Implementation Of Non-invasive Prenatal Testing Research Articles

Oral Abstracts of the ISPD 19th International Conference on Prenatal Diagnosis and Therapy, Washington, DC, USA, 12-15 July 2015.

OBJECTIVES: The TRIDENT study (Trial by Dutch laboratories for Evaluation of Non-Invasive Prenatal Testing) evaluates the implementation of non-invasive prenatal testing (NIPT) in the Dutch healthcare system. Here we report on the preferences and experiences of pregnant women at high risk for fetal aneuploidy who were offered a choice between NIPT, invasive testing or no follow-up test. METHODS: A nationwide prospective cohort study among pregnant women at high risk for fetal aneuploidy because of first trimester screening results (risk ≥1:200) or medical history. Questionnaires were administered to the women, to be completed after counselling and after receiving the test-results, at seven (of the eight) prenatal diagnostic centers in the Netherlands. The questionnaires addressed: women's preference for follow-up testing, intention to terminate the pregnancy, attitudes, knowledge, decisional conflict, anxiety and satisfaction. RESULTS: Pre- and post-test questionnaires were completed by n = 1,106 (86% response) and n = 686 (67% response) women, respectively. Preliminary analyses show that the majority of respondents (92%) preferred NIPT, 5% invasive testing, 2% were unsure, and 1% declined testing. The main reason to prefer NIPT was safety for the child (92%). Of the 60 women preferring invasive testing, 52% did so because of test-accuracy, 25% desired more rapid test-results, 5% because it provides more information, and 18% reported other reasons. Most women (92%) felt that they made a well-informed decision, and 75% reported that this decision was easy to make. Intention to terminate the pregnancy for Down syndrome was lower among women preferring NIPT (58%) compared to women preferring invasive testing (87%). Women were highly satisfied with NIPT. However, 64% perceived the waiting time for NIPT results (mean: 11 days (range 5-32)) as too long, while 3% in retrospect would have preferred a different follow-up test, mostly to avoid the long waiting time. CONCLUSIONS: Most pregnant women in our study felt they could make an informed decision. The majority of women prefer NIPT, mainly because it has no miscarriage risk. Reducing turnaround time for test-results is our next challenge in meeting women's needs.

Soft markers for aneuploidy following reassuring first trimester screening: what should be done?

The present article aims to review the current role of the soft markers on the second trimester ultrasound (STUS) in women after reassuring first trimester screening (FTS) in singleton pregnancies. Improvements in the FTS and the recent implementation of noninvasive prenatal testing (NIPT) for common aneuploidies have important impact on the prevalence of these conditions in the STUS. Some studies suggest that soft markers in the second trimester of the fetus without structural anomalies have a minor or no role in Down syndrome detection in a prescreened population with reassuring results. However, NIPT could be offered as a next step in the management of such pregnancies if the calculated new composite risk (NCR) for aneuploidy is increased. In the case of reassuring results, pregnancy follow-up for certain markers is advised. NIPT has emerged as a new method of prenatal testing and is feasible in the second trimester in women with increased NCR. However, apart from the Down syndrome screening, STUS screening remains a powerful tool in screening for other fetal aneuploidies, structural anomalies and pathological placental conditions and detection of specific soft markers that require pregnancy follow-up.

A Cost-Effectiveness Analysis Comparing Different Strategies to Implement Noninvasive Prenatal Testing Into a Down Syndrome Screening Program

