Prenatal Testing For Aneuploidy Research Articles

Neonatal mortality and morbidity in Down syndrome in the time of prenatal aneuploidy testing: a retrospective cohort study

The total uptake of prenatal aneuploidy screening for Down syndrome (DS) is increasing worldwide. As a result of increasing prenatal diagnosis of DS and subsequent termination of pregnancy, livebirth prevalence of DS is decreasing. The aim of this study is to explore the impact of an increasing uptake of prenatal aneuploidy screening on the neonatal mortality and morbidity in DS. This is a retrospective cohort study of 253 neonates with DS born between 2012 and 2018 that were seen at the outpatient clinic of five hospitals in the Netherlands. The medical files were reviewed for maternal and neonatal characteristics and neonatal morbidities. The Dutch national birth registry (Perined) provided mortality numbers of neonates with DS. The results were interpreted in the context of other published studies. Neonatal mortality in DS remained stable, ranging from 1.4 to 3.6%. A congenital heart defect (CHD) was found in 138 of the 251 neonates (55.0%) with atrial septal defect, atrioventricular septal defect, and ventricular septal defect being the most common. The type of CHD in DS did not change over time. Gastro-intestinal defects were present in 22 of the 252 neonates with DS (8.7%), with duodenal atresia as the most reported anomaly. Persistent pulmonary hypertension of the neonate (PPHN) was found in 31 of the 251 infants (12.4%). Conclusions: Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in DS appears to be stable. An increased incidence of PPHN was found.What is Known:• The total uptake of prenatal aneuploidy screening for Down syndrome is increasing worldwide.• As a result of increasing prenatal diagnosis of Down syndrome and subsequent termination of pregnancy, the livebirth prevalence of Down syndrome is decreasing.What is New:• Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in Down syndrome appears to be stable.• An increased incidence of persistent pulmonary hypertension of the neonate was found.

VP17.05: Improved patient education for prenatal aneuploidy testing using a digital tool: a multicentre randomised controlled trial

VP17.05: Improved patient education for prenatal aneuploidy testing using a digital tool: a multicentre randomised controlled trial

OP479 - Patient education for prenatal aneuploidy testing using a chatbot: a multicenter randomized controlled trial

OP479 - Patient education for prenatal aneuploidy testing using a chatbot: a multicenter randomized controlled trial

PREIMPLANTATION GENETIC TESTING: Non-invasive prenatal testing for aneuploidy, copy-number variants and single-gene disorders.

The discovery of cell-free fetal DNA (cffDNA) in maternal plasma has enabled a paradigm shift in prenatal testing, allowing for safer, earlier detection of genetic conditions of the fetus. Non-invasive prenatal testing (NIPT) for fetal aneuploidies has provided an alternative, highly efficient approach to first-trimester aneuploidy screening, and since its inception has been rapidly adopted worldwide. Due to the genome-wide nature of some NIPT protocols, the commercial sector has widened the scope of cell-free DNA (cfDNA) screening to include sex chromosome aneuploidies, rare autosomal trisomies and sub-microscopic copy-number variants. These developments may be marketed as 'expanded NIPT' or 'NIPT Plus' and bring with them a plethora of ethical and practical considerations. Concurrently, cfDNA tests for single-gene disorders, termed non-invasive prenatal diagnosis (NIPD), have been developed for an increasing array of conditions but are less widely available. Despite the fact that all these tests utilise the same biomarker, cfDNA, there is considerable variation in key parameters such as sensitivity, specificity and positive predictive value depending on what the test is for. The distinction between diagnostics and screening has become blurred, and there is a clear need for the education of physicians and patients regarding the technical capabilities and limitations of these different forms of testing. Furthermore, there is a requirement for consistent guidelines that apply across health sectors, both public and commercial, to ensure that tests are validated and robust and that careful and appropriate pre-test and post-test counselling is provided by professionals who understand the tests offered.

Noninvasive prenatal testing: from aneuploidy to single genes.

Noninvasive prenatal testing has undergone rapid advances in the last few years. Although researchers have long known about circulating pregnancy-based cell-free fragments of DNA in maternal plasma, it was the introduction of massively parallel sequencing that allowed noninvasive prenatal testing to become a widely used clinical test. This review will begin with an in-depth analysis of the use of noninvasive prenatal testing for aneuploidy, including common causes for inaccurate and/or discordant results. It will also review the ongoing expansion of noninvasive prenatal testing to include copy number variants and select single-gene disorders. Finally, integrated throughout the review is a comparison of noninvasive prenatal testing to more traditional screening methods along with some medical and ethical implications of the widespread use of this new technology.

