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Background: Next-generation sequencing is emerging as a viable alternative to chromosome microarray analysis for the diagnosis of chromosome disease syndromes. One next-generation sequencing methodology, copy number variation sequencing, has been shown to deliver high reliability, accuracy, and reproducibility for detection of fetal copy number variations in prenatal samples. However, its clinical utility as a first-tier diagnostic method has yet to be demonstrated in a large cohort of pregnant women referred for fetal chromosome testing., Objective: We sought to evaluate copy number variation sequencing as a first-tier diagnostic method for detection of fetal chromosome anomalies in a general population of pregnant women with high-risk prenatal indications., Study Design: This was a prospective analysis of 3429 pregnant women referred for amniocentesis and fetal chromosome testing for different risk indications, including advanced maternal age, high-risk maternal serum screening, and positivity for an ultrasound soft marker. Amniocentesis was performed by standard procedures. Amniocyte DNA was analyzed by copy number variation sequencing with a chromosome resolution of 0.1 Mb. Fetal chromosome anomalies including whole chromosome aneuploidy and segmental imbalances were independently confirmed by gold standard cytogenetic and molecular methods and their pathogenicity determined following guidelines of the American College of Medical Genetics for sequence variants., Results: Clear interpretable copy number variation sequencing results were obtained for all 3429 amniocentesis samples. Copy number variation sequencing identified 3293 samples (96%) with a normal molecular karyotype and 136 samples (4%) with an altered molecular karyotype. A total of 146 fetal chromosome anomalies were detected, comprising 46 whole chromosome aneuploidies (pathogenic), 29 submicroscopic microdeletions/microduplications with known or suspected associations with chromosome disease syndromes (pathogenic), 22 other microdeletions/microduplications (likely pathogenic), and 49 variants of uncertain significance. Overall, the cumulative frequency of pathogenic/likely pathogenic and variants of uncertain significance chromosome anomalies in the patient cohort was 2.83% and 1.43%, respectively. In the 3 high-risk advanced maternal age, high-risk maternal serum screening, and ultrasound soft marker groups, the most common whole chromosome aneuploidy detected was trisomy 21, followed by sex chromosome aneuploidies, trisomy 18, and trisomy 13. Across all clinical indications, there was a similar incidence of submicroscopic copy number variations, with approximately equal proportions of pathogenic/likely pathogenic and variants of uncertain significance copy number variations. If karyotyping had been used as an alternate cytogenetics detection method, copy number variation sequencing would have returned a 1% higher yield of pathogenic or likely pathogenic copy number variations., Conclusion: In a large prospective clinical study, copy number variation sequencing delivered high reliability and accuracy for identifying clinically significant fetal anomalies in prenatal samples. Based on key performance criteria, copy number variation sequencing appears to be a well-suited methodology for first-tier diagnosis of pregnant women in the general population at risk of having a suspected fetal chromosome abnormality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To evaluate in twin pregnancy the utility of non-invasive prenatal testing using circulating cell-free fetal DNA (cfDNA) in screening for the three main autosomal fetal trisomies., Methods: cfDNA testing was offered to 492 patients with a twin pregnancy without ultrasound anomaly as a first-line screening test or after routine serum screening. Data were collected prospectively and a retrospective analysis was performed. cfDNA analysis was performed by massively parallel sequencing. The fetal-fraction threshold used for test evaluation was 8%. Regression analysis was performed to investigate the effect on the test failure rate of maternal and pregnancy characteristics, and the performance of the test was also reported., Results: cfDNA analysis was performed as a first-line test (after the first-trimester scan) in 377 patients and following serum screening in 115. Of the 420 pregnancies for which outcome was available and cfDNA screening was assessed, 78.7% were dichorionic-diamniotic. The test failed on the first attempt in 12 (2.9%) pregnancies, and regression analysis demonstrated that only maternal weight was a significant independent predictor of test failure. A result was subsequently achieved in the 10 cases for which a second sample was obtained. cfDNA analysis identified all three cases of trisomy 21 and the only case of trisomy 18. For trisomy 21, the specificity was 99.8% (95% CI, 98.7-100.0%). When considering pregnancies according to whether they were conceived spontaneously or after assisted reproductive technology, there were no significant differences in terms of maternal weight or no-result rate for cfDNA screening between these two groups., Conclusions: In twin pregnancy without fetal ultrasound abnormality, cfDNA screening for trisomies 21, 18 and 13 had a high success rate and good performance. Therefore, in routine practice, cfDNA analysis could be considered as a first- or second-line screening test. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

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.

