Non-invasive prenatal testing: Special interest groups vs women's autonomy.

Non-invasive prenatal testing (NIPT) for trisomies 21, 18, 13 and monosomy X is widely utilized with massively parallel shotgun sequencing (MPSS), digital analysis of selected regions (DANSR), and single nucleotide polymorphism (SNP) analyses being the most widely reported methods. We searched the literature to find all NIPT clinical validation and clinical experience studies between January 2011 and January 2022. Meta-analyses were performed using bivariate random-effects and univariate regression models for estimating summary performance measures across studies. Bivariate meta-regression was performed to explore the influence of testing method and study design. Subgroup and sensitivity analyses evaluated factors that may have led to heterogeneity. Based on 55 validation studies, the detection rate (DR) was significantly higher for retrospective studies, while the false positive rate (FPR) was significantly lower for prospective studies. Comparing the performance of NIPT methods for trisomies 21, 18, and 13 combined, the SNP method had a higher DR and lower FPR than other methods, significantly so for MPSS, though not for DANSR. The performance of the different methods in the 84 clinical experience studies was consistent with validation studies. Clinical positive predictive values of all NIPT methods improved over the last decade. We conclude that all NIPT methods are highly effective for fetal aneuploidy screening, with performance differences across methodologies.

Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions in Average-Risk Pregnancies: A Cost-Effectiveness Analysis.

The term 'Non invasive prenatal testing' is used to describe the rapidly emerging molecular technologies related to cell free DNA assessment that are being applied to prenatal screening for Down syndrome and other chromosomal abnormalities. This technology is now available to Australian women through a number of off-shore laboratories. We review the basis of this method of testing, the literature describing the effectiveness of NIPT in screening for trisomy 21 and the potential methods by which this tool could be incorporated into current screening strategies.

To examine combined first trimester screening (FTS), noninvasive prenatal testing (NIPT) and a two-step policy that combines FTS and NIPT in screening for aneuploidy. Retrospective study involving 21,052 pregnancies where FTS was performed at the Praxis Praenatal.de in Duesseldorf, Germany. In each case, the sum risk of trisomy 21, 18 and 13 was computed. We assumed that NIPT detects 99 %, 98 %, 90 % and 99 % of cases with trisomy 21, 18, 13 and sex chromosomal abnormalities and that the false-positive rate is 0.5 %. The following screening policies were examined: NIPT or FTS with sum risk cut-offs of 1 in 50 and 1 in 250 in all patients or a two-step-policy with FTS in all patients followed by NIPT in the intermediate sum risk group. For the intermediate risk group, sum risk cut-offs of 1 in 50 and 1 in 1000 and 1 in 150 and 1 in 500 were used. There were 127, 34, 13 and 15 pregnancies with trisomy 21, 18, 13 and sex chromosomal abnormalities. 23 fetuses had other chromosomal abnormalities with an increased risk for adverse outcome that are not detectable by NIPT. 20,840 pregnancies were classified as normal as ante- and postnatal examinations did not show any signs of clinically significant chromosomal abnormalities. FTS with a sum risk cut-off of 1 in 50 and 1 in 250 detects 81 % and 91 % for all aneuploidies. NIPT detects 88 % of the respective pregnancies. The 2-step approach with sum risk cut-offs of 1 in 50 and 1 in 1000 detects 94 % of all aneuploidies. With sum risk cut-offs of 1 in 150 and 1 in 500, the detection rate is 93 %. A 2-step policy with FTS for all patients and NIPT in the intermediate risk group results in the highest detection rate of all aneuploidies.

Recent advancements in high-throughput sequencing have validated the accuracy, safety, and effectiveness of non-invasive prenatal testing (NIPT) for Down syndrome (DS). This study aims to assess the effectiveness and economic implications of NIPT versus second-trimester serum screening (STSS) for DS and the different screening strategies through retrospectively analyzing data from 140,472 pregnant women who completed both NIPT and STSS (provided for free by local public welfare programs) between March 1, 2018 and December 31, 2020. Data were categorized into eight groups based on different screening strategies. The sensitivity, specificity, and positive predictive value of NIPT for detecting trisomy 21 were significantly higher compared with those of STSS. The universal NIPT screening strategy demonstrated the best effectiveness, detecting 163 DS cases with the highest net benefit and a cost-effectiveness ratio of 1:9.53. The STSS and NIPT combined screening strategy detected 128 DS cases with the lowest cost-effectiveness at RMB 341,800. The incremental cost-effectiveness ratio of the universal NIPT screening strategy was RMB 1,186,200, significantly lower than the socioeconomic burden associated with a DS case. NIPT demonstrated significantly superior testing performance compared to STSS. At a unit cost of RMB 600, the universal NIPT screening strategy is the most effective and holds substantial health economic value.

