T21 Cases Research Articles

A Novel Nomogram for Estimating a High-Risk Result in the EndoPredict® Test for Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Carcinoma

Background/Objectives: The EndoPredict® assay has been widely used in recent years to estimate the risk of distant recurrence and the absolute chemotherapy benefit for patients with estrogen (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, there are no well-defined criteria for selecting patients who may benefit from the test. The aim of this study was to develop a novel nomogram to estimate the probability of obtaining a high-risk EndoPredict® result in clinical practice. Methods: The study cohort comprised 348 cases of T1-3/N0-1a/M0 ER-positive/HER2-negative breast carcinoma. A multivariate analysis was conducted using a training cohort (n = 270) based on clinicopathological features that demonstrated a statistically significant correlation with the EndoPredict® result in a univariate analysis. The predictive model was subsequently represented as a nomogram to estimate the probability of obtaining a high-risk result in the EndoPredict® assay. The predictive model was then validated using a separate validation cohort (n = 78). Results: The clinicopathological features incorporated into the nomogram included tumor size, tumor grade, sentinel lymph node status, pN stage, and Ki67. The internal validation of the model yielded an area under the curve (AUC) of 0.803 (95% CI = 0.751, 0.855) in the receiver operating characteristic (ROC) curve for the training cohort, with an optimal sensitivity and specificity at a threshold of 0.536. The external validation yielded an AUC of 0.789 (95% CI = 0.689, 0.890) in its ROC curve, with optimal sensitivity and specificity achieved at a threshold of 0.393. Conclusions: This study presents, for the first time, the development of a clinically accessible nomogram designed to estimate the probability of obtaining a high-risk result in the EndoPredict® assay. The use of easily available clinicopathological features allows for the optimization of patient selection for the EndoPredict® assay, ensuring that those who would most benefit from undergoing the test are identified.

Cell-free DNA screening for common autosomal trisomies using rolling-circle replication in twin pregnancies.

To evaluate the performance of prenatal screening for common autosomal trisomies in twin pregnancies through the use of rolling-circle replication (RCR)-cfDNA as a first-tier test. Prospective multicenter study. Women who underwent prenatal screening for trisomy (T) 21, 18 and 13 between January 2019 and March 2022 in twin pregnancies were included. Patients were included in two centers. The primary endpoint was the rate of no-call results in women who received prenatal screening for common autosomal trisomies by RCR-cfDNA at the first attempt, compared to that in prospectively collected samples from 16,382 singleton pregnancies. The secondary endpoints were the performance indices of the RCR-cfDNA. 862 twin pregnancies underwent screening for T21, T18 and T13 by RCR-cfDNA testing at 10-33weeks' gestation. The RCR-cfDNA tests provided a no-call result from the first sample obtained from the patients in 107 (0.7%) singleton and 17 (2.0%) twin pregnancies. Multivariable regression analysis demonstrated that significant independent predictors of test failure were twin pregnancy and in vitro fertilization conception. All cases of T21 (n=20/862; 2.3%), T18 (n=4/862; 0.5%) and T13 (n=1/862; 0.1%) were correctly detected by RCR-cfDNA (respectively, 20, 4 and 1 cases). Sensitivity was 100% (95% CI, 83.1%-100%), 100% (95% CI 39.8%-100%) and 100% (95% CI 2.5%-100%) for T21, T18 and T13, respectively, in twin pregnancies. The RCR-cfDNA test appears to have good accuracy with a low rate of no-call results in a cohort of twin pregnancies for the detection of the most frequent autosomal trisomies.

Comparison of the performance of NIPT and NIPT-plus for fetal chromosomal aneuploidy and high Z-score increases the positive predictive value.

