Non-invasive Prenatal Testing Screening Research Articles

Noninvasive prenatal screening in southeast China: clinical application and accuracy evaluation

ABSTRACT Objective To assess the clinical performance of noninvasive prenatal screening (NIPS) for both common trisomy and sex chromosome aneuploidy (SCA). Methods We recruited 71,888 pregnant women to undergo NIPS testing from December 2015 to June 2021. Demographic characteristics, diagnostic results, and follow-up outcomes were collected. Results There were a total of 381 high-risk cases for common trisomy and 343 positive screens for SCA. Invasive prenatal diagnosis (IPD) was performed in 507 (70.0%) participants. The positive predictive value (PPV) was 83.7% for T21, 72.5% for T18, 14.3% for T13, 31.9% for 45,X, 72.0% for 47,XXX, 89.8% for 47,XXY, and 72.2% for 47,XYY, respectively. Logistic regression analysis presented a significant association between Z-score and PPV in common trisomy (P < 0.05) while not in SCA (P > 0.05). PPV in the high-risk group (Z-score ≥ cutoff) was superior to that in the intermediate risk group (3 ≤ Z-score < cutoff) for T21/T18/T13. PPV for 45,X, 47,XXY, and 47,XYY tended to be higher with the increasing Z-score, except for 47,XXX. Conclusions NIPS would be a valuable strategy in prenatal screening, while cautions should be kept in mind for subsequent genetic consulting about the risk of Z-score.

Combining Z-Score and Maternal Copy Number Variation Analysis Increases the Positive Rate and Accuracy in Non-Invasive Prenatal Testing.

Objective: To evaluate positive rate and accuracy of non-invasive prenatal testing (NIPT) combining Z-score and maternal copy number variation (CNV) analysis. To assess the relationship between Z-score and positive predictive value (PPV). Methods: This prospective study included 61525 pregnancies to determine the correlation between Z-scores and PPV in NIPT, and 3184 pregnancies to perform maternal CNVs analysis. Positive results of NIPT were verified by prenatal diagnosis and/or following-up after birth. Z-score grouping, logistic regression analysis, receiver operating characteristic (ROC) curves, and S-curve trends were applied to correlation analysis of Z-scores and PPV. The maternal CNVs were classified according to the technical standard for the interpretation of ACMG. Through genetic counseling, fetal and maternal phenotypes and family histories were collected. Results: Of the 3184 pregnant women, 22 pregnancies were positive for outlier Z-scores, suggesting fetal aneuploidy. 12 out of 22 pregnancies were true positive (PPV = 54.5%). 17 pregnancies were found maternal pathogenic or likely pathogenic CNVs (> 0.5 Mb) through maternal CNV analysis. Prenatal diagnosis revealed that 7 out of 11 fetuses carried the same CNVs as the mother. Considering the abnormal biochemical indicators during pregnancy and CNV-related clinical phenotypes after birth, two male fetuses without prenatal diagnosis were suspected to carry the maternally-derived CNVs. Further, we identified three CNV-related family histories with variable phenotypes. Statistical analysis of the 61525 pregnancies revealed that Z-scores of chromosomes 21 and 18 were significantly associated with PPV at 3 ≤ Z ≤ 40. Notably, three pregnancies with Z > 40 were both maternal full aneuploidy. At Z < -3, fetuses carried microdeletions instead of monosomies. Sex chromosome trisomy was significantly higher PPV than monosomy. Conclusion: The positive rate of the NIPT screening model combining Z-score and maternal CNV analysis increased from 6.91‰ (22/3184) to 12.25‰ (39/3184) and true positives increased from 12 to 21 pregnancies. We found that this method could improve the positive rate and accuracy of NIPT for aneuploidies and CNVs without increasing testing costs. It provides an early warning for the inheritance of pathogenic CNVs to the next generation.

Peripheral Blood Microbiome Analysis via Noninvasive Prenatal Testing Reveals the Complexity of Circulating Microbial Cell-Free DNA.