Management of children with trisomy 13 (T13) is controversial because of a paucity of evidence of the natural history, especially focusing on efficacy of treatment. There has been no report regarding natural history of children with T13 receiving intensive neonatal and pediatric treatment without cardiac surgery, although several reports have suggested efficacy of cardiac surgery. To describe the detailed and comprehensive natural history of children with T13 receiving intensive neonatal and pediatric treatment without cardiac surgery, we reviewed clinical information of 24 children with full T13 (15 boys, 9 girls) who were admitted to Nagano Children's Hospital from 1994 to 2016. Intensive neonatal and pediatric treatment without cardiac surgery was provided through careful discussion with the parents. We detailed accurate frequencies of complications, survival, underlying factors and the final modes of death, and psychomotor development of survivors. Unpublished complications including aortopulmonary window, pulmonary-ductus-descending aorta-trunk, biliary system abnormalities, eosinophilic enteritis, and neuroblastoma were described. Accurate frequencies of congenital heart defects (92%) and laryngomalacia and/or tracheomalacia (42%) were determined. The median survival time was 451 days and the 1-year survival rate was 54%. The major underlying factor associated with death was congenital heart defects and heart failure (63%) and the major final mode of death was heart failure (50%). Long-term survivors appeared to show slow but constant psychomotor development. Intensive neonatal and pediatric treatment without cardiac surgery for children with T13 is efficient for survival and psychomotor development, and could be a reasonable choice for parents having fetuses or children with T13., (© 2018 Wiley Periodicals, Inc.)

Cell-free DNA screening has quickly become established in Australia as an accurate - albeit costly - prenatal screening test for trisomy 21, 18 and 13. It is also commonly used for the detection of sex chromosome abnormalities. The increasing number of prenatal screening pathways available to women has increased the complexity of pretest counselling. Concurrent advances in diagnostic testing with the widespread use of chromosomal microarrays create further challenges for the continuing education of clinicians and health consumers. This article aims to answer common clinical questions in this rapidly evolving field and complements the recently updated Royal Australian and New Zealand College of Obstetricians and Gynaecologists Statement on Prenatal Screening for Fetal Chromosome and Genetic Conditions., (© 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Purpose: The purpose of the study was to determine the screening performance of prenatal reflex DNA screening for trisomies 21 (T21), 18 (T18), and 13 (T13) as part of a routine service at five hospitals., Methods: Women who accepted screening had a first-trimester combined test (pregnancy-associated plasma protein A, free β-human chorionic gonadotropin, nuchal translucency interpreted with maternal age). Those with a risk of having an affected pregnancy ≥1 in 800 were reflexed to a DNA sequencing test using stored plasma from the original blood sample, thereby avoiding the need to recall them., Results: Of 22,812 women screened (including 106 with affected pregnancies), 2,480 (10.9%) were reflexed to DNA testing; 101/106 were detected (69/73 T21, 24/25 T18, and 8/8 T13), a 95% detection rate (95% confidence interval 89-98%) with four false positives (0.02%, 95% confidence interval 0.00-0.05%). The odds of being affected given a positive result were 25:1. Of the 105 screen-positive pregnancies, 91 (87%) had an invasive diagnostic test. Reflex DNA screening avoided up to 530 invasive diagnostic tests compared with using the combined test., Conclusion: Reflex DNA screening was successfully implemented in routine care, achieving a high detection rate, low false-positive rate, and, consequently, greater safety with fewer invasive diagnostic tests than other methods of screening.