To evaluate non-invasive prenatal testing (NIPT) and expanded non-invasive prenatal testing (NIPT-plus) for detecting aneuploidies at different sequencing depths and assess Z-score accuracy in predicting trisomies 21, 18, 13, 45X, and 47XXX. Pregnancies with positive NIPT or NIPT-plus results detected at the prenatal diagnosis center of Nanfang Hospital were included in this retrospective study, between January 2017 and December 2022. Invasive prenatal diagnostic results were collected. Logistic regression analyses were used to study the relationship between Z-score and positive predictive value (PPV). Optimal cut-off values were obtained based on receiver operating characteristic analysis, and PPVs were calculated in different groups. We evaluated 1348 pregnant women with positive results, including 930 reported by NIPT and 418 reported by NIPT-plus. NIPT reported significantly more rare chromosomal aneuploidies (RCAs), and NIPT-plus had a significantly higher PPV for trisomy 21 (T21). Logistic regression analyses showed a significant association (P < 0.001) between Z-score and PPVs for T21 and trisomy 18 (T18). A linear relationship was observed between fetal fraction (FF) and Z-values in the true positive cases of T21 and T18.The high Z-score group had significantly higher PPVs than the low Z-score group for T21, T18, trisomy 13, and 47XXX, but not for 45X. The Z-score is helpful in assessing NIPT or NIPT-plus results. Therefore, we suggest including the Z-score and FF in the results. By combining the Z-score, FF, and maternal age, clinicians can interpret NIPT results more accurately and improve personal counsel to reduce patients' anxiety.

Application of non-invasive prenatal testing to 91,280 spontaneous pregnancies and 3477 pregnancies conceived by in vitro fertilization

BackgroundMany clinical studies based on spontaneous pregnancies (SPs) have demonstrated the superiority of non-invasive prenatal testing (NIPT), and the question of whether this technology is suitable for offspring conceived by assisted reproductive technology has attracted attention. This study aimed to evaluate the application value of NIPT in screening for trisomy (T)21, T18, T13 and sex chromosome aneuploidy (SCA) in pregnant women who conceived by in vitro fertilization (IVF).ResultsIn total, there were 804 high-risk cases [0.88% (804/91280), singleton = 795, twin = 9] in the SP group. Among the 558 invasive prenatal diagnosis (IPD) cases (singleton = 556, twin = 2), 343 (singleton = 342, twin = 1) were true positive, including 213 cases of T21, 28 of T18, 5 of T13 and 97 (singleton = 96, twin = 1) of SCA. The positive predictive values (PPVs) of T21, T18, T13, SCA and T21/T18/T13 combined in singleton pregnancy were 89.12% (213/239), 51.85% (28/54), 21.74% (5/23), 40.00% (96/240), and 77.85% (246/316), respectively, and the PPV of SCA in twin pregnancy was 100.00%. In the IVF group, IPD was performed in 19 (singleton = 16, twin = 3) of the 27 high-risk cases [0.78% (27/3477), singleton = 16, twin = 3], of which 9 (singleton = 8, twin = 1) were true positive, including 5 cases (singleton = 4, twin = 1) of T21 and 4 of SCA. The PPVs of singleton T21, SCA and T21/T18/T13 combined were 66.67% (4/6), 50.00% (4/8) and 57.14% (4/7), respectively, and the PPV of twin T21 was 100.00% (1/1). There were no significant differences in PPV among T21, SCA and T21/T18/T13 combined in singletons between the groups (89.12% vs. 66.67%, p = 0.09; 40.00% vs. 50.00%, p = 0.57; 77.85% vs. 57.14%, p = 0.20). The sensitivity and specificity were higher for singleton and twin pregnancies in the two groups. Based on follow-up results, 1 case of false negative T21 was found in the singleton SP group. Additionally, the mean foetal fraction (FF) of the IVF group was lower than that of the SP group (11.23% vs. 10.51%, p < 0.05).ConclusionNIPT has high sensitivity and specificity in screening chromosomal aneuploidies in both IVF pregnancy and spontaneous pregnancy, so it is an ideal screening method for IVF pregnancy.

Retrospective analysis of cell-free fetal DNA prenatal testing of maternal peripheral blood