ABSTRACTWhile circulating cell-free DNA (cfDNA) is becoming a powerful marker for noninvasive identification of infectious pathogens in liquid biopsy specimens, a microbial cfDNA baseline in healthy individuals is urgently needed for the proper interpretation of microbial cfDNA sequencing results in clinical metagenomics. Because noninvasive prenatal testing (NIPT) shares many similarities with the sequencing protocol of metagenomics, we utilized the standard low-pass whole-genome-sequencing-based NIPT to establish a microbial cfDNA baseline in healthy people. Sequencing data from a total of 107,763 peripheral blood samples of healthy pregnant women undergoing NIPT screening were retrospectively collected and reanalyzed for microbiome DNA screening. It was found that more than 95% of exogenous cfDNA was from bacteria, 3% from eukaryotes, and 0.4% from viruses, indicating the gut/environment origins of many microorganisms. Overall and regional abundance patterns were well illustrated, with huge regional diversity and complexity, and unique interspecies and symbiotic relationships were observed for TORCH organisms (Toxoplasma gondii, others [Treponema pallidum {causing syphilis}, hepatitis B virus {HBV}, and human parvovirus B19 {HPV-B19}], rubella virus, cytomegalovirus [CMV], and herpes simplex virus [HSV]) and another common virus, Epstein-Barr virus (EBV). To sum up, our study revealed the complexity of the baseline circulating microbial cfDNA and showed that microbial cfDNA sequencing results need to be interpreted in a more comprehensive manner.IMPORTANCE While circulating cell-free DNA (cfDNA) has been becoming a powerful marker for noninvasive identification of infectious pathogens in liquid biopsy specimens, a baseline for microbial cfDNA in healthy individuals is urgently needed for the proper interpretation of microbial cfDNA sequencing results in clinical metagenomics. Standard low-pass whole-genome-sequencing-based NIPT shares many similarities with the sequencing protocol for metagenomics and could provide a microbial cfDNA baseline in healthy people; thus, a reference cfDNA data set of the human microbiome was established with sequencing data from a total of 107,763 peripheral blood samples of healthy pregnant women undergoing NIPT screening. Our study revealed the complexity of circulating microbial cfDNA and indicated that microbial cfDNA sequencing results need to be interpreted in a more comprehensive manner, especially with regard to geographic patterns and coexistence networks.

Noninvasive Prenatal Test Results Indicative of Maternal Malignancies: A Nationwide Genetic and Clinical Follow-Up Study.

Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. Diagnostic routing after malignancy suspicious-NIPT faces many challenges. Here, we detail malignancy suspicious-NIPT cases, and describe the clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Clinical lessons can be learned from our experience. Patients with NIPT results indicative of a malignancy referred for tumor screening between April 2017 and April 2020 were retrospectively included from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. Malignancy suspicious-NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, and a malignancy was confirmed in 16 patients (16/23, 69.6%). After targeted NIPT, 0.005% malignancy suspicious-NIPT results were reported, in 2/3 patients a malignancy was confirmed. Different tumor types and stages were diagnosed, predominantly hematologic malignancies (12/18). NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Referral for extensive oncologic examination is recommended, and may be guided by tumor-specific hallmarks in the NIPT profile.

RHD exon 5, 7 and 10 targeted non-invasive prenatal screening of fetal Rhesus-D (RhD) in selected RhD negative pregnant women in Ethiopia.