Objectives: To evaluate parental decisions following a prenatal diagnosis of trisomy 13 (T13) or trisomy 18 (T18), prenatal counseling received, and pregnancy outcomes., Study Design: Single-center, retrospective cohort study of families with a prenatal diagnosis of T13 or T18 from 2000 to 2016., Results: Out of 152 pregnancies, 55% were terminated. Twenty percent chose induction with palliative care, 20% chose expectant management, 2% chose full interventions, and 3% were lost to follow-up. Counseling was based on initial parental goals, but most women were given options besides termination. Women who chose expectant management had a live birth in 50% of the cases. Women who chose neonatal interventions had a live birth in 100% of the cases, but there were no long-term survivors., Conclusions: The majority of women who continue their pregnancy after a fetal diagnosis of T13 or T18 desire expectant management with palliative care. A live birth can be expected at least half of the time.

Massively parallel sequencing of circulating fetal DNA in the plasma of pregnant women is a common method for noninvasive prenatal testing (NIPT) of fetal trisomy 13, 18, and 21. However, circulating DNA is not restricted to pregnant women, with increased levels of plasma DNA also frequently detected in the plasma of cancer patients. Among pregnant women whose NIPT results were inconsistent with the fetal karyotype, a small number of patients have subsequently been diagnosed with a previously undetected malignancy. However, the extent to which circulating tumor DNA (ctDNA) affects the results of NIPT is still unclear. We examined serum from 50 nonpregnant women with breast tumors by NIPT. These samples were then added to serum containing trisomy 13, 18, and 21 fetal DNA to figure out the extent to which maternal tumors can interrupt NIPT results in pregnant women with breast tumors. Concentrations of cell-free DNA (cfDNA) were higher in both pregnant women and breast tumor patients, relative to nonpregnant healthy controls. Among the 50 samples evaluated, 3 produced false positive NIPT results for trisomy 13, 18, or 21, indicating that genomic copy number variations (CNVs) had occurred. Simulation testing also showed that ctDNA can increase the standard deviation of the associated z-scores, which lower absolute z-scores by decreasing the proportion of circulating fetal DNA relative to total DNA. Of the 50 samples tested, 9 fell within the equivocal range and 8 produced false negative results for trisomy 13, 18, or 21. Data presented here show for the first time that ctDNA is able to affect NIPT results in two ways. First, ctDNA can lead to false positive results due to the detection of genomic CNVs in tumor DNA. Alternatively, ctDNA can increase the likelihood of a false negative by decreasing the proportion of circulating fetal DNA in serum.

Objectives: We have established an open source platform for non-invasive prenatal testing (NIPT) based on massively parallel whole-genome sequencing in a public setting. The objective of this study was to investigate factors of importance for correct interpretation of NIPT results to ensure a high sensitivity and specificity., Study Design: This investigation is a retrospective case-control study performed in a public NIPT center. The study included 108 aneuploid cases and 165 euploid controls. MPS was performed on circulating cell-free DNA in maternal blood. The pipeline included automated library preparation and sequencing on a HiSeq1500 (Illumina). The software programmes WISECONDOR and SeqFF were used for data analysis of aneuploidy status and fetal fraction of cell-free DNA, respectively. Lower limit of fetal fraction for aneuploidy testing was 0.02., Results: We identified four false negative aneuploidy cases of which two were explained by a vanishing twin. The number of no-call cases due to low fetal fraction was 8 out of 273 (2.9%). The sensitivity and specificity, when no-calls and vanished twins were excluded, were 100% and 99.5% for T21, 91% and 99.2% for T18, and 100% and 99.6% for T13. By multiple regression analysis we found a significant association between fetal fraction and gestational age, maternal BMI and ART treatment., Conclusion: With a non-commercial open source NIPT set-up having the same high test-performance as reported by large private laboratories, we show that fetal fraction, a vanishing twin, BMI, gestational age and ART treatment are important factors in the interpretation of NIPT results., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Intensive treatment including surgery for patients with trisomy 13 (T13) remains controversial. This study aimed to evaluate the safety and efficacy of noncardiac surgical intervention for T13 patients. Medical records of patients with karyotypically confirmed T13 treated in the neonatal intensive care unit in Nagano Children's Hospital from January 2000 to October 2016 were retrospectively reviewed, and data from patients who underwent noncardiac surgery were analyzed. Of the 20 patients with T13, 15 (75%) underwent a total of 31 surgical procedures comprising 15 types, including tracheostomy in 10 patients and gastrostomy in 4. Operative time, anesthesia time, and amount of bleeding are described for the first time in a group of children with T13. All the procedures were completed safely with no anesthetic complications or surgery-related death. The overall rate of postoperative complications was 19.3%. Patients receiving tracheostomy had stable or improved respiratory condition. Six of them were discharged home and were alive at the time of this study. These results suggest at least short-term safety and efficacy of major noncardiac surgical procedures, and long-term efficacy of tracheostomy on survival or respiratory stabilization for home medical care of children with T13. Noncardiac surgical intervention is a reasonable choice for patients with T13., (© 2018 Wiley Periodicals, Inc.)

