred for definitive prenatal diagnosis using an invasive test, at a sensitivity of (only) 72.5%. The sensitivity and specificity of the non-invasive prenatal test (NIPT) are over 99% but come at a cost of €460 (£373) per test. The objective is to estimate the consequences of introducing NIPT for the detection of T21.
Methods:
A cost-consequences analysis was performed presenting the impact on benefits, harms and costs. Context-specific real-world information was available to set up a model reflecting the current screening situation in Belgium. This model was used to construct the second and first line NIPT screening scenarios applying information from the literature on NIPT's test accuracy.
Results:
Introducing NIPT in the first or second line reduces harm by decreasing the number of procedure-related miscarriages after invasive testing. In contrast with NIPT in the second line, offering NIPT in the first line additionally will miss fewer cases of T21 due to less false-negative test results. The introduction of NIPT in the second line results in cost savings, which is not true for NIPT at the current price in the first line. If NIPT is offered to all pregnant women, the price should be lowered to about €150 to keep the screening cost per T21 diagnosis constant.
Conclusions:
In Belgium, the introduction and reimbursement of NIPT as a second line triage test significantly reduces procedure-related miscarriages without increasing the short-term screening costs. Offering and reimbursing NIPT in the first line to all pregnant women is preferred in the long term, as it would, in addition, miss fewer cases of T21. However, taking into account the government's limited resources for universal reimbursement, the price of NIPT should first be lowered substantially before this can be realised.
Background
Currently, noninvasive prenatal testing (NIPT) is only recommended in high-risk women following conventional Down syndrome (DS) screening, and it has not yet been included in the Australian DS screening program. AimsTo evaluate the cost-effectiveness of different strategies of NIPT for DS screening in comparison with current practice. MethodsA decision-analytic approach modelled a theoretical cohort of 300,000 singleton pregnancies. The strategies compared were the following: current practice, NIPT as a second-tier investigation, NIPT only in women >35years, NIPT only in women >40years and NIPT for all women. The direct costs (low and high estimates) were derived using both health system costs and patient out-of-pocket expenses. The number of DS cases detected and procedure-related losses (PRL) were compared between strategies. The incremental cost per case detected was the primary measure of cost-effectiveness. ResultsUniversal NIPT costs an additional $134,636,832 compared with current practice, but detects 123 more DS cases (at an incremental cost of $1,094,608 per case) and avoids 90 PRL. NIPT for women >40years was the most cost-effective strategy, costing an incremental $81,199 per additional DS case detected and avoiding 95 PRL. Conclusions
The cost of NIPT needs to decrease significantly if it is to replace current practice on a purely cost-effectiveness basis. However, it may be beneficial to use NIPT as first-line screening in selected high-risk patients. Further evaluation is needed to consider the longer-term costs and benefits of screening.
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.
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.
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.
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.
Objective:
To estimate the proportion of other chromosomal abnormalities that could be missed if combined testing was replaced by cell-free (cf) DNA testing as the method of screening for trisomies 21, 18 and 13.
Methods:
The prevalence of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities was examined in pregnancies undergoing first-trimester combined screening and chorionic villus sampling (CVS).
Results:
In 1,831 clinically significant chromosomal abnormalities in pregnancies with combined risk for trisomies 21, 18 and 13≥1:100, the contribution of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities at high risk of adverse outcome was 82.9, 8.2, 3.9 and 5.0%, respectively. Combined screening followed by CVS for risk≥1:10 and cfDNA testing for risk 1:11-1:2,500 could detect 97% of trisomy 21 and 98% of trisomies 18 and 13. Additionally, 86% of monosomy X, half of 47,XXY, 47,XYY or 47,XXX, half of other chromosomal abnormalities and one third of triploidies, which are currently detected by combined screening and CVS for risk≥1:100, could be detected.
Conclusions:
Screening by cfDNA testing, contingent on results of combined testing, improves detection of trisomies, but misses a few of the other chromosomal abnormalities detected by screening with the combined test.