BackgroundA majority of non-invasive prenatal screening studies determining fetal RhD status have been tested on Caucasian and Asian populations, but limited or no studies have been conducted on the Ethiopian population. In the current study, we carried non-invasive prenatal screening of fetal RHD genotype in selected RhD negative Ethiopian pregnant women.MethodsCell-free DNA was extracted from the plasma samples of 117 RhD pregnant women between 9 and 38 weeks of gestation. Fetal RHD genotypes were detected by targeting exons 5, 7 and 10 of the RHD gene by using real-time PCR assay. RHD genotypic results were confirmed by neonatal cord blood serology.ResultsFetal RHD genotyping was conclusive in all 117 subjects. RHD genotype was correctly predicted in 115 of 117 cases, thus the test yielded 98.3% accuracy (95%CI: 97.3–99.1%). Among 115 cases, 105 were genotyped as RHD positive and 12 were genotyped as RHD negative. The sensitivity and specificity of the test were 99.1% (95% CI: 94.8–99.9%) and 91.7% (95%CI: 61.5–99.7%) respectively. The negative and positive predictive values were 99.9% (95%CI: 99.2–99.9%) and 54.0% (95% CI: 15.2–88.4%) respectively. SRY genotyping results were in complete concordance with fetal sex.ConclusionMulti exon targeted non-invasive prenatal screening test for fetal RhD determination exhibited high accuracy and sensitivity. A confirmatory study with a bigger size of study subjects is warranted before enabling clinical implementation.

EP463: Inconclusive Duchenne Muscular Dystrophy (DMD) carrier screening and atypical SNP-based NIPS sex chromosomes analysis suggest maternal sex chromosome abnormality

As of 2021, ACMG has expanded the recommended carrier screening panel to constitute 113 genes, now including the X-linked Duchenne Muscular Dystrophy (DMD) gene. Copy number variant (CNV) analysis by next-generation sequencing (NGS) of DMD yields inconclusive results for a small number of individuals due to the duplication/deletion of all DMD exons and adjacent regions on the X chromosome. In addition, a small number of SNP-based noninvasive prenatal screening (NIPS) tests yield no results for sex chromosomes due to a suspected maternal X chromosome abnormality.

Niet-invasieve prenatale testen: detecteren van numerieke afwijkingen van geslachtschromosomen. Is het wenselijk om deze informatie mee te delen aan zwangere vrouwen?

Non-invasive prenatal screening: detection of sex chromosomal aneuploidies. Desirability of reporting these findings to pregnant women On 30 April 2021, the Belgian Advisory Committee on Bioethics issued opinion No. 76 regarding the desirability to report sex chromosomal aneuploidies (SCAs) detected by non-invasive prenatal testing (NIPT). Debate is ongoing in the medical community as to whether it is appropriate to report an SCA of the fetus to the pregnant woman when this abnormality is detected by a genome-wide NIPT. This question presupposes that SCAs should be screened for in the first place. This does not necessarily have to be the case, neither technically nor ethically: if a targeted genome screening was to be conducted instead of the nowadays preferred genome-wide approach, these SCAs would not be automatically identified. The Committee argues that there are insufficient reasons for including SCAs in standard prenatal NIPT screening and reporting. Good quality pre- and post-test counseling is paramount to make sure that expectant parents are making decisions they feel comfortable with down the line. This requires manageable information about the general aim, scope and method of NIPT screening, the reliability and validity of the test, the need to perform invasive prenatal testing in case of positive results, clarity on what the results may imply, and information that extends beyond medical descriptions of the conditions screened for. The Committee stresses that this condition is, at this moment, insufficiently met.

A microfluidic platform for high-purity cell free DNA extraction from plasma for non-invasive prenatal testing.

Increase the yield and purity of cell-free DNA (cfDNA) extracted from plasma for non-invasive prenatal testing (NIPT) as inefficiencies in this extraction and purification can dramatically affect the sensitivity and specificity of the test. This work integrates cfDNA extraction from plasma with a microfluidic chip platform by combining magnetic bead-based extraction and electroosmotic flow on the microfluidic chip. Various wash buffers and voltage conditions were simulated using COMSOL Multiphysics Modeling and tested experimentally. When performing the first wash step of this assay on the microfluidic chip with 300V applied across the channel there was a six-fold increase in the A260 /A230 ratio showing a significant improvement (p value 0.0005) in the purity of the extracted sample all while maintaining a yield of 68.19%. These values are critical as a high yield results in more sample to analyze and an increase in A260 /A230 ratio corresponds to a decrease in salt contaminants such as guanidinium thiocyanate which can interfere with downstream processes during DNA library preparation and potentially hinder the NIPT screening results. This technique has the potential to improve NIPT outcomes and other clinically relevant workflows that use cfDNA as an analyte such as cancer detection.