To assess the value of non-invasive prenatal testing (NIPT) for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies, chromosomal microdeletions and microduplications using cell-free fetal DNA from peripheral blood samples of pregnant women. A total of 15 237 pregnant women who had undergone NIPT testing at the Maternity and Child Health Care Hospital of Zaozhuang from February 2015 to December 2021 were enrolled in this study. For those with a high risk by NIPT, amniotic fluid samples were collected for G-banding chromosomal karyotyping analysis and chromosomal microarray analysis to verify the consistency of NIPT with results of prenatal diagnosis. All of the women were followed up by telephone for pregnancy outcomes. Among the 15 237 pregnant women, 266 (1.75%) were detected with a high risk for fetal chromosomal abnormality were detected. Among these, 79 (29.7%) were at a high risk for T21, 26 (9.77%) were at a high risk for T18, 9 (3.38%) were at a high risk for T13, 74 (27.82%) were at a high risk for sex chromosome aneuploidies, 12 (4.51%) were at a high risk for other autosomal aneuploidies, and 66 (24.81%) were at a high risk for chromosomal microdeletions or microduplications. 217 women had accepted invasive prenatal diagnosis and respectively 50, 13, 1, 25, 1 and 18 were confirmed with T21, T18, T13, sex chromosome aneuploidies, autosomal aneuploidies and microdeletions/microduplications, and the positive predictive values were 75.76%, 68.42%, 11.11%, 40.32%, 10% and 35.29%, respectively. For 13 042 women (85.59%), the outcome of pregnancy were successfully followed up. During the follow-up, one false negative case of T21 was discovered. No false positive cases for T13 and T18 were found. NIPT has a sound performance for screening T13, T18 and T21, and is also valuable for screening other autosomal aneuploidies, sex chromosome aneuploidies and chromosomal microdeletions/microduplications.

Association between cell-free DNA fetal fraction and pregnant character: a retrospective cohort study of 27,793 maternal plasmas

To determine the association between cell-free DNA fetal fraction (cffDNA) and various prenatal characters to better guide the clinical application of noninvasive prenatal screening (NIPS), a retrospective cohort study of 27,793 women with singleton pregnancies was conducted. Results indicated that no significant difference on cffDNA between trisomy/sex chromosome aneuploidy (SCA) and non-trisomy groups was found. However, the fetal fraction (FF) in the T18 and T13 subgroups were significantly lower than that in the non-trisomy group, while the FF in the T21 group was significantly higher than the non-trisomy group. Pearson’s correlation analysis revealed a positive correlation between √FF and gestational week in the T21, SCA, and non-trisomy groups. A negative correlation between maternal age and √FF in T21 and non-trisomy cases was found, but a positive correlation in SCA group. Compared to the decreasing trend in FF in the T21 group, no significant difference was observed in the SCA group. The √FF level was negatively correlated to maternal BMI in T21 and non-trisomy group, while a positive correlation in SCA group. FF was close related to the result of NIPS and related maternal factors. Though NIPS has increased accuracy, the complexity still should be recognized especially in clinical practice.

Evaluation of the clinical effects of non-invasive prenatal screening for diseases associated with aneuploidy and copy number variation.

To explore and compare the clinical effects of high-resolution non-invasive prenatal screening (NIPS-Plus) for common/uncommon chromosomal aneuploidy and microdeletion/microduplication syndromes (MMS). The current prospective study included a total of 25,380 pregnant women who performed NIPS-Plus, and amniocentesis was performed on women with MMS with the screening results to diagnose patients with suspected MMS. There were 415 samples with positive results for NIPS-Plus, included 275 with aneuploidy and 140 with MMS. After diagnosis by amniocentesis, 188 cases were confirmed as true positive, included46 cases of T21, 9 cases of T18, 1 case of T13, 34 cases of SCA, 41 cases of other chromosomal euploidy and 57 cases of MMS. In addition, no false negative cases were found, MMS was classified with 5 Mb with the cutoff value, and the PPV of different fragment size was counted, respectively. We found that the corresponding PPV was 44.66% with the fragment of copy number variation (CNV) being less than or equal to 5 Mb, and when it was greater than 5 Mb, the PPV was 29.73%, which suggested that NIPS-Plus was more suitable for screening the PPV of small fragment abnormalities. NIPS-Plus has a good application effect in routine aneuploidy screening and had the best detection effect for T21; moreover, it performed well in screening of MMS and had better detection effect on MMS with CNV fragment length less than 5 Mb. Based on the current results, we suggested that NIPS-Plus should be used as a comprehensive elementary prenatal screening method for all pregnant women, but for MMS caused by abnormal large fragment CNV, the detection method and efficiency still need to be improved.

Effect of trisomy 21 on long-term gastrointestinal outcomes in duodenal atresia.