Noninvasive prenatal testing (NIPT) can analyze cell-free DNA of placental origin in maternal serum for trisomy 21. The detection rate is 99.5%, and the false-positive rate (FPR) is 0.2%. Noninvasive prenatal testing is recommended only for highrisk women after conventional screening. Noninvasive prenatal testing is deemed a screening modality, and invasive diagnostic testing is required for confirmation following a “positive” result. The present study was performed to evaluate NIPT by comparing 4 strategies examining cost-effectiveness and budget impacts for health care systems and parturients. A decision-analytic model was created to compare screening-related costs and consequences of NIPT implementation. The first strategy involved current practices using combined first-trimester screening (CFTS) is offered to all women at 11 to 13 weeks’ gestation. Women at high risk for DS are offered invasive diagnostic testing, via amniocentesis with fluorescence in situ hybridization and karyotyping. For strategy 2, NIPT is a second investigation after high-risk CFTS stratification. It was assumed that only women with a positive NIPT undergo invasive diagnostic testing and further counseling. Strategies 3A and 3B categorize women as high or low risk. Women 35 years or older are considered high risk and are initially offered NIPT; all others are offered CFTS, and only those considered at high risk for DS undergo NIPT. All women who are NIPT positive are referred for invasive diagnostic testing. In strategy 4, universal NIPT replaces CFTS with NIPT as the primary screening modality. All women with a positive NIPT undergo invasive diagnostic testing and counseling. Estimated costs for each strategy were those directly related to screening and accruing to government agencies and out-of-pocket costs to the woman. Outcomes included the number of DS cases detected and the number of procedure-related losses (PRLs) avoided by not performing invasive diagnostic testing. Two cost estimates for each strategy were calculated. The low estimate included costs to the health system and patients based on the current Medicare Benefits Schedule cost and the lowest estimate of patient outof-pocket costs; the high estimate was based on both Medicare costs and the highest estimates of private health care prices. Universal NIPT was the most effective strategy and detected 657 DS cases, resulting in 11 PRLs. Strategies 3A and 3B (maternal ages >35 and >40 years, respectively) were more effective than current practices for detecting DS and avoiding PRLs. Strategy 2 was less effective for DS detection, but more effective in avoiding PRLs. Five to 11 PRLs occurred with the new strategies compared with 101 PRLs for the current practice. Strategy 2 was the least expensive option. Implementing universal NIPT would cost more than 4 times the current expenditures on DS screening. The higher cost estimates were double or triple those of the low cost, with higher out-of-pocket costs for patients. Based on DS detection, the most cost-effective new strategy was 3B. Strategies 3A and 4 offered less value for money compared with current practice. Although strategy 2 was less costly and less effective for DS detection, when based on avoiding PRLs, it was the most cost-effective. Strategy 4 had the highest incremental cost per PRL avoided. The benefits of NIPT are its ability to detect a high percentage of DS cases while decreasing the number of PRLs. These advantages generate higher costs to health systems and parturients. The substitution of NIPT for CFTS would be significantly more expensive. Benefits of replacing CFTS with NIPT include an 18% increase in DS cases detected and a decrease in the overall screening positive rate from 3.8% to less than 0.42%. Additional research is necessary to confirm these results.

Noninvasive Prenatal Testing: Implications for Muslim Communities

Noninvasive prenatal testing (NIPT), a new technology that uses cell-free fetal DNA in maternal plasma to detect fetal aneuploidies, is currently entering clinical practice. NIPT offers great clinical benefits as it is much more accurate than current screening, allows earlier testing, and eliminates the risk of miscarriage associated with amniocentesis and chorionic villus sampling (CVS). In the future, it may become accurate enough to replace invasive testing. To date, no attention has been given in the literature to the role that earlier testing through NIPT might play in the context of religious traditions with particular attitudes toward abortion, such as in Muslim communities. This article presents some Islamic views regarding fetal development and abortion as well as some recent legislative developments surrounding abortion for fetal conditions, focusing on Iran and Saudi Arabia. It then offers a discussion of possible implications of NIPT for Muslim communities, such as its potential to allow access to diagnostic information before “ensoulment,” the point of fetal development at which the fetus is bestowed the moral status of a human being. The possible impact of early access to information on the evolution of legislation surrounding abortion for fetal conditions is also discussed. Finally, we suggest future research directions based on empirical studies with women, partners, health professionals, and religious authorities in Muslim countries and in countries with a Muslim majority in order to explore their preferences and attitudes regarding the future implementation of NIPT within those communities.

Advantages and Disadvantages of Different Implementation Strategies of Non-Invasive Prenatal Testing in Down Syndrome Screening Programmes

Background: Implementation of non-invasive prenatal testing (NIPT) in Down syndrome screening programmes requires health policy decisions about its combination with other tests and its timing in pregnancy. Aim: Our aim was to aid health policy decision makers by conducting a quantitative analysis of different NIPT implementation strategies. Methods: Decision trees were created to illustrate all plausible alternatives in a theoretical cohort of 100,000 pregnant women in five screening programmes: classical screening by the first-trimester combined test (FCT), pre-selection of high-risk women prior to NIPT by the FCT, NIPT as the first screening test at 10 weeks and at 13 weeks, and the simultaneous conductance of NIPT and the FCT. Results: Pre-selection by FCT prior to NIPT reduces the number of amniocenteses to a minimum because of a reduction of false-positive NIPT results. If NIPT is the first screening test, it detects almost all fetal Down syndrome cases. NIPT at 10 weeks reassures women early in pregnancy, while NIPT at 13 weeks prevents unnecessary tests due to spontaneous miscarriages and allows for immediate confirmation by amniocentesis. Conclusion: Every implementation strategy has its advantages and disadvantages. The most favourable implementation strategy may be NIPT as the first screening test at 13 weeks, offering the most accurate screening test for Down syndrome, when the risk for spontaneous miscarriage has declined remarkably and timely confirmation by amniocentesis can be performed.