Clinical experience with non-invasive prenatal screening for single-gene disorders.

ABSTRACTObjectiveTo assess the performance of a non‐invasive prenatal screening test (NIPT) for a panel of dominant single‐gene disorders (SGD) with a combined population incidence of 1 in 600.MethodsCell‐free fetal DNA isolated from maternal plasma samples accessioned from 14 April 2017 to 27 November 2019 was analyzed by next‐generation sequencing, targeting 30 genes, to look for pathogenic or likely pathogenic variants implicated in 25 dominant conditions. The conditions included Noonan spectrum disorders, skeletal disorders, craniosynostosis syndromes, Cornelia de Lange syndrome, Alagille syndrome, tuberous sclerosis, epileptic encephalopathy, SYNGAP1‐related intellectual disability, CHARGE syndrome, Sotos syndrome and Rett syndrome. NIPT‐SGD was made available as a clinical service to women with a singleton pregnancy at ≥ 9 weeks' gestation, with testing on maternal and paternal genomic DNA to assist in interpretation. A minimum of 4.5% fetal fraction was required for test interpretation. Variants identified in the mother were deemed inconclusive with respect to fetal carrier status. Confirmatory prenatal or postnatal diagnostic testing was recommended for all screen‐positive patients and follow‐up information was requested. The screen‐positive rates with respect to the clinical indication for testing were evaluated.ResultsA NIPT‐SGD result was available for 2208 women, of which 125 (5.7%) were positive. Elevated test‐positive rates were observed for referrals with a family history of a disorder on the panel (20/132 (15.2%)) or a primary indication of fetal long‐bone abnormality (60/178 (33.7%)), fetal craniofacial abnormality (6/21 (28.6%)), fetal lymphatic abnormality (20/150 (13.3%)) or major fetal cardiac defect (4/31 (12.9%)). For paternal age ≥ 40 years as a sole risk factor, the test‐positive rate was 2/912 (0.2%). Of the 125 positive cases, follow‐up information was available for 67 (53.6%), with none classified as false‐positive. No false‐negative cases were identified.ConclusionsNIPT can assist in the early detection of a set of SGD, particularly when either abnormal ultrasound findings or a family history is present. Additional clinical studies are needed to evaluate the optimal design of the gene panel, define target populations and assess patient acceptability. NIPT‐SGD offers a safe and early prenatal screening option. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Trends in Non-invasive Prenatal Screening and Invasive Testing in Denmark (2000-2019) and Israel (2011-2019).

Introduction: Following the wide distribution of non-invasive prenatal genetic screening (NIPS), numerous studies have reported a decline in total invasive tests in the recent years, up to 50–70% in some countries. However, in Denmark and Israel we have not experienced these declines. The objective of our study was to evaluate the trends in NIPS and chromosomal microarray analysis (CMA) use in Denmark and Israel.Methods: This retrospective study was performed by data acquisition from the Danish Cytogenetics Central Registry throughout the years 2000–2019, and Israeli Public Health Services, Ministry of Health computerized database (from 2011).Results: Of the 1,243,956 live births registered in Denmark over the years 2000–2019, a relatively steady level of invasive testing around 6% was noted since 2004, as opposed to 13.0% in Israel based on 1,594,962 live births between 2011 and 2019. The average uptake of NIPS was 1.1 ± 0.5% in Denmark vs. 4.3% in Israel (2013–2019). Relatively steady rates of invasive testing were noted in both countries, compared to a slight decline in NIPS in the recent years.Discussion: The recent decrease in the rates of invasive testing in the NIPS era was not observed in Denmark or in Israel. These results imply that Danish and Israeli women and/or health providers might favor the high resolution and yield of CMA testing over the non-invasiveness of NIPS. We explore and discuss this phenomenon, based on five central factors.