Objectives: The primary aim of this study was to compare the screening performance for trisomy 21 (T21) between combined first-trimester screening (cFTS) with referral for invasive testing at a T21 risk ≥ 1 in 300, and contingent screening consisting of referral for invasive testing at a cFTS-T21 risk ≥ 1 in 100 and referral for cell-free DNA (cfDNA) testing at a cFTS-T21 risk between 1 in 100 and 1 in 1000. Secondary aims were to compare the incidence of fetuses diagnosed with trisomy 18 (T18), trisomy 13 (T13) or sex chromosome aneuploidy, and examine the association between fetal fraction of cfDNA in maternal blood and maternal/fetal characteristics., Methods: Women with a singleton pregnancy and a cFTS-T21 risk of ≥ 1 in 1000 were recruited consecutively from two Danish hospitals between August 2014 and May 2015. First-trimester combined screening was based on maternal age, nuchal translucency thickness and levels of pregnancy-associated plasma protein A (PAPP-A) and β-human chorionic gonadotropin (β-hCG). Blood samples for cfDNA testing were analyzed for risks of T21, T18, T13 and sex chromosomal aneuploidies. cfDNA analysis was conducted blinded to the cFTS assessment and karyotype results. Pregnancy outcomes and pre- and postnatal karyotypes were obtained from the Danish Fetal Medicine Database., Results: Among 6449 women who underwent cFTS risk assessment, 869 (13.5%) had a T21 risk of ≥ 1 in 1000 and 597 were included for cfDNA testing. Among these, there were 15 cases of T21, one case of T18 and two cases of T13. The sensitivity for detection of T21 was 100% using both screening strategies, while specificity increased significantly (P < 0.0001) from 97.0% using the cFTS strategy to 98.8% using the contingent approach. The sensitivity for detection of T21, T18 and T13 increased from 94.4% using the cFTS strategy to 100% using the contingent approach, with overlapping CIs, while specificity increased significantly (P < 0.0001) from 97.1% for cFTS to 98.9% for the contingent strategy. Seven pregnancies were categorized as being at increased risk of a sex chromosomal aneuploidy by cfDNA testing but chromosome analysis was discordant, corresponding to a false-positive rate of 1.2%. The fetal fraction decreased significantly with increasing maternal weight and increased significantly with the level of β-hCG and PAPP-A and among female fetuses, in both univariate and multivariate analyses., Conclusions: In a clinical setting with efficient cFTS, contingent screening offering women with a cFTS risk of ≥ 1 in 100 an invasive test and women with a risk from 1 in 100 to 1 in 1000 a cfDNA test had the same sensitivity for T21, T18 and T13, but significantly increased specificity, when compared with offering an invasive test to all women with a risk of ≥ 1 in 300. Implementing contingent screening would therefore reduce significantly the number of invasive tests performed at no loss of sensitivity. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Introduction: Currently, prenatal diagnosis of genetic disorders requires chorionic villus sampling or amniocentesis carried out after 11 and 16 weeks of gestation, respectively. Celocentesis is a procedure for prenatal diagnosis that could be used from as early as 7 weeks. The present investigation evaluated the feasibility of performing diagnosis for monogenic diseases using celomic fluid containing cells of fetal origin., Material and Methods: Analysis consisted of 489 singleton pregnancies undergoing celocentesis for the prenatal diagnosis of hemoglobinopathies (n = 367) or before surgical termination of pregnancy for social indications (n = 122). Embryo-fetal cells were isolated from celomic fluid using CD71 antibodies or by micromanipulation. Quantitative fluorescent polymerase chain reaction of short tandem repeat sequences of chromosomes 13, 18, 21, X and Y were used to determine the presence of maternal DNA., Results: 357/489 (73%) of celomic fluid samples were contaminated with maternal cells. In two cases, diagnosis was not possible due to the high contamination of celomic fluid. Eighty-seven (23.8%) fetuses were affected by hemoglobinopathies and, in five cases, chromosomal aneuploidies were found, including three cases of trisomy 21, one of trisomy 13 and one of triploidy. In all cases, the diagnosis of hemoglobinopathies and chromosomal abnormalities was confirmed by molecular and traditional cytogenetic analysis after amniocentesis, chorionic villus or placental tissue collection following pregnancy termination., Conclusions: The findings of this study demonstrate that embryo-fetal cell selection from celomic fluid allows reliable and early prenatal diagnosis of hemoglobinopathies and can give more information on any fetal aneuploidy following the control of maternal contamination by quantitative fluorescent-PCR., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Advanced paternal age is related to poor sperm quality; however, little is known on its effect on aneuploidy embryo rates and, more importantly, on chromosomal abnormalities like trisomy 21, 18 and 13. The objective of this study was to evaluate the effect of advanced paternal age on the trisomy rates of the chromosomes 21, 18 or 13 in embryos obtained from donated oocytes., Methods: A total of 378 embryos, obtained from 52 IVF/ICSI cycles with donated oocytes in conjunction with PGD, were allocated according to paternal age in three groups: Group A: ≤39 years (n=115 embryos), Group B: 40-49 years (n=157 embryos) and Group C: ≥50 year (n=106 embryos). Fertilization rates, embryo quality at day 3, blastocysts development, and aneuploidy embryo rates were then compared., Results: There was no difference in seminal parameters (volume, concentration and motility) in the studied groups. Fertilization rate, percentages of zygotes that underwent cleavage, and good-quality embryos on Day 3 were similar between the three groups evaluated. The group of men ≥50 years had significantly more sperm with damaged DNA, higher global aneuploidy rates, and significantly more embryos with trisomy 21, 18 or 13 compared to the other two evaluated groups (p<0.05)., Conclusions: Our data shows that advanced paternal age increases global chromosomal abnormalities, and percentages of trisomy 21, 18 or 13 in embryos, and such effect is significantly important as of the age of 50. Embryo genetic screening is highly recommended in patients in which paternal age is ≥50 years old.