Abstract Prenatal testing for Down syndrome through the use of noninvasive prenatal testing (NIPT) has been increasingly implemented in clinical practice and a recent cost analysis suggests that NIPT is cost effective when compared to other screening modalities in high risk populations. However, this anaylsis makes many assumptions regarding uptake of testing and pregnancy termination, which cannot be applied to all populations in the United States. Additionally, this cost analysis, which hinges on fewer Down syndrome births, does not align with the goals of prenatal testing to support autonomous and value consistent decisions. NIPT is an expensive new technology and more careful analysis is needed to determine the impact of NIPT on outcomes and overall healthcare costs.
Objective:
To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies.
Methods:
Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 4 January 2015.
Results:
In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5-99.6%) and 0.09% (95% CI, 0.05-0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3-97.9%) and 0.13% (95% CI, 0.07-0.20) for trisomy 18, 91.0% (95% CI, 85.0-95.6%) and 0.13% (95% CI, 0.05-0.26%) for trisomy 13, 90.3% (95% CI, 85.7-94.2%) and 0.23% (95% CI, 0.14-0.34%) for monosomy X and 93.0% (95% CI, 85.8-97.8%) and 0.14% (95% CI, 0.06-0.24%) for sex chromosome aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6-99.2%) and the FPR was 0.23% (95% CI, 0.00-0.92%).
Conclusion:
Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and sex chromosome aneuploidies is considerably worse than that for trisomy 21.
(Abstracted from Genet Med 2016;18(10):1056–1065)
Rapid advancements in genomic technologies led to the introduction in 2011 of noninvasive prenatal screening (NIPS) that used cell-free DNA (cfDNA) derived from the placenta and circulating in maternal blood. Noninvasive prenatal screening is addressed in this American College of Medical Genetics and Genomics (ACMG) guideline to assist patients who are in search of prenatal screening information and health care providers who are responsible for providing precise and up-to-date information to their patients.
Disclaimer: This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9–10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result.
Genet Med18 10, 1056–1065.
Objective:
To provide data on how screen-positive and detection rates of first trimester prenatal screening for fetal Down syndrome vary with changes in the risk cut-off and maternal age to inform contingency criteria for publicly funded noninvasive prenatal testing.
Materials and methods:
First trimester screening and diagnostic data were collected for all women attending for first trimester fetal aneuploidy screening in Western Australia between 2005 and 2009. Prenatal screening and diagnostic data were linked to pregnancy outcomes, including data from the Midwives' Notification System and the Western Australian Registry of Developmental Anomalies. The prevalence of Down syndrome and performance of screening by risk cut-off and/or for women >35 years were analysed.
Results:
The current screening risk cut-off of 1:300 has screen-positive and detection rates of 3.5% and 82%. The screen-positive rate increases by 0.7-0.8% for each 100 point change in risk, up to 19.2% at 1:2500 (96% detection rate). Including all women >35 years as screen positive would increase the screen-positive rate and detection rates to 30.2% and 97.2%.
Conclusion:
Variation in screening risk cut-off and the use of maternal age to assess eligibility for noninvasive testing could significantly impact the demand for, and cost of, the test. A contingent first trimester screening approach for risk assessment is superior to the use of a combination of screening and maternal age alone. These data will inform decisions regarding the criteria used to determine eligibility for publicly funded noninvasive prenatal testing.
Objectives:
Cell-free DNA (cfDNA) analysis of maternal blood for detection of trisomies 21, 18 and 13 is superior to other methods of screening but is expensive. One strategy to maximize performance at reduced cost is to offer cfDNA testing contingent on the results of the first-trimester combined test that is used currently. The objectives of this study were to report the feasibility of implementing such screening, to examine the factors affecting patient decisions concerning their options for screening and decisions on the management of affected pregnancies and to report the prenatal diagnosis of fetal trisomies and outcome of affected pregnancies following the introduction of contingent screening.
Methods:
We examined routine clinical implementation of contingent screening in 11,692 singleton pregnancies in two National Health Service (NHS) hospitals in the UK. Women with a risk ≥ 1 in 100 (high-risk group) were offered options of invasive testing, cfDNA testing or no further testing, and those with a risk between 1 in 101 and 1 in 2500 (intermediate-risk group) were offered cfDNA testing or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or by examination of the neonates.