Knowledge and Attitudes toward Non-invasive Prenatal Testing among Pregnant Japanese Women.

To assess the knowledge and attitudes of pregnant Japanese women regarding non-invasive prenatal testing (NIPT). Between March and June 2013, 557 pregnant women in the Hyogo and Hiroshima Prefectures were surveyed using an anonymous, self-completed questionnaire. A total of 91.9% respondents (512/557) stated that they "agree" or "conditionally agree" with NIPT implementation in Japan. Approximately 28.5% of respondents stated that they knew that the accuracy of a positive NIPT result can be affected by mother's age and background, while 34.5% of respondents stated that it was necessary for pregnant women with a positive result to undergo fetal chromosome diagnosis using amniocentesis;both percentages were low. Additionally, 92.3% of respondents would "like a detailed explanation of the test," 65.1% of them would "like psychological support if the NIPT test results came back positive," and 5.7% would terminate the pregnancy if the NIPT test results came back positive without undergoing fetal chromosome diagnosis via amniocentesis. Although a high proportion of pregnant Japanese women agreed with the introduction of NIPT into Japanese obstetrical care, there was insufficient knowledge regarding the test. It is necessary for women undergoing NIPT to be provided sufficient information and psychological support.

Noninvasive Prenatal Test by Cell-Free Fetal DNA in Maternal Plasma: Current Progress and Prospective Clinical Applications

Context: Prenatal testing aims to identify fetal chromosomal and genetic disorders prior to delivery. Current invasive procedures such as amniocentesis and chorionic villus sampling (CVS) pose a risk to mother and fetus and such diagnostic procedures are available only to high-risk pregnancies, which limits aneuploidy detection rate. The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made noninvasive prenatal testing (NIPT) possible. This review seeks to highlight the necessity of investing in NIPT and briefly summarizes the technical aspects of the NIPT and application of this method in clinical practice. Evidence Acquisition: PubMed, OVID, SCOPUS, and the Cochrane database were searched for relevant articles published between 1995 and 2014, using appropriate keywords including prenatal screening, noninvasive testing, prenatal diagnosis, cell free fetal DNA, maternal circulation, chromosomal aneuploidies, trisomy, and sex determination. Results were restricted to systematic reviews, randomized clinical trials, meta-analysis, and observational studies. Results: The importance of prenatal diagnosis and risks associated with current invasive techniques makes NIPT research morally and commercially beneficial. The outstanding advantages of NIPT over current prenatal diagnosis techniques include increasing detection rate, enabling earlier diagnosis, and eliminating iatrogenic fetal loss and risk to the mother due to invasive procedures. At present, two major techniques for isolating cffDNA, namely digital PCR and massively parallel sequencing (MPS), have enabled the successful implementation of NIPT into clinical practice such as fetal sex determination, RhD genotyping, and fetal chromosomal aneuploidy detection. Conclusions: The advent of new NIPT using cffDNA has been regarded as a revolution in prenatal testing and has attracted significant commercial interest in the field. It is not overoptimistic to predict that NIPT will supplement or replace existing screening and diagnostic tools.

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

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

Impact of noninvasive prenatal testing in regionally dispersed medical centers in the United States

Noninvasive prenatal testing using cell-free DNA is a new alternative to screen for common fetal aneuploidies. It is not known what impact regional location may play on noninvasive prenatal testing implementation and downstream invasive prenatal procedure use in the United States. Six different regionally based centers collected data on noninvasive prenatal testing indication and results between February and November 2012, as well as their invasive prenatal procedure rates before and after offering noninvasive prenatal testing. Statistical analyses were performed using the 2-proportion Z-test. Of 1477 patients who underwent noninvasive prenatal testing; 693 (47%) were from centers in the West; 522 (35.3%) from centers in the East; and 262 (17.7%) from 1 center in the Midwest. Statistically significant differences were observed between West Coast and nonWest Coast sites for gestational age (14.1 weeks; P ≤ .0001). Advanced maternal age (AMA-only) was the most frequent indication in 5 of 6 sites (range, 21.8-62.9%) Atotal of 98 invasive prenatal procedures performed on 94 (6.4%) patients of which 64 (65.3%) were performed at centers in the West. More invasive procedures were performed following negative noninvasive prenatal testing results (n= 61) than abnormal noninvasive prenatal testing results (n= 30). The overall rate of patients undergoing invasive procedure after an abnormal noninvasive prenatal testing result was 32.6% (30 of 92). All 6 centers reported a decrease in invasive procedure volume after noninvasive prenatal testing introduction. This study demonstrates differences in clinical implementation of noninvasive prenatal testing across regionally dispersed centers in the United States, suggesting patient demographics and views toward prenatal testing influence use as well as downstream management.