Counseling for non-invasive prenatal testing (NIPT): what pregnant women may want to know

The performance of noninvasive prenatal testing (NIPT) in monochorionic diamniotic twin pregnancies with treatment of assisted reproductive techniques (ART)

The value of detailed first-trimester ultrasound in the era of noninvasive prenatal testing

Prenatal aneuploidy screening changed significantly in 2012 when cell-free fetal deoxyribonucleic acid (DNA) was introduced as a noninvasive prenatal test. A noninvasive prenatal test detects cell free fragments of fetal DNA from the placenta circulating in maternal blood that coexist with cell-free DNA (cfDNA) of maternal origin. Using next-generation sequencing, the noninvasive prenatal test compares maternal and fetal cfDNA ratios for chromosomes of interest (i.e., 21, 18, 13, X, and Y) to assess chromosomal aneuploidy. Compared to traditional screening using ultrasound and serum markers, the noninvasive prenatal test has superior test characteristics, including a higher detection rate and positive predictive value, and a lower false-positive rate. The noninvasive prenatal test is already used for primary screening in high-risk women and is rapidly expanding to all women. Given its increasing use, understanding the noninvasive prenatal test's limitations is critical. Discordant results (i.e. noninvasive prenatal test is positive for aneuploidy with a normal fetal karyotype) can occur because of biological processes such as aneuploidy confined to the placenta, a vanished twin, maternal aneuploidy or maternal cancer. Use of the noninvasive prenatal test for screening beyond the most common aneuploidies is not recommended. The noninvasive prenatal test is a major advance in prenatal aneuploidy screening but it is not diagnostic and does not replace invasive testing (i.e. chorionic villous sampling or amniocentesis) for confirmation of fetal chromosomal disorders.

Personalized medicine for the embryo and the fetus - Options in modern genetics influence preconception and prenatal choices.

Genome-wide sequencing of maternal plasma cell-free DNA (cfDNA) enables non-invasive prenatal testing (NIPT) of all 24 chromosomes. An expanded NIPT approach can identify rare autosomal trisomies (RATs). However, this is not without interpretative challenges. More evidence is needed to determine pregnancy outcome in cases of RAT detected by NIPT. Between January 2016 and December 2017, a total of 42 924 maternal blood samples were received from Dongguan, Guangdong Province, China, for NIPT as a first-tier screening test as part of a government-funded pilot program. The suggested gestational age for NIPT was 12–22 weeks, and a nuchal translucency or second-trimester ultrasound examination before blood sampling was mandatory. We documented 72 (0.17%) NIPT results positive for RAT, 11 of which were excluded from this study because of loss to follow-up. Trisomy 7 was the most commonly detected RAT, followed equally by trisomies 3 and 16. Pregnancy characteristics, NIPT results and pregnancy outcome are summarized in Table 1. Placental karyotyping confirmed confined placental mosaicism in 54 cases, and the remaining seven had normal placental and maternal lymphocyte karyotype. Nineteen cases opted for amniocentesis, all of which showed normal karyotype; among these, only five (three at risk for trisomy 14 and two at risk for trisomy 15) opted for additional chromosomal microarray analysis, which did not show unbalanced rearrangements or uniparental disomy (UPD) in any case. At follow-up, isolated intrauterine growth restriction (IUGR) was identified in one case of trisomy 16 and one of compound trisomy 7/8. There was no case with a sonographic structural anomaly. All neonates were karyotyped, and none had evidence of true fetal mosaicism. In this study, we found no correlation between NIPT Z-score value and the percentage of abnormal cells observed in the placenta. However, these cell percentages might not represent the true condition of the affected placentas because of biopsy samplingbias. Several genome-wide cfDNA-based NIPT studies have reported RATs in association with a range of pregnancy complications, including miscarriage, true fetal mosaicism and UPD, as well as IUGR1–3. However, our results indicate favorable pregnancy outcome. Ninety-five percent of our cases had an uncomplicated pregnancy. Three reasons might contribute to this discrepancy. First, the a-priori risk in our population may explain the lower incidence of pregnancy complications. Our patients came from the general rather than a high-risk population, as in other studies. As a result, NIPT was positive for RAT in only 0.17% of cases, which is much lower than that (0.43%) in a previous study1. Second, the fact that all NIPT samples were taken only after a pretest ultrasound examination may also explain the relatively favorable outcome, as most of the affected fetuses would have been identified before performing NIPT. Third, the gestational age at NIPT in our study was relatively late, further reducing the incidence of finding an affected pregnancy. We observed a positive predictive value (PPV) of 0 for RATs. Expanding the range of aneuploidies that NIPT targets compounds this problem. Our results showed that RATs are most often mosaic and confined to the placenta. It seems that the risk of adverse pregnancy outcome associated with confined placental mosaicism for RATs is not higher than that in the general population, except for trisomy 164,5. Nevertheless, we found that the PPVs for RATs reflected closely those predicted by placental data. Eighty-eight percent of positive NIPT cases were confirmed by placental investigation. Although the clinical utility of expanding NIPT to include RATs has yet to be demonstrated and, as such, the clinical implementation of this testing is premature in the general population, screening for RATs using NIPT might benefit pregnancy management in some specific situations such as in cases of IUGR with a normal chromosomal microarray analysis result.