We aimed to determine if Trisomy 21 (T21) affected gastrointestinal outcomes for children with duodenal atresia (DA). We identified children born with DA between 1991 and 2017. Cases were divided into DA with T21 and DA without T21. Ten healthy controls per case were included. Esophageal, ulcerative, obstructive and stomach complaints were assessed. Risk ratios (RR), rate ratios (RaR) and Cox models were constructed. Analyses were performed for cases versus controls, and for T21 cases versus non-T21 cases. DA cases totaled 52: 22 had T21 and 30 did not. There were 520 controls. DA cases had more gastrointestinal complaints than controls. T21 cases were at greater risk and frequency of esophageal disease than non-T21 cases (RR = 4.08, p = 0.002, RaR = 69.8, p < 0.001). T21 and non-T21 cases were equally likely to present with obstruction (RR = 0.91, p = 1), but T21 cases complained of obstructive symptoms less (RaR = 0.57, p = 0.003). T21 and non-T21 cases had the same risk of stomach diseases, but T21 cases complained more frequently (RaR = 6.20, p < 0.001). Cox models supported these observations. T21 did not affect ulcerative diseases. DA cases had more gastrointestinal problems than controls. T21 increased esophageal and gastric complaints in DA cases but did not affect ulcerative and obstructive complaints.

Survival rates and outcomes of pregnancies with prenatal diagnosis of trisomy 18: A 16-year experience from a public hospital in South Africa.

Many studies, largely from high-income countries (HIC), have reported outcomes in babies with trisomy 18 (T18), with a paucity of data from Africa. Knowledge of outcomes is important in counselling women prenatally diagnosed with T18. We aimed to review all prenatally diagnosed cases of T18 between January 2006 and December 2021. Demographic data, diagnosis, gestation and outcome data were obtained from the Astraia® database and patient files. We included 88 pregnant women of whom 46 terminated their pregnancies (30 beyond 24weeks' gestation). Three underwent foeticides, one had a caesarean section for maternal obstetric reasons and 26 underwent inductions of labour without foetal monitoring. Four neonates were live born but none lived >8h. In those who continued their pregnancies, the mean gestation at delivery was 34.8weeks, 14 (33%) were live births and only 5 survived for >24h with none surviving to 1year of life. In our cohort, infants with T18 had lower live birth rates and shorter survival than in the current literature from HIC. This may be due to the implementation of non-aggressive intrapartum care and comfort care for the neonates. This has implications for counselling in our setting.

Non-invasive prenatal testing for the detection of trisomy 13, 18, and 21 and sex chromosome aneuploidies in 68,763 cases.

Objectives: Non-invasive prenatal testing (NIPT) has been widely used in recent years. According to clinical experience from all hospitals providing prenatal screening services in Beijing, we explored the feasibility of using NIPT for the analysis of common foetal aneuploidies among pregnancies. Methods: In total, 68,763 maternal blood samples were collected from January 2020 to December 2020 at the Beijing prenatal diagnosis agency. Cases with positive screening results by NIPT detection were validated using prenatal diagnosis. Results: In total, 920 cases had a high-risk NIPT result, and 755 cases were shown to be truly positive by a chromosome karyotyping analysis; the prenatal diagnosis rate was 82.07% (755/920). Of the920 cases, there were 164 cases of T21, 70 cases of T18, 38 cases of T13, 360 cases of SCAs and 288 cases of other chromosomal abnormalities. The positive rates of T21, T18, T13, and SCAs were 0.24% (164/68,763), 0.10% (70/68,763), 0.06% (38/68,763) and 0.52% (360/68,763), respectively. The sensitivity and specificity were 98.17% and 99.92% for T21, 96.15% and 99.93% for T18, and 100% and 99.95% for T13, respectively. The PPVs of T21,T18,T13 and SCAs were65.24% (107/164), 35.71% (25/70), 18.42% (7/38) and 31.39% (113/360), respectively. For all indications, there were more higher T21/18/13 in the high-risk group than in the low-risk group (comprising only cases of voluntary request), with a positive rate of 0.46% vs. 0.27% (p < 0.001), sensitivity of 99.16% vs. 91.30% (p = 0.02) and PPV of 56.73%vs.32.81% (p = 0.001), but there was no significant difference in specificity between the groups (p = 0.71). The detection indication with the highest PPV (100%) by NIPT was ultrasound structural abnormalities and ultrasound soft marker abnormalities for T21 and ultrasound structural abnormalities and NT thickening for T18 and T13. The PPVs of different clinical indications of T21 (p = 0.002), T13 (p = 0.04) and SACs (p = 0.02) were statistically significant. Conclusion: The high specificity, efficiency and safety (non-invasiveness) of NIPT can effectively improve the detection rate of common chromosomal aneuploidy, thereby reducing the occurrence of birth defects. We should encourage pregnant women with NIPT-high-risk results to undergo a prenatal diagnosis to determine whether the foetus has chromosomal abnormalities. More importantly, the screening efficiency of NIPT in the low-risk group was significantly lower than that in the high-risk group. Therefore, the use of NIPT in low-risk groups should be fully promoted, and socioeconomic benefits should be considered.