Results:
In the study population of 11,692 pregnancies, there were 47 cases of trisomy 21 and 28 of trisomies 18 or 13. Screening with the combined test followed by invasive testing for all patients in the high-risk group potentially could have detected 87% of trisomy 21 and 93% of trisomies 18 or 13, at a false-positive rate of 3.4%; the respective values for cfDNA testing in the high- and intermediate-risk groups were 98%, 82% and 0.25%. However, in the high-risk group, 38% of women chose invasive testing and 60% chose cfDNA testing; in the intermediate-risk group 92% opted for cfDNA testing. A prenatal diagnosis was made in 43 (91.5%) pregnancies with trisomy 21 and all pregnancies with trisomies 18 or 13. In many affected pregnancies the parents chose to avoid testing or termination and 32% of pregnancies with trisomy 21 resulted in live births.
Conclusions:
Screening for fetal trisomies by cfDNA analysis of maternal blood, contingent on the results of the combined test, can be implemented easily in routine clinical practice. In the high-risk group from the combined test, most but not all women chose cfDNA testing rather than invasive testing. Performance of screening for trisomy 21 was superior by the cfDNA test than by the combined test. However, prenatal detection of trisomies and pregnancy outcome depend not only on performance of screening tests but also on parental choice.
Background:
Several countries today struggle with suboptimal performances in many aspects of the fetal aneuploidy screening process and consider introducing non-invasive prenatal screening (NIPT) as a solution. In this study, costs and benefits of different scenarios for contingent NIPT screening in Belgium are evaluated with respect to partial redistribution of the national screening budget into quality improving measures for those screening activities that will be maintained when full NIPT screening is implemented.
Methods:
Data from the Belgian National Institute for Health and Disability Insurance and the Study Centre for Perinatal Epidemiology were used in modeled calculations of medical and economic impact of NIPT after prior conventional screening (1) at thresholds 1:300 and 1:600, and (2) at current and improved screening sensitivity.
Results:
Contingent NIPT screening under current screening conditions would maintain today's 7.9(0) /000 live birth prevalence of Down syndrome (LBPD) at an 11% reduction of overall short-term costs. Lowering the screening threshold to 1:600 or increasing sensitivity by 10% would reduce LBPD to 7(0) /000 at a maximum 3% increase of overall short-term costs.
Conclusion:
Today, in Belgium and in many other countries, full NIPT screening is considered too expensive for immediate introduction into the national fetal aneuploidy screening program. Contingent NIPT screening is both clinically and economically beneficial. A temporary contingent NIPT protocol allows for reinvesting economic savings into optimization of those screening aspects, which are to be maintained in parallel to full NIPT screening.
AimTo describe the potential impact of using noninvasive prenatal testing (NIPT) as a second-tier test, on the diagnosis and outcomes of pregnancies identified as high risk through first trimester screening (FTS) in a cohort of real pregnancies.Materials and Methods
Western Australian FTS and diagnostic data (2007–2009) were linked to pregnancy outcomes. Karyotype results from invasive prenatal testing in high-risk women were analysed. The outcomes of abnormal results that would not be detected by NIPT, assuming a panel of trisomy 21/18/13 and sex chromosome aneuploidies, and the likelihood of diagnosis in a screening model using NIPT as a second-tier test are described.ResultsAbnormal karyotype results were reported in 224 of 1488 (15%) women with high-risk pregnancies having invasive diagnostic testing. NIPT potentially would have identified 85%. The 33 abnormalities unidentifiable by NIPT were triploidies (n = 7, 21%), balanced (n = 8, 24%) and unbalanced rearrangements (n = 10, 30%) and level III mosaicisms (n = 8, 24%). For conditions not identifiable by NIPT, fetal sonographic appearance was likely to have led to invasive testing for 10 of 17 (59%) pathogenic abnormalities. If a policy was adopted recommending invasive testing for FTS risk >1:50 and/or ultrasound detected abnormality, the residual risk of an unidentified pathogenic chromosomal abnormality in those without a diagnosis would have been 0.33% (95% CI 0.01–0.65%).ConclusionsA screening model with NIPT as a second-tier for high-risk pregnancies would be unlikely to have changed the outcome for the majority of pregnancies. Optimising the diagnosis of rare pathogenic abnormalities requires clear indicators for invasive testing over NIPT.