Variations in prenatal screening in a US federal healthcare system: Same coverage, different options.

The Military Health System (MHS) is a federally funded organization that provides care to active duty service members and their beneficiaries. Our objective was to determine what methods of prenatal screening are used by military treatment facilities (MTFs), assess variations between institutions, and determine how practice patterns align with national recommendations. We surveyed all MTFs offering comprehensive prenatal care (n=49). Departments were asked about aneuploidy screening options, availability of diagnostic testing, and carrier screening. In all, 43 MTFs (88%) completed the survey. Most (39/43) patients were stratified based on risk (predominantly maternal age at delivery and history). The most commonly offered test was combined 1st/2nd trimester screening (59%). Sixty percent routinely offered diagnostic testing, though less than half routinely offered microarrays. The majority offered universal carrier screening for cystic fibrosis (98%) and complete blood count with screening for thalassemias and hemoglobinopathies (88%). At the time of data collection, only five facilities (12%) had implemented spinal muscular atrophy carrier screening. Considerable heterogeneity exists in prenatal aneuploidy testing and carrier screening within the MHS. Standardized guidelines, protocols, and laboratory support would improve processes across the system. Additional resources including genetic counseling support and provider education are needed.

The influence of fetal gender and maternal characteristics on fetal cell-free DNA in maternal plasma

ObjectiveTo examine the possible effects of fetal gender and maternal characteristics on concentration of fetal cell-free DNA (cfDNA). MethodsMaternal plasma that collected from 2638 singleton pregnancies women were analyzed using non-invasive prenatal testing for aneuploidy by next generation sequence technology. The effects of fetal gender and maternal BMI on fetal cfDNA was measured by Pearson correlation analysis. ResultsThe proportion of fetal cfDNA was positively correlated with gestational age (regression equation: Y=16.2483+6.8856X, r=0.1660, p<0.0001); and negatively correlated with BMI (Body Mass Index) (regression equation: Y=25.6342–19.0065X, r=−0.2146, p<0.0001); Concentration of female fetal cfDNA (mean fetal cfDNA is 13.07%, p<0.0001) is higher than male fetal cfDNA (mean fetal cfDNA is 8.37%, p<0.0001). ConclusionsFetal cfDNA increases stably between 12 and 20 weeks of gestation, and increases in a higher rate after 20 weeks. The maternal BMI is an important factor affecting fetal cfDNA, should be paid enough attention in clinical application.

Development of Reference Materials for Noninvasive Prenatal Aneuploidy Testing by Massively Parallel Sequencing: A Proof-of-Concept Study

Noninvasive prenatal aneuploidy testing (NIPT) represents the first large-scale clinical application of massively parallel sequencing technology. However, no NIPT reference material (RM) has yet been widely adopted, impeding the development of quality management systems and standardization. Developing an NIPT RM from a biological sample is complicated by the low concentration of cell-free DNA (cfDNA), which implies pooling specimens and frequent resampling. We tested the feasibility of using DNA from immortalized cell lines of a woman and her aneuploid offspring to spike an artificial plasma matrix. Enzymatic fragmentation of extracted DNA was optimized to achieve fragment size profiles with a mode of 150 to 200 bp, similar to biological cfDNA. This synthetic material was compared with routine biological samples from pregnant women by a targeted NIPT assay in a multiplex sequencing run on a Proton platform. Sequencing statistics were similar between artificially prepared material and routine biological samples, as well as relative chromosomal representation, and no matrix effects could be detected. Estimate of fetal fraction (FF) was within the range of expected value, and aneuploidy detection statistic (z-score) was also comparable between both types of samples. Artificial plasma spiked with DNA from cell lines of mother and offspring is a promising strategy for developing NIPT RM. This type of material would offer the advantage of a constant and stable composition, allowing for greater standardization of NIPT assays. Moreover, it preserves the parental relatedness used by targeted assay to estimate FF by identification of paternal alleles in single-nucleotide polymorphisms or other variable regions.