Whole genome non-invasive prenatal testing in prenatal screening algorithm: clinical experience from 12,700 pregnancies

BackgroundA fast adoption of a non–invasive prenatal testing (NIPT) in clinical practice is a global tendency last years. Firstly, in Russia according a new regulation it was possible to perform a widescale testing of pregnant women in chromosomal abnormality risk. The aim of the study—to assess efficiency of using NIPT as a second-line first trimester screening test in Moscow.MethodsBased on the first trimester combined prenatal screening results 12,700 pregnant women were classified as a high-risk (cut-off ≥ 1:100) and an intermediate-risk (cut-off 1:101 – 1:2500) groups followed by whole genome NIPT. Women from high-risk group and those who had positive NIPT results from intermediate-risk group were considered for invasive prenatal diagnostic.Results258 (2.0%) samples with positive NIPT results were detected including 126 cases of trisomy 21 (T21), 40 cases of T18, 12 cases of T13, 41 cases of sex chromosome aneuploidies (SCAs) and 39 cases of rare autosomal aneuploidies (RAAs) and significant copy number variations (CNVs). Statistically significant associations (p < 0.05) were revealed for fetal fraction (FF) and both for some patient’s (body mass index and weight) and fetus’s (sex and high risk of aneuploidies) characteristics. NIPT showed as a high sensitivity as specificity for common trisomies and SCAs with an overall false positive rate 0.3%.ConclusionsNIPT demonstrated high sensitivity and specificity. As a second-line screening test it has shown a high efficiency in detecting fetus chromosomal anomalies as well as it could potentially lower the number of invasive procedures in pregnant women.

Optimizing care and consultation in trisomy 13 and 21

The paradigm that infants with trisomy 13 (T13) or trisomy 18 (T18) do not benefit from supportive care was driven largely by a dearth of data surrounding if and how survival outcomes change with medical and/or surgical intervention. In this volume, Coretzzo et al. assess outcomes in and characteristics of a retrospective cohort of pre- and post-natal cases of T13 and T18 using a population-based and multi-centered approach.

Expanding the application of non-invasive prenatal testing in the detection of foetal chromosomal copy number variations

PurposeThe aim of this study was to assess the detection efficiency and clinical application value of non-invasive prenatal testing (NIPT) for foetal copy number variants (CNVs) in clinical samples from 39,002 prospective cases.MethodsA total of 39,002 pregnant women who received NIPT by next-generation sequencing (NGS) with a sequencing depth of 6 M reads in our centre from January 2018 to April 2020 were enrolled. Chromosomal microarray analysis (CMA) was further used to diagnose suspected chromosomal aneuploidies and chromosomal microdeletion/microduplication for consistency assessment.ResultsA total of 473 pregnancies (1.213%) were positive for clinically significant foetal chromosome abnormalities by NIPT. This group comprised 99 trisomy 21 (T21, 0.254%), 30 trisomy 18 (T18, 0.077%), 25 trisomy 13 (T13, 0.064%), 155 sex chromosome aneuploidy (SCA, 0.398%), 69 rare trisomy (0.177%), and 95 microdeletion/microduplication syndrome (MMS, 0.244%) cases. Based on follow-up tests, the positive predictive values (PPVs) for the T21, T18, T13, SCA, rare trisomy, and MMS cases were calculated to be 88.89%, 53.33%, 20.00%, 40.22%, 4.88%, and 49.02%, respectively. In addition, the PPVs of CNVs of < 5 Mb, 5–10 Mb, and > 10 Mb were 54.55%, 38.46%, and 40.00%, respectively. Among the 95 cases with suspected CNVs, 25 were diagnosed as true positive and 26 cases as false positive; follow-up prenatal diagnosis by CMA was not performed for 44 cases. Moreover, among the 25 true positive cases, 10 were pathogenic, 3 were likely pathogenic, and 12 were of uncertain significance.ConclusionNIPT is not only suitable for screening T21, T18, T13, and SCA but also has potential significance for CNV detection. As combined with ultrasound, extended NIPT is effective for screening MMS. However, NIPT should not be recommended for whole-chromosome aneuploidy screening.