The effect of co-payments on the take-up of prenatal tests

Noninvasive prenatal screening tests help identify genetic disorders in a fetus, but their take-up remains low in several countries. Using a regression discontinuity design, we test the causal effect of a policy that eliminated co-payments for noninvasive screening tests in Italy. We identify the treatment effects by a discontinuity in women's eligibility for a free test based on their conception date. We find that the policy increases the probability of women's undergoing noninvasive screening tests by 5.5 percentage points, and the effect varies by socioeconomic status. We do not find evidence of substitution effects with more expensive and riskier invasive diagnostic tests. In addition, the increase in take-up does not affect pregnancy termination or newborn health. We find some evidence of positive effects on mothers’ health behaviors during pregnancy as measured by reductions in mothers’ weight gain and hospital admissions during pregnancy, but these are statistically significant only at the 10 percent level.

Nanostructures in non-invasive prenatal genetic screening.

Prenatal screening is an important issue during pregnancy to ensure fetal and maternal health, as well as preventing the birth of a defective fetus and further problems such as extra costs for the family and society. The methods for the screening have progressed to non-invasive approaches over the recent years. Limitations of common standard screening tests, including invasive sampling, high risk of abortion and a big delay in result preparation have led to the introduction of new rapid and non-invasive approaches for screening. Non-invasive prenatal screening includes a wide range of procedures, including fetal cell-free DNA analysis, proteome, RNAs and other fetal biomarkers in maternal serum. These biomarkers require less invasive sampling than usual methods such as chorionic villus sampling, amniocentesis or cordocentesis. Advanced strategies including the development of nanobiosensors and the use of special nanoparticles have provided optimization and development of NIPS tests, which leads to more accurate, specific and sensitive screening tests, rapid and more reliable results and low cost, as well. This review discusses the specifications and limitations of current non-invasive prenatal screening tests and introduces a novel collection of detection methods reported studies on nanoparticles' aided detection. It can open a new prospect for further studies and effective investigations in prenatal screening field.

Clinical effect of expanded non-invasive prenatal testing for serological screening of fetuses with high-risk for Down's syndrome

To investigate the clinical effect of expanded non-invasive prenatal testing (NIPT-plus) for serological screening of fetuses with high-risk for Down's syndrome. To retrospectively study the screening results, prenatal diagnosis and pregnancy outcomes of 1561 midterm pregnant women underwent NIPT-plus in our center from September 2018 to December 2019 due to serological screening with high-risk for Down's syndrome(≥ 1/270). 45 pregnant women had a high-risk with a detection rate of 2.88% (45/1561) of 1561 pregnant women who performed NIPT-plus. 40 pregnant women underwent invasive prenatal diagnosis and 20 cases were confirmed with a positive predictive value of 50.0% (20/40). Statistical analysis showed that NIPT-plus has a high detection rate for trisomy 21, sex chromosomal aneuploidy, and MMS in the 0.1/90 group, but with a positive predictive value lower than the other two groups. The detection rate and PPVs of NIPT-plus in different groups of Down's high-risk pregnant women was different. NIPT-plus can reduce the pressure of prenatal diagnosis and can be used as a screening method for Down's syndrome with high risk in pregnant women.

Non-invasive prenatal testing (NIPT) and pregnant women's views on good motherhood: a qualitative study.