Non-invasive prenatal aneuploidy testing: Critical diagnostic performance parameters predict sample z-score values

ObjectivesNon-invasive prenatal aneuploidy testing (NIPT) by next-generation sequencing of circulating cell-free DNA in maternal plasma relies on chromosomal ratio (chrratio) measurements to detect aneuploid values that depart from euploid ratios. Diagnostic performances are known to depend on the fraction of fetal DNA (FF) present in maternal plasma, although how this translates into specific quantitative changes in specificity/positive predictive values and which other variables might also be important is not well understood. Design & methodsTo explore this issue, theoretical relationships between FF and various measures of diagnostic performances were assessed for a range of parameter values. Empirical data from three NIPT assays were then used to validate theoretical calculations. ResultsFor a given positivity threshold, dramatic changes in specificity and positive predictive values (PPV) as a function of both FF and the coefficient of variation (CV) of the chrratio measurement were observed. Theoretically predicted and observed chrratio z-scores agreed closely, confirming the determinant impact of small changes in both FF and chrratio CV. ConclusionsEvaluation of NIPT assay performances therefore requires knowledge of the FF distribution in the population in which the test is intended to be used and, in particular, of the precise value of the assay chrratio CV for each chromosome or genomic region of interest. Laboratories offering NIPT testing should carefully measure these parameters to ensure test reliability and clinical usefulness in interpreting individual patients' results.

Re: Cell‐free fetal DNA‐based noninvasive prenatal testing of aneuploidy

Re: Cell‐free fetal <scp>DNA</scp>‐based noninvasive prenatal testing of aneuploidy

Implementing non-invasive prenatal testing for aneuploidy in a national healthcare system: global challenges and national solutions

BackgroundSince the introduction of non-invasive prenatal testing (NIPT) in 2011, mainly by commercial companies, a growing demand for NIPT from the public and healthcare professionals has been putting pressure on the healthcare systems of various countries. This study identifies the challenges of establishing a responsible implementation of NIPT for aneuploidy in prenatal healthcare, by looking at the Netherlands.MethodsA mixed methods approach involving 13 stakeholder interviews, document analysis and (participatory) observations of the Dutch NIPT Consortium meetings were used. The Diffusion of Innovation Theory and a Network of Actors model were used to interpret the findings.ResultsImplementation of NIPT was facilitated by several factors. The set-up of a national NIPT Consortium enabled discussion and collaboration between stakeholders. Moreover, it led to the plan to offer NIPT through a nationwide research setting (TRIDENT studies), which created a learning phase for careful implementation. The Dutch legal context was perceived as a delaying factor, but eventually gave room for the parties involved to organise themselves and their practices.ConclusionsThis study shows that implementing advanced technologies with profound effects on prenatal care benefit from a learning phase that allows time to carefully evaluate the technical performance and women’s experiences and to enable public debate. Such a coordinated learning phase, involving all stakeholders, will stimulate the process of responsible and sustainable implementation.

Cell‐free fetal DNA‐based noninvasive prenatal testing of aneuploidy

Key content Noninvasive prenatal testing (NIPT) uses cell‐free fetal DNA (cffDNA) to test for aneuploidy, as opposed to noninvasive prenatal diagnosis (NIPD), which uses cffDNA to diagnose fetal sex, Rhesus D status and monogenic disorders. This classic review focuses on screening for aneuploidy. NIPT is a screening test and needs confirmatory invasive testing in cases of a high‐risk (positive) result. NIPT demonstrates high sensitivities and specificities according to our recent meta‐analysis, although it is less accurate for Trisomy 18, Trisomy 13, Monosomy X and sex chromosomal aneuploidies than for Trisomy 21. It is imperative that the implications of false positive and false negative results are investigated and considered in a clinical context. Learning objectives To be able to discuss NIPT with patients, including test accuracy and disadvantages. To be up to date with the implementation of NIPT in the National Health Service (NHS). Ethical issues NIPT requires careful counselling: patients may consider it a ‘trivial’ or routine blood test and may not fully understand the implications of a high‐risk (positive) result. There are issues surrounding other diagnoses that NIPT can potentially reveal, including maternal cancers, maternal sex chromosome aneuploidies and milder fetal phenotypes.

A qualitative study looking at informed choice in the context of non-invasive prenatal testing for aneuploidy.