In late 2012, a new screening test for fetal aneuploidy based on circulating cell-free DNA (cfDNA) became available to Australian women. The introduction of this technology in the United States has led to a reduction in invasive diagnostic procedures. Analysis of the number of amniocentesis and chorionic villus sampling (CVS) procedures performed in Australia from 1994 to 2014 shows that the introduction of cfDNA testing has been associated with the most rapid decline in invasive procedures in the last 20 years. This change has important implications for training in, and maintenance of, the procedural skills of amniocentesis and CVS.
© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.
Cell-free DNA based methods of aneuploidy screening represent the most accurate form of screening for trisomy 21 to date. Its clinical implementation has varied considerably between countries due to local factors such as existing care models, insurance coverage and legal restrictions. In response to concerns about the appropriate implementation of NIPT, a group of Australian obstetric sonologists formed a collaboration to document the collective national experience of NIPT using a variety of NIPT providers. Our experience of implementing NIPT should resonate with many clinicians, being drawn from a developed country with a universal health care system, high uptake of prenatal screening and diagnosis, and patient-funded NIPT. In our high risk population of 1839 cases, we found screen positive (2.4%), false positive (0.3%) and "no result" (2.8%) rates consistent with those reported in the literature. The dependence on overseas commercial laboratories is likely to change in the near future, underscoring the importance of continued monitoring of trends in prenatal screening and diagnosis.
Objective
To examine performance of screening for major trisomies by a policy of first-line assessment of risk with maternal age, fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins (DV-PIV) followed by cell-free (cf) DNA testing, in pregnancies with an intermediate risk.Methods
We estimated the distribution of risks based on maternal age, fetal NT and DV-PIV in a dataset of 86 917 unaffected and 491 trisomic pregnancies undergoing prospective screening for trisomies. Performance of screening for trisomies by cfDNA testing was derived from a meta-analysis of clinical validation studies. We estimated performance and cost of screening for trisomies by different combinations of ultrasound screening and cfDNA testing.ResultsScreening for trisomies 21, 18 and 13 by a combination of maternal age, fetal NT and DV-PIV in all pregnancies, followed by invasive testing in the high-risk group (≥1:10) and cfDNA testing in the intermediate-risk group (1:11–1:3000) can potentially detect about 96%, 95% and 91% of cases, respectively, with an FPR of 0.8%. On the assumption that the costs for ultrasound screening, cfDNA testing and invasive testing are €150, €500 €1000, respectively, the overall cost of such a policy would be about €250 per patient. The alternative policy of universal screening by cfDNA testing, can potentially detect about 99%, 97% and 92% of cases of trisomies 21, 18 and 13, but at the overall cost of more than €500 per patient.Conclusion
Combined screening by first-trimester ultrasound examination and cfDNA testing can detect a high proportion of trisomies with a low FPR.
Objective:
Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Clinical trials have shown high sensitivity and specificity for trisomy 21 (T21) in both high-risk and average-risk populations. Although its great potential for prenatal medicine is evident, more information regarding the consequences of implementing NIPT in a national programme for prenatal screening is required.
Study design:
A decision-analytic model was developed to compare costs and outcomes of current clinical practice in The Netherlands using conventional screening only, with two alternatives: implementing NIPT as an optional secondary screening test for those pregnancies complicated by a high risk for T21, and implementing NIPT as primary screening test, replacing conventional screening. Probability estimates were derived from a systematic review of international literature. Costs were determined from a health-care perspective. Data were analysed to obtain outcomes, total costs, relative costs and incremental cost-effectiveness ratios (ICERs) for the different strategies. Sensitivity analysis was used to assess the impact of assumptions on model results.
Results:
Implementing NIPT as an optional secondary, or as primary screening test will increase T21 detection rate by 36% (from 46.8% to 63.5%) and 54% (from 46.8% to 72.0%), simultaneously decreasing the average risk of procedure-related miscarriage by 44% (from 0.0168% to 0.0094% per pregnant woman) and 62% (from 0.0168% to 0.0064% per pregnant woman), respectively. None of the strategies clearly dominated: current clinical practice is the least costly, whereas implementing NIPT will cause total costs of the programme to increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when utilised as an optional secondary screening test and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when utilised as primary screening test. However, implementing NIPT as triage test did result in the lowest expected relative costs per case of T21 diagnosed (k€141).
Conclusion:
NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21.