Women's views on responsible motherhood influence decision-making regarding participation in prenatal screening. Previous studies showed that the probabilistic nature of the first-trimester combined test and the potential requirement for subsequent invasive diagnostics serve as legitimate reasons for women to exclude prenatal screening from their moral responsibilities. These moral barriers might now be less relevant with the introduction of the non-invasive prenatal test (NIPT) resulting in women feeling a moral duty to use NIPT screening as part of responsible motherhood. This qualitative study explores the impact of NIPT on women's moral beliefs about the meaning of prenatal screening in relation to responsible motherhood. We performed semi-structured interviews with 29 pregnant women who were offered NIPT as a first-tier screening test within a Dutch nationwide study (TRIDENT-2). Results show that the inherent uncertainty about the fetus's health despite improved accuracy and the lack of treatment for a detected disorder, combined with the possibility to obtain information about actionable anomalies through the fetal anomaly scan, support women's perspectives that NIPT is not an obligation of responsible motherhood. Acceptance of NIPT is considered to be a free decision related to the information each woman needs to be a good mother for her child and her family. Women's views may change when NIPT has expanded to include treatable or preventable conditions.

Low fetal fraction in obese women at first trimester cell‐free DNA based prenatal screening is not accompanied by differences in total cell‐free DNA

Reasons for first trimester noninvasive prenatal screening (NIPS) test failure in obese women remain elusive. As dilution from maternal sources may be explanatory, we determined the relationship between obesity, fetal fraction (FF), and total cell-free DNA (cfDNA) using our NIPS platform. We assessed differences in first trimester (≤14weeks) FF, indeterminate rate, and total cfDNA between obese (n=518) and normal-weight women (n=237) after exclusion of confounders (anticoagulation, autoimmunity, aneuploidy) and controlling for covariates. Fetal fraction was lower, and the indeterminate rate higher, in obese compared to controls (9.2%±4.4 vs. 12.5%±4.5, p<0.001 and 8.4 vs. 1.7%, p<0.001, respectively), but total cfDNA was not different (92.0 vs. 82.1 pg/µl, p=0.10). For each week, the FF remained lower in obese women (all p<0.01) but did not increase across the first trimester for either group. Obesity increased the likelihood of indeterminate result (OR 6.1, 95% CI 2.5, 14.8; p<0.001) and maternal body mass index correlated with FF (β -0.27, 95% CI -0.3, -0.22; p<0.001), but not with total cfDNA (β 0.49, 95% CI -0.55, 1.53; p=0.3). First trimester obese women have persistently low FF and higher indeterminate rates, without differences in total cfDNA, suggesting placental-specific mechanisms versus dilution from maternal sources as a potential etiology.

Progress of research on clinical use of non-invasive prenatal screening for special groups of pregnant women

As a prenatal testing for chromosomal abnormalities, non-invasive prenatal testing (NIPT) has been integrated into prenatal healthcare service. NIPT has shown a high sensitivity and specificity for screening fetal trisomies 13, 18 and 21, and has attained excellent clinical results. With the propagation of the NIPT screening, international organizations have issued guidelines and comments for its clinical utility with regular updating. China has also developed guidelines for NIPT in 2016. NIPT guidelines in various countries have provided valuable guidance for its target diseases and suitable patient groups, but there has been few research data on its clinical application for special groups of patients. Based on the guidelines and comments of various professional bodies and published data on the clinical utility of NIPT, in addition with consideration of the conditions in China, clinical utility of NIPT for particular groups of pregnant women, including those with advanced maternal age, obesity, twin pregnancy and fetal ultrasonographic anomalies, are reviewed. The value of genetic counseling for NIPT is also emphasized, which is critical for the clinical application of NIPT.

The potential of expanded noninvasive prenatal screening for detection of microdeletion and microduplication syndromes.