ObjectiveTo explore women's attitudes towards non‐invasive prenatal testing (NIPT) and determine factors influencing their decisions around uptake of NIPT.MethodWe conducted qualitative interviews to assess knowledge, attitude and deliberation amongst women offered NIPT in a public health service. In total, 45 women took part in telephone interviews (79% participation rate).ResultsMost women could recount the key aspects of NIPT discussed during pre‐test counselling but had variable knowledge about Down syndrome. Analysis of women's attitudes towards undergoing NIPT revealed three dominant factors they considered when reflecting on the test: (1) how NIPT compared with alternative testing options, (2) reflections on coping and (3) moral or religious values. Exploring the deliberative process revealed the different paths women take when making decisions. For some, it was an extension of the decision to have Down syndrome screening; some considered it early on following the booking‐in appointment; others made step‐wise decisions about NIPT when it became relevant to them.ConclusionOur findings support the importance of personalised counselling, whereby women and their partners have the opportunity to reflect on the implications of the test results in the context of their own lives and values. Our data highlight the influence of personal circumstances on decision‐making. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Report on noninvasive prenatal testing: classical and alternative approaches

Concerns of traditional prenatal aneuploidy testing methods, such as low accuracy of noninvasive and health risks associated with invasive procedures, were overcome with the introduction of novel noninvasive methods based on genetics (NIPT). These were rapidly adopted into clinical practice in many countries after a series of successful trials of various independent submethods. Here we present results of own NIPT trial carried out in Moscow, Russia. 1012 samples were subjected to the method aimed at measuring chromosome coverage by massive parallel sequencing. Two alternative approaches are ascertained: one based on maternal/fetal differential methylation and another based on allelic difference. While the former failed to provide stable results, the latter was found to be promising and worthy of conducting a large-scale trial. One critical point in any NIPT approach is the determination of fetal cell-free DNA fraction, which dictates the reliability of obtained results for a given sample. We show that two different chromosome Y representation measures—by real-time PCR and by whole-genome massive parallel sequencing—are practically interchangeable (r=0.94). We also propose a novel method based on maternal/fetal allelic difference which is applicable in pregnancies with fetuses of either sex. Even in its pilot form it correlates well with chromosome Y coverage estimates (r=0.74) and can be further improved by increasing the number of polymorphisms.

Report on noninvasive prenatal testing: classical and alternative approaches

Concerns of traditional prenatal aneuploidy testing methods, such as low accuracy of noninvasive and health risks associated with invasive procedures, were overcome with the introduction of novel noninvasive methods based on genetics (NIPT). These were rapidly adopted into clinical practice in many countries after a series of successful trials of various independent submethods. Here we present results of own NIPT trial carried out in Moscow, Russia. 1012 samples were subjected to the method aimed at measuring chromosome coverage by massive parallel sequencing. Two alternative approaches are ascertained: one based on maternal/fetal differential methylation and another based on allelic difference. While the former failed to provide stable results, the latter was found to be promising and worthy of conducting a large-scale trial. One critical point in any NIPT approach is the determination of fetal cell-free DNA fraction, which dictates the reliability of obtained results for a given sample. We show that two different chromosome Y representation measures-by real-time PCR and by whole-genome massive parallel sequencing-are practically interchangeable (r=0.94). We also propose a novel method based on maternal/fetal allelic difference which is applicable in pregnancies with fetuses of either sex. Even in its pilot form it correlates well with chromosome Y coverage estimates (r=0.74) and can be further improved by increasing the number of polymorphisms.

Women's Experiences and Preferences for Service Delivery of Non-Invasive Prenatal Testing for Aneuploidy in a Public Health Setting: A Mixed Methods Study.