Background: The usage of Artificial Neural Networks (ANNs) for genome-enabled classifications and establishing genome-phenotype correlations have been investigated more extensively over the past few years. The reason for this is that ANNs are good approximates of complex functions, so classification can be performed without the need for explicitly defined input-output model. This engineering tool can be applied for optimization of existing methods for disease/syndrome classification. Cytogenetic and molecular analyses are the most frequent tests used in prenatal diagnostic for the early detection of Turner, Klinefelter, Patau, Edwards and Down syndrome. These procedures can be lengthy, repetitive; and often employ invasive techniques so a robust automated method for classifying and reporting prenatal diagnostics would greatly help the clinicians with their routine work., Methods: The database consisted of data collected from 2500 pregnant woman that came to the Institute of Gynecology, Infertility and Perinatology "Mehmedbasic" for routine antenatal care between January 2000 and December 2016. During first trimester all women were subject to screening test where values of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (β-hCG) were measured. Also, fetal nuchal translucency thickness and the presence or absence of the nasal bone was observed using ultrasound., Results: The architectures of linear feedforward and feedback neural networks were investigated for various training data distributions and number of neurons in hidden layer. Feedback neural network architecture out performed feedforward neural network architecture in predictive ability for all five aneuploidy prenatal syndrome classes. Feedforward neural network with 15 neurons in hidden layer achieved classification sensitivity of 92.00%. Classification sensitivity of feedback (Elman's) neural network was 99.00%. Average accuracy of feedforward neural network was 89.6% and for feedback was 98.8%., Conclusion: The results presented in this paper prove that an expert diagnostic system based on neural networks can be efficiently used for classification of five aneuploidy syndromes, covered with this study, based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics. Developed Expert System proved to be simple, robust, and powerful in properly classifying prenatal aneuploidy syndromes.