Clinical implementation of noninvasive prenatal testing among maternal fetal medicine specialists

To assess the clinical implementation of non-invasive prenatal testing (NIPT) among maternal-fetal medicine (MFM) specialists. Practicing MFMs were invited by email to complete questionnaires via SurveyMonkey©. Of 278 respondents, 56% were male, 48% practiced in academic centers, and 94% currently offer NIPT. NIPT is most often being offered 'to specific patients meeting certain criteria' (59.2%), for indications of advanced maternal age (87.5%), abnormal screen results (94.9%), abnormal ultrasound findings (90.2%), and 'when a high-risk patient declines invasive diagnostic testing' (73.7%). Thirteen percent indicated NIPT is being offered as a diagnostic test. Regardless of whether NIPT was presented as a diagnostic or screening test, 65.3% of MFMs estimate 'some' of their patients have undergone invasive testing for confirmation. Responses were mixed concerning appropriate populations and diagnostic capabilities of NIPT, but MFMs generally agree NIPT should be confirmed with invasive testing and will replace conventional screening procedures. Assessment indicates NIPT is being adopted by MFMs, largely in accord with recently published American College of Obstetricians and Gynecologists and the Society for MFM guidelines. Cost and test performance remain factors for not adopting NIPT. Further research on clinical management based on NIPT results and patient understanding of NIPT results is suggested.

A new era in prenatal care: non-invasive prenatal testing in Switzerland

Prenatal care has been significantly influenced by the introduction of non-invasive prenatal testing (NIPT) for aneuploidies in 2012. The aim of this study was to describe the current impact of NIPT on prenatal care. We performed a retrospective data analysis including all women with singleton pregnancies who presented for first trimester screening (FTS) between 1 October 2011 and 30 March 2013 and those seeking NIPT. According to the results of FTS the women were categorised into three risk groups: low risk for aneuploidy (<1:300), intermediate risk (1:300-1:50) and high risk (>1:50). They were counselled about the available options for invasive prenatal testing (IPT) and NIPT available at the time of FTS. The nine months before and after the introduction of NIPT were evaluated regarding further testing after FTS. In total, 951 women were included: 505 examinations (group 1) were carried out before NIPT became available, 446 (group 2) thereafter. In group 2, 9.0% (40/446) had NIPT. Here, 60.0% (24/40) had a low risk according to FTS. In group 2 there was an increase of 3.6% of additional prenatal tests after FTS. The greatest increase was noted in the intermediate-risk category (10.7%). The number of invasive prenatal tests decreased by 67.4%. We observed a notable increase in prenatal testing after the implementation of NIPT. NIPT is an additional test for women who need more reassurance. Since the options for pregnant women become more complex and the costs of NIPT are high, prenatal counselling has become more challenging.

Non-invasive prenatal testing for Down's syndrome—Where are we now?

Non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cffDNA) is an area of development in screening for Down's syndrome (DS) that has generated great interest. Analysis of cffDNA found in the maternal blood circulation from 4-weeks gestation is a more accurate screening blood test than is currently available on the NHS. The implementation of NIPT for DS in the NHS has the potential to increase the number of DS cases detected while reducing the number of invasive tests needed and their associated miscarriages. This article will provide an overview of NIPT for DS, the current evidence and what questions need to be answered before implementation within the NHS.

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

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.

The impact of utilization of early aneuploidy screening on amniocenteses available for training in obstetrics and fetal medicine

First-trimester aneuploidy screening has high detection rates and low false-positive rates. Their use as well as the implementation of non-invasive prenatal testing may affect specialty training in prenatal diagnosis procedures. Descriptive study of first-trimester aneuploidy screening and amniocentesis in an obstetric training program. Screening methods were tracked from their introduction in 2004 through 2011. The volume of amniocentesis procedures from 2000 to 2011 was evaluated. First-trimester screening tests increased from 283 to 1225 between 2005 and 2011, whereas genetic amniocenteses declined from 460 to 168 during the same period. The percent of older women who chose a first-trimester screen test rose from 12.7% to 44.2% First-trimester screening options reduce genetic amniocenteses available for training. Fetal medicine and general obstetrics training programs need to evaluate their clinical experience and determine whether simulation training methods are needed for education.