The Natural History of Trisomy 21: Outcome Data from a Large Tertiary Referral Centre

Objective: The aim of the study was to prospectively gather data on pregnancy outcomes of prenatally diagnosed trisomy 21 (T21) in a large tertiary referral centre. Methods: Data were gathered prospectively in a large tertiary referral centre over 5 years from 2013 to 2017 inclusively. Baseline demographic and pregnancy outcome data were recorded on an anonymized computerized database. Results: There were 1,836 congenital anomalies diagnosed in the study period including 8.9% (n = 165) cases of T21. 79% (n = 131) were age 35 or older at diagnosis. 79/113 (69.9%) women chose a termination of pregnancy (TOP) following a diagnosis of T21. Amongst pregnancies that continued, there were 4 second-trimester miscarriages (4/34, 11.7%), 9 stillbirths (9/34, 26.4%), and 1 neonatal death, giving an overall pregnancy and neonatal loss rate of 14/34 (41.1%). Conclusion: The risk of foetal loss in prenatally diagnosed T21 is high at 38% with an overall pregnancy loss rate of 41.1%. This information may be of benefit when counselling couples who are faced with a diagnosis of T21 particularly in the context of limited access to TOP.

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.

Performance of cell-free DNA sequencing-based non-invasive prenatal testing: experience on 36,456 singleton and multiple pregnancies

BackgroundThis paper describes the clinical practice and performance of cell-free DNA sequencing-based non-invasive prenatal testing (NIPT) as a screening method for fetal trisomy 21, 18, and 13 (T21, T18, and T13) and sex chromosome aneuploidies (SCA) in a general Italian pregnancy population.MethodsThe AMES-accredited laboratory offers NIPT in maternal blood as a screening test for fetal T21, T18, T13 and SCA. Samples were sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay.ResultsA retrospective analysis was performed on 36,456 consecutive maternal blood samples, including 35,650 singleton pregnancies, 800 twin pregnancies, and 6 triplet pregnancies. Samples were tested between April 2017 and September 2019. The cohort included 46% elevated-risk and 54% low-risk patients. A result indicative of a classic trisomy was found in 356 (1%) of singleton or twin samples: 254 T21, 69 T18, and 33 T13. In addition, 145 results (0.4%) were indicative of a SCA. Of the combined 501 screen-positive cases, 484 had confirmatory diagnostic testing. NIPT results were confirmed in 99.2% (247/249) of T21 cases, 91.2% (62/68) of T18 cases, 84.4% (27/32) of T13 cases, and 86.7% (117/135) of SCA cases. In the 35,955 cases reported as unaffected by a classic trisomy or SCA, no false negative cases were reported. Assuming that false negative results would be reported, the sensitivity of NIPT was 100.00% for T21 (95% Cl 98.47–100.0), T18 (95% Cl 94.17–100.0), and T13 (95% Cl 87.54–100.0). The specificities were 99.99% (95% Cl 99.98–100.0), 99.98% (95% Cl 99.96–100.0), 99.99% (95% Cl 99.97–100.0), and 99.95% (95% Cl 99.92–99.97) for T21, T18, T13, and SCA, respectively.ConclusionThis retrospective analysis of a large cohort of consecutive patients who had whole-genome sequencing-based NIPT for classic trisomies and SCA shows excellent detection rates and low false positive rates.