There is great need for the development of highly accurate cost effective technologies that could facilitate the widespread adoption of noninvasive prenatal testing (NIPT). We developed an assay based on the targeted analysis of cell-free DNA for the detection of fetal aneuploidies of chromosomes 21, 18, and 13. This method enabled the capture and analysis of selected genomic regions of interest. An advanced fetal fraction estimation and aneuploidy determination algorithm was also developed. This assay allowed for accurate counting and assessment of chromosomal regions of interest. The analytical performance of the assay was evaluated in a blind study of 631 samples derived from pregnancies of at least 10 weeks of gestation that had also undergone invasive testing. Our blind study exhibited 100% diagnostic sensitivity and specificity and correctly classified 52/52 (95% CI, 93.2%-100%) cases of trisomy 21, 16/16 (95% CI, 79.4%-100%) cases of trisomy 18, 5/5 (95% CI, 47.8%-100%) cases of trisomy 13, and 538/538 (95% CI, 99.3%-100%) normal cases. The test also correctly identified fetal sex in all cases (95% CI, 99.4%-100%). One sample failed prespecified assay quality control criteria, and 19 samples were nonreportable because of low fetal fraction. The extent to which free fetal DNA testing can be applied as a universal screening tool for trisomy 21, 18, and 13 depends mainly on assay accuracy and cost. Cell-free DNA analysis of targeted genomic regions in maternal plasma enables accurate and cost-effective noninvasive fetal aneuploidy detection, which is critical for widespread adoption of NIPT.

Purpose: Our study’s primary objective is to assess the knowledge and attitudes regarding non-invasive prenatal testing (NIPT) to screen for 22q11.2 deletion syndrome in healthcare providers caring for obstetrical patients. Introduction: 22q11.2 deletion syndrome is a clinically significant microdeletion syndrome associated with substantial morbidity and mortality. Non-invasive prenatal testing (NIPT) has revolutionized prenatal screening, offering a non-invasive method to detect various genetic abnormalities, including 22q11.2 deletion. Despite its potential benefits, the integration of NIPT for 22q11.2 deletion into clinical practice remains inconsistent. This study aims to assess the knowledge and attitudes of healthcare providers towards NIPT for 22q11.2 deletion, shedding light on current practices and identifying gaps in provider education and confidence in patient counseling. By understanding these factors, we can better inform future clinical guidelines and educational initiatives to enhance the utilization of NIPT in prenatal care. Methods: A cross-sectional survey using an online multiple-choice format was conducted among healthcare providers in OB/GYN departments and Maternal-Fetal Medicine divisions at an academic medical center and a large referral center-community hospital system in Northwest Ohio. Participants included trainees, staff, and faculty members, who accessed the anonymous survey via a link or QR code. The survey, administered using QuestionPro software, is comprised of 18 multiple-choice questions covering demographics, clinical use of carrier and NIPT screening, and knowledge and attitudes towards NIPT for 22q11.2 deletion syndrome. The Delphi method was employed to achieve consensus on the final question list. Data collection began on April 23, 2024 and was completed on June 5, 2024. Results: Thirteen physicians completed the survey: five OB/GYN residents, six OB/GYN generalists, and two Maternal-Fetal Medicine specialists. All non-trainee respondents had at least five years of practice experience. All physicians reported using NIPT for fetal aneuploidies (Trisomies 21, 18, and 13), and 92% offered carrier screening. The initial data indicated variability in the use of NIPT based on years in practice. None of the residents reported using NIPT for sex chromosome aneuploidies or microdeletion syndromes, including 22q11.2 deletion. Conversely, all experienced physicians used expanded NIPT panels, with 50% selecting 22q11.2 screening as an add-on. 63% of experienced physicians screened all obstetric patients for 22q11.2 deletion, whereas the other physicians in our sample selected screening only for patients who presented with a detected fetal congenital anomaly or family history of aneuploidy or other genetic disorder. Additionally, 88% of experienced physicians offered multiple NIPT options, compared to 100% of residents who offered a single option which excludes 22q11.2 screening. Regarding provider knowledge, 15% (two experienced OB/GYN physicians) incorrectly equated screening sensitivities for 22q11.2 deletion and common Trisomies. Only 46% of respondents, including both Maternal-Fetal Medicine specialists, felt adequately informed to counsel patients on 22q11.2 deletion screening. However, 77% indicated confidence in managing positive screening results. Conclusions: Given the significant morbidity and mortality associated with 22q11.2 deletion syndrome, early intervention via expanded NIPT is clinically beneficial. However, the performance of NIPT for 22q11.2 deletion lags behind that of the common Trisomies, with an 83% sensitivity reported. Insufficient research exists on how clinicians utilize this information for patient counseling. Our study highlights that only trained physicians use NIPT for 22q11.2 deletion, with limited confidence in counseling. These findings underscore the need for enhanced education during residency to ensure comprehensive patient counseling. Continued recruitment aims to expand these initial findings to inform future clinical recommendations and standardize counseling guidelines.