To evaluate the clinical potential of a higher resolution noninvasive prenatal screening (NIPS-Plus) test for detection of microdeletion/microduplication syndromes (MMS) in addition to common aneuploidies. In a multicenter prospective study, 37,002 pregnant women with unremarkable first-trimester ultrasound scans had a NIPS-Plus test. Ultrasound screen positive women were not included in this study. Of 36,970 ultrasound negative women there were 291 NIPS-Plus screen positive results indicating 237 aneuploidies and 54 MMS. Following amniocentesis, 171 (72%) were confirmed as genuine, comprising 3 T13s, 10 T18s, 61 T21s, 70 SCAs and 27 MMS. The PPV for MMS with unremarkable ultrasound findings was 50%. Routine clinical examination of children born from NIPS-Plus negative pregnancies revealed no obvious signs of chromosome disease syndromes at one year of age. NIPS-Plus has the potential for clinical utility not only for routine aneuploid screening but also for MMS that do not show overt signs during early pregnancy ultrasound screening. We suggest that ultrasound with NIPS-Plus in combination with appropriate counselling could be considered as a comprehensive first-tier prenatal screening approach for all pregnant women.

Introducing the non-invasive prenatal testing for detection of Down syndrome in China: a cost-effectiveness analysis

ObjectiveThis study aimed to compare the health economic value of a non-invasive prenatal testing (NIPT) strategy against a second-trimester triple screening (STS) strategy for the detection of Down syndrome based...

Utility of noninvasive genome-wide screening: a prospective cohort of obstetric patients undergoing diagnostic testing

PurposeCopy-number variant (CNV) assessment is recommended for patients undergoing prenatal diagnostic testing. Noninvasive screening tests have not been extensively validated for CNV detection. The objective of this study was to compare the ability of genome-wide noninvasive prenatal screening (NIPS) to chromosomal microarray to detect clinically significant findings. MethodsWe prospectively enrolled 198 subjects at the time of consent for diagnostic prenatal testing. Genome-wide NIPS results were compared with diagnostic testing results to assess NIPS test performance (n = 160, 38 subjects without microarray results excluded). Cohen’s kappa statistic was used to assess test agreement. ResultsGenome-wide NIPS did not detect clinically significant chromosomal abnormalities at the same rate as diagnostic testing, κ = 0.75 (95% confidence interval [CI], 0.62–0.87). When excluding CNVs <7 Mb and findings outside the limits of genome-wide NIPS, test agreement improved, κ = 0.88 (0.79–0.97) driven by agreement for common aneuploidies (κ = 1.0). However, among patients with an abnormal fetal survey, agreement was only fair, κ = 0.38 (0.08–0.67). ConclusionWhile NIPS is an excellent screening test for common aneuploidies, genome-wide NIPS misses clinically significant findings detected on routine diagnostic testing. False positive and false negative cases highlight the importance of pretest counseling regarding NIPS limitations, especially in the setting of fetal anomalies.

Performance of non-invasive prenatal testing for foetal chromosomal abnormalities in 1048 twin pregnancies

ObjectiveTo investigate the clinical value of non-invasive prenatal testing (NIPT) to screen for chromosomal abnormalities in twin pregnancies and to provide further data on NIPT manifestations in twin pregnancies.Materials and methodsIn a 4-year period, 1048 women with twin pregnancies were voluntarily prospectively tested by NIPT to screen for chromosomal abnormalities by sequencing cell-free foetal DNA (cffDNA) in maternal plasma. Positive NIPT results were confirmed by karyotyping, while negative results were followed up 42 days after delivery.ResultsThirteen women had positive NIPT results as follows: 2 cases of trisomy 21 (T21), 1 of trisomy 18 (T18), 7 of sex chromosome aneuploidy (SCA), 1 of microdeletion, and 2 of microduplication. Of these 13 cases, 2 were true-positive cases confirmed by foetal karyotype analysis, namely, 1 case of T21 and 1 of microdeletion. Furthermore, the remaining 11 high-risk pregnant women were confirmed as false positive by foetal karyotyping. Thus, the combined positive predictive value (PPV) of NIPT screening for chromosomal abnormalities in twin pregnancies was 15.4% (2/13). There were no false-negative case via our follow-up results.ConclusionSafe and rapid NIPT has a certain clinical application value; however, the PPV is limited, and the screening efficiency is not stable. Careful use should be made in the screening of chromosomal abnormalities in twin pregnancies.