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

PurposeTo evaluate the noninvasive prenatal testing (NIPT) results of 36,913 cases in Jiangxi province of central China and explore its application value in prenatal screening and diagnosis.MethodsThis retrospective analysis included 36,913 singleton pregnant women who underwent NIPT because of moderate-/high-risk pregnancy or voluntary requirements between January 2017 and December 2019 in our hospital. Chromosomal abnormalities such as trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs) were judged by standard Z-score analysis. Positive NIPT results were confirmed by amniocentesis and karyotyping. Pregnancy outcomes were followed up via telephone interview.ResultsA total of 1.01% (371/36,913) positive cases were detected by NIPT, comprising 137, 46, 31, and 157 cases of T21, T18, T13, and SCAs, respectively. A total of 116 of T21, 27 of T18, 13 of T13, and 51 of SCAs were confirmed to be true positive; all normal cases that had been followed up were verified to be true negative. The NIPT sensitivity in T21, T18, T13, and SCAs was 100.00% individually, whereas the specificity was 99.94% (36,488/36,509), 99.95% (36,579/36,598), 99.95% (36,594/36,612), and 99.72% (36,472/36,574), respectively. Furthermore, the negative predictive values of T21, T18, T13, and SCAs were all 100%, while the positive predictive values were 84.67%, 58.70%, 41.94%, and 33.33%, respectively.ConclusionNIPT is highly sensitive and has a low false positive rate in testing clinically significant fetal aneuploidies of general reproductive women. However, this technique cannot substitute for amniocentesis and karyotyping, and detailed genetic counseling is also essential for the high-risk group of NIPT.

First-trimester presentation of ultrasound findings in trisomy 13 and validation of multiparameter ultrasound-based risk calculation models to detect trisomy 13 in the late first trimester.

To identify the most common ultrasound patterns of markers and anomalies associated with Patau syndrome (PS), to explore the efficacy of multiparameter sonographic protocols in detecting trisomy 13 (T13) and to analyze the influence of maternal age (MA) on screening performance. The project was a prospective study based on singleton pregnancies referred for a first-trimester screening examination. The scan protocol included nuchal translucency (NT), fetal heart rate (FHR), secondary ultrasound markers [nasal bone (NB), tricuspid regurgitation (TR), ductus venosus reversed a-wave (revDV)] and major anomaly findings. The study population comprised 6133 pregnancies: 6077 cases of euploidy and 56 cases of T13. Statistically significant differences were found in MA, FHR, NT, absence of NB, presence of revDV, TR and single umbilical artery. Fourteen cases of T13 (25%) demonstrated no markers of aneuploidy. The best general detection rate (DR) (DR of 78.6% with an false positive rate (FPR) of 1.2%) was obtained for a cutoff of 1/300 utilizing the "NT+T13" algorithm. The logistic regression model revealed that the central nervous system (CNS) anomalies had the greatest odds ratio (of 205.4) for T13. The effectiveness of the multiparameter sonographic protocol used for T13 screening showed promising results in patients older than 36 years and suboptimal results in patients between 26 and 36 years old. When screening for T13 left heart defects, CNS anomalies, abdominal anomalies, FHR above the 95th percentile, increased NT, revDV and lack of NB should receive specific attention.

State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.

To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Clinical and Economic Evaluation after Adopting Contingent Cell-Free DNA Screening for Fetal Trisomies in South Spain

Introduction: Contingent cell-free (cf) DNA screening on the basis of the first-trimester combined test (FCT) results has emerged as a cost-effective strategy for screening of trisomy 21 (T21). Objectives: To assess performance, patients’ uptake, and cost of contingent cfDNA screening and to compare them with those of the established FCT. Methods: This is a prospective cohort study including all singleton pregnancies attending to their FCT for screening of T21 at 2 university hospitals in South Spain. When the FCT risk was ≥1:50, there were major fetal malformations, or the nuchal translucency was ≥3.5 mm, women were recommended invasive testing (IT); if the risk was between 1:50 and 1:270, women were recommended cfDNA testing; and for risks bellow 1:270, no further testing was recommended. Detection rate (DR), false-positive rate (FPR), patients’ uptake, and associated costs were evaluated. Results: We analyzed 10,541 women, including 46 T21 cases. DR of our contingent strategy was 89.1% (41/46) at 1.4% (146/10,541) FPR. Uptake of cfDNA testing was 91.2% (340/373), and overall IT rate was 2.0%. The total cost of our strategy was €1,462,895.7, similar to €1,446,525.7 had cfDNA testing not been available. Conclusions: Contingent cfDNA screening shows high DR, low IT rate, and high uptake at a similar cost than traditional screening.