Objectives: The aim of this study is to gain a rich understanding of early experiences with emerging non-invasive prenatal diagnosis (NIPD) and non-invasive prenatal testing (NIPT) testing technologies. The study aims to identify issues of common interest and concern to both patients and professionals located in a wide variety of settings. Methods: This qualitative PhD study is based on data gathered through a total of forty-three in-depth (narrative) interviews with patients and professionals in the UK. Twenty-three experts with direct professional experience of NIPD or NIPT (including scientists, fetal medicine consultants, policy makers and genetic counsellors) were interviewed, along with ten patients with direct experience of NIPD or NIPT, and ten parents with more general experience of prenatal screening or diagnosis. Clinicians involved in both the NHS-based provision of NIPD and the private provision of NIPT participated in the study. The interviews yielded a rich and diverse dataset, and were analysed for crosscutting themes. Results: A number of core themes were identified as being of significance across the data set. These included: test accuracy; the boundary between NIPD and NIPT; the boundary between ‘high risk’ and ‘low risk’ populations; hopes around NIPT as a possible replacement technology; anxieties around the possible routinisation of selective termination; tensions between the aims of public health screening programmes and individualised care. Conclusions: The rapid development of NIPD and NIPT has very quickly given rise to a diverse and rich set of patient and professional experiences. The issues of interest and concern identified within patient and professional accounts of this new testing technology present a complex ethical, legal, political and social landscape. Knowledge of these early experiences with NIPD and NIPT may enable a better understanding of the advantages these tests may offer, as well as practical and ethical problems that are likely to arise in future, as both NIPD and NIPT become further embedded in specialist clinical practice and routine prenatal care.

The aim of this paper was to conduct a systematic review of the cost-effectiveness of the analysis of cell-free DNA in maternal blood, often called the non-invasive prenatal test (NIPT), in the prenatal screening of trisomy in chromosomes 21, 18 and 13. MEDLINE, MEDLINE in process, EMBASE, and Cochrane Library were searched in April 2017. We selected: (1) economic evaluations that estimated the costs and detected cases of trisomy 21, 18 or 13; (2) comparisons of prenatal screening with NIPT (universal or contingent strategies) and the usual screening without NIPT, (3) in pregnant women with any risk of foetal anomalies. Studies were reviewed by two researchers. Data were extracted, the methodological quality was assessed and a narrative synthesis was prepared. In total, 12 studies were included, four of them performed in Europe. Three studies evaluated NIPT as a contingent test, three studies evaluated a universal NIPT, and six studies evaluated both. The results are heterogeneous, especially for the contingent NIPT where the results range from NIPT being dominant to a dominated strategy. Universal NIPT was found to be more effective but also costlier than the usual screening, with very high incremental cost-effectiveness ratios. One advantage of screening with NIPT is lower invasive procedure-related foetal losses than with usual screening. In conclusion, the cost-effectiveness of contingent NIPT is uncertain according to several studies, while the universal NIPT is not cost-effective currently.