Objective
Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Clinical trials have shown high sensitivity and specificity for trisomy 21 (T21) in both high-risk and average-risk populations. Although its great potential for prenatal medicine is evident, more information regarding the consequences of implementing NIPT in a national programme for prenatal screening is required.
Study design
A decision-analytic model was developed to compare costs and outcomes of current clinical practice in The Netherlands using conventional screening only, with two alternatives: implementing NIPT as an optional secondary screening test for those pregnancies complicated by a high risk for T21, and implementing NIPT as primary screening test, replacing conventional screening. Probability estimates were derived from a systematic review of international literature. Costs were determined from a health-care perspective. Data were analysed to obtain outcomes, total costs, relative costs and incremental cost-effectiveness ratios (ICERs) for the different strategies. Sensitivity analysis was used to assess the impact of assumptions on model results.
Results
Implementing NIPT as an optional secondary, or as primary screening test will increase T21 detection rate by 36% (from 46.8% to 63.5%) and 54% (from 46.8% to 72.0%), simultaneously decreasing the average risk of procedure-related miscarriage by 44% (from 0.0168% to 0.0094% per pregnant woman) and 62% (from 0.0168% to 0.0064% per pregnant woman), respectively. None of the strategies clearly dominated: current clinical practice is the least costly, whereas implementing NIPT will cause total costs of the programme to increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when utilised as an optional secondary screening test and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when utilised as primary screening test. However, implementing NIPT as triage test did result in the lowest expected relative costs per case of T21 diagnosed (k€141).
Conclusion
NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21.
To assess the views and likely uptake of non-invasive prenatal testing (NIPT) for trisomy 21 among potential service users in the UK.
Cross-sectional survey.
Four antenatal clinics in England and two websites.
A total of 1131 women and partners.
Questionnaire conducted with women (and partners) recruited through antenatal clinics, a random sample of members of the website Mumsnet, and viewers of the website and Facebook page of the support group Antenatal Results and Choices (ARC).
Factors impacting decision-making towards prenatal testing; views on NIPT, including service delivery and likely uptake; hypothetical scenarios, focused on current screening, invasive testing, and NIPT offered to women with a high-risk screening result.
The vast majority (95.7%; 1071/1119; 95% CI 94.4-96.8%) thought NIPT was a positive development in prenatal care, with 88.2% (972/1103; 95% CI 86.1-90%) indicating that they would use the test, including respondents who would currently decline trisomy 21 screening (P < 0.001). Of the respondents who would have NIPT, 30.7% (299/973; 95% CI = 27.8-33.7%) said that they were 'likely' to terminate an affected pregnancy (including those who would currently decline screening or invasive testing), and 36.5% (355/973; 95% CI 33.5-39.6%) were 'not likely' to terminate an affected pregnancy. Respondents overwhelmingly indicated that safety for the baby was the most important attribute of NIPT (70.1%; 712/1015; 95% CI 67.2-73%).
Respondents were overwhelmingly positive towards the introduction of NIPT. Uptake is likely to be high, and includes women who currently decline screening as well as those who will use the test for information only. Pre-test counselling to ensure that women understand the implications of the test result is essential.
To analyse the cost-effectiveness and performance of noninvasive prenatal testing (NIPT) for high-risk pregnancies following first-trimester screening compared with current practice.
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.
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.
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.
To define risk cut-offs with corresponding detection rates (DR) and false-positive rates (FPR) in screening for trisomy 21 using maternal age and combinations of first-trimester biomarkers in order to determine which women should undergo contingent maternal blood cell-free (cf) DNA testing.
From singleton pregnancies undergoing screening for aneuploidies at three UK hospitals between March 2006 and May 2012, we analyzed prospectively collected data on the following biomarkers: fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins (DV-PIV) at 11 + 0 to 13 + 6 weeks' gestation and serum free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and alpha-fetoprotein (AFP) at 8 + 0 to 13 + 6 weeks. Estimates of risk cut-offs, DRs and FPRs were derived for combinations of biomarkers and these were used to define the best strategy for contingent cfDNA testing.
In contingent screening, detection of 98% of fetuses with trisomy 21 at an overall invasive testing rate < 0.5% can be potentially achieved by offering cfDNA testing to about 36%, 21% and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum PlGF and AFP and using the combined test with the addition of PlGF, AFP and DV-PIV, respectively.