Non-invasive prenatal testing (NIPT) for aneuploidy is currently only available in the UK through the private sector outside of the research arena. As part of an implementation study in the UK National Health Service we conducted a mixed methods study to assess women’s experience of being offered NIPT using validated measures of decisional conflict, decisional regret and anxiety. Clinical service preferences were also explored. Women with a Down syndrome screening risk >1:1000 were invited to take part in the study and offered NIPT, NIPT and invasive testing (for women with a risk above 1:150) or no further testing. A cross-sectional survey and semi-structured interviews were conducted at two time points; at the time of testing and one month following receipt of results (or equivalent for NIPT decliners). In total, 845 questionnaires and 81 interviews were analysed. The main motivation to accept NIPT was for reassurance (30.8%). Decisional conflict occurred in a minimal number of cases (3.8%), however, none of the participants experienced decisional regret. Around a third (29.9%) of women had elevated anxiety at the time of testing, including intermediate risk women who traditionally would not be offered further testing (54.4% high risk; 20.1% medium risk), a finding supported through the qualitative interviews where prolonged or additional anxiety was found to occur in some medium risk cases. Women were overwhelmingly positive about the opportunity to have a test that was procedurally safe, accurate, reduced the need for invasive testing and identified cases of Down syndrome that might otherwise have been missed. Reassurance was identified as the main motivator for accepting NIPT, particularly amongst medium risk women, with high risk women inclined to accept NIPT to inform decisions around invasive testing. The current turnaround time for test result was identified as a key limitation. All the women interviewed thought NIPT should be adopted as part of NHS clinical practice, with the majority favouring NIPT offered as a first-line test. Our study highlights the potential that NIPT has to positively impact women’s experience of prenatal testing for aneuploidy.

Non-Invasive Prenatal Testing for Aneuploidy: A Review of the Literature

Aneuploidy is one of the leading causes of perinatal deaths and childhood handicaps. An important issue that has led to heated debates in the agenda of maternal-fetal medicine and that has been widely investigated in recent years is ‘the isolation of fetal deoxyribonucleic acid (DNA) from maternal blood. It is agreed that fetal DNA can be used in fetal aneuploidy screening and in predicting some pregnancy complications that are considered to be of placenta-based such as preeclampsia and preterm labor. The fetal DNA testing of maternal blood is regarded as an advanced screening test and generally named as ‘noninvasive prenatal test’ (NIPT). In this meta-study, we will review the accumulated data on the increasing clinical use of NIPT in perinatology as well as the other presently used conventional noninvasive aneuploidy screening methods.

Development and validation of a measure of informed choice for women undergoing non-invasive prenatal testing for aneuploidy.

Non-invasive prenatal testing (NIPT) using cell-free DNA for aneuploidy is a highly accurate screening test; however, concerns exist around the potential for routinisation of testing. The multidimensional measure of informed choice (MMIC) is a quantitative instrument developed to assess informed choice for Down syndrome screening (DSS). We have validated a modified MMIC for NIPT and measured informed choice among women offered NIPT in a public health service. The measure was distributed to women recruited across eight maternity units in the United Kingdom who had accepted DSS. Construct validity was assessed by simultaneously conducting qualitative interviews. Five hundred and eighty-five questionnaires were completed and 45 interviews conducted after blood-draw (or equivalent for those that declined NIPT). The measure demonstrated good internal consistency and internal validity. Results indicate the vast majority of women (89%) made an informed choice; 95% were judged to have good knowledge, 88% had a positive attitude and 92% had deliberated. Of the 11% judged to have made an uninformed choice, 55% had not deliberated, 41% had insufficient knowledge, and 19% had a negative attitude. Ethnicity (OR=2.78, P=0.003) and accepting NIPT (OR=16.05, P=0.021) were found to be significant predictors of informed choice. The high rate of informed choice is likely to reflect the importance placed on the provision of pre-test counselling in this study. It will be vital to ensure that this is maintained once NIPT is offered in routine clinical practice.

Erratum: Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening

Erratum: Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening

Non-invasive prenatal testing for aneuploidy: a systematic review of Internet advertising to potential users by commercial companies and private health providers.

The development of non-invasive prenatal testing has increased accessibility of fetal testing. Companies are now advertising prenatal testing for aneuploidy via the Internet. The aim of this systematic review of websites advertising non-invasive prenatal testing for aneuploidy was to explore the nature of the information being provided to potential users. We systematically searched two Internet search engines for relevant websites using the following terms: 'prenatal test', 'antenatal test', 'non-invasive test', 'noninvasive test', 'cell-free fetal DNA', 'cffDNA', 'Down syndrome test' or 'trisomy test'. We examined the first 200 websites identified through each search. Relevant web-based text was examined, and key topics were identified, tabulated and counted. To analyse the text further, we used thematic analysis. Forty websites were identified. Whilst a number of sites provided balanced, accurate information, in the majority supporting evidence was not provided to underpin the information and there was inadequate information on the need for an invasive test to definitely diagnose aneuploidy. The information provided on many websites does not comply with professional recommendations. Guidelines are needed to ensure that companies offering prenatal testing via the Internet provide accurate and comprehensible information.