Effective first-trimester screening for trisomy 21, with DR of 98% and invasive testing rate < 0.5%, can be potentially achieved by contingent screening incorporating biomarkers and cfDNA testing. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.
Objective:
The aim of this study was to investigate how the introduction of noninvasive prenatal testing (NIPT) impacted women's testing choices following a positive prenatal screening (PNS) result.
Methods:
Beginning in March 2012, women referred to our Prenatal Diagnosis Center following a positive PNS result were offered NIPT or invasive prenatal diagnosis. Rates of invasive testing and declining follow-up were compared with testing decisions the prior year. Differences were compared using t-test and chi-square. Multivariable logistic regression was performed to identify predictors of test choice.
Results:
Between March 2012 and February 2013, 398 screen positive women were seen: 156 (39.2%) underwent invasive testing, 157 (39.4%) had NIPT and 84 (21.1%) declined further testing. In the prior year, 638 screen positive patients were seen: 301 (47.2%) had invasive testing and 337 (52.8%) declined. The rate of invasive testing declined significantly (p = 0.012). Moreover, fewer women declined follow-up testing after introduction of NIPT, 21.2% versus 52.8%, p ≤ 0.001. Race/ethnicity and timing of results (first versus second trimester) were predictors of testing choices; payer and maternal age were not.
Conclusion:
The introduction of NIPT resulted in a significant decrease in invasive diagnostic testing. Additionally, fewer women declined further testing when NIPT was available.
Since the early 1980s, prenatal screening using ultrasound and biochemical markers has been used to refine the risk of Down syndrome and other fetal anomalies prior to considering fetal karyotyping. The performance of prenatal screening is subject to ongoing monitoring in Western Australia. The collection of these data can also assist in the identification of any potential inequities of access to prenatal screening within the state-wide programme.
Prenatal screening data (2005-2006) were collected from accredited ultrasound and pathology laboratories in Western Australia. Screening data were linked to diagnostic and pregnancy outcome data. Performance characteristics of screening and uptake by socio-demographic characteristics were analysed.
Complete screening data were collected for 35,142 of the estimated 38,081 women screened during 2005 and 2006. There were 59,999 births related to this screening period. The lowest uptake of screening was among women who were Aboriginal (14.9%), living in remote areas (38.0%), under the age of 25 (40.2%), in the lowest quintile of the SEIFA index (41.6%) and with three or more children (48.4%). Logistic regression analysis showed all socio-demographic factors to be strongly associated with screening behaviour, with adjustment for ethnicity, socio-economic status, age, parity and area of residence.
Our results have important implications for the delivery of prenatal screening services in Western Australia. While the screening programme meets international and national performance standards, the disparities in screening uptake suggest inequity in access to services, particularly for Aboriginal, remote and socio-economically disadvantaged women.
A relatively few centres across Australia provide screening tests for maternal serum markers or ultrasound measurement of fetal nuchal translucency to assess risk of fetal anomalies such as Down syndrome. While providers engage in external accreditation and quality assurance programs, state and federal governments have been slow to formulate relevant policies and standards.
In this paper we review the current practices across Australian states and territories and propose recommendations for developing a national policy framework.
Data on the number and types of screening tests provided as well as state policies, where they are available, were obtained from government reports and supplemented by a mail survey to selected stakeholders in each state or territory.
At a jurisdictional level, our results highlight the need to integrate the collection and monitoring of antenatal population-screening programs to assess clinical effectiveness and program performance (detection and screen-positive rates, uptake of diagnostic tests as a result of screening). Women's expectations and satisfaction with the information they are provided should be evaluated and used to adjust education resources. At a local level, collaboration between providers of the separate tests, both public and private, would enable the ascertainment of outcomes of integrated screening programs. To complete the cycle, these data should inform decisions to improve antenatal screening programs at a national level.
A primary goal at a national level would be to develop a consensus on key performance indicators for programs that clarify best practice guidelines and establish optimal performance and accreditation standards.
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- E Pergement
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First trimester screening cut-offs for noninvasive prenatal testing as a contingent screen: balancing detection and screen-positive rates for trisomy 21
- S Maxwell
- I James
- J E Dickinson
- O Leary
Maxwell S, James I, Dickinson JE, O'Leary P. First trimester screening cut-offs for noninvasive prenatal testing as a contingent
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