We are reporting a rare case of foetal trisomy 13 due to a robertsnonian translocation. Further to the study of both parents karyotypes, genetic councelling is advisable in order to assess the potential risk of trisomy that may occur during a future pregnancy.

Background: Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management., Objective: The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies., Study Design: We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data., Results: The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY., Conclusion: The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We present prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome., Case Report: A 35-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+13[5]/46,XY[20]. Oligonucleotide array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed arr [GRCh37] (13)×3 [0.10], (X,Y)×1 compatible with trisomy 13 mosaicism. Prenatal ultrasound was unremarkable. Repeat amniocentesis was performed at 21 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed a mosaic trisomy 13 level of 10% (10/100 cells). aCGH analysis on uncultured amniocytes revealed a result of arr 13q12.11q34 (20,407,323-115,092,619)×2.1 with a log 2 ratio of 0.06 compatible with a 10% level of mosaicism. Polymorphic DNA marker analysis excluded uniparental disomy 13. The parental karyotypes were normal. Conventional cytogenetic analysis using cultured amniocytes at repeat amniocentesis revealed a karyotype of 46,XY in 23/23 colonies. The pregnancy was carried to 37 weeks of gestation, and a 3600-g phenotypically normal male baby was delivered. When examined at 8 months of age, the infant was doing well and was normal in psychomotor and growth development. The peripheral blood had a karyotype of 46,XY, and interphase FISH analysis on uncultured urinary cells revealed a mosaic trisomy 13 level of 4.4% (2/45 cells)., Conclusion: Low-level true mosaicism for trisomy 13 at amniocentesis without ultrasound abnormalities can be associated with a favorable fetal outcome., (Copyright © 2017. Published by Elsevier B.V.)

Background: Chromosomal trisomies are associated with advancing maternal age. In Ireland, information on the total prevalence and outcome of trisomy affected pregnancies is unavailable. This study aimed to ascertain more precise data on Trisomies 21, 18 and 13 in a large Irish region during the period 2011-2013., Methods: Multiple information sources were used in case finding, including a regional congenital anomaly register, all maternity and paediatric hospitals in the region and the regional Department of Clinical Genetics., Results: There were 394 trisomy cases from 80 894 total births, of which 289 were Trisomy 21, 75 were Trisomy 18 and 30 were Trisomy 13. The total prevalence rate was 48.9/10 000 births, 35.7, 9.3 and 3.7 for Trisomies 21, 18 and 13, respectively. Over 90% of Trisomies 18/13 and 47% of Trisomy 21 were diagnosed prenatally; 61% of Trisomy 21 cases and nearly 30% of Trisomies 18/13 were live births; 38% all trisomy affected pregnancies ended in a termination., Conclusions: This study provides precise data on the total prevalence and outcome of trisomy affected pregnancies in the East of Ireland. Total prevalence rates were higher than previously reported. Prenatal diagnosis had a significant impact on outcome. These data provide a better basis for planning of services for live-born children affected by trisomy., (© The Author 2016. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Non-invasive prenatal testing (NIPT), also known as cell-free DNA testing and non-invasive prenatal screening (NIPS), is an important addition to the range of screening tests for fetal chromosomal abnormalities. For trisomy 21 in particular, NIPT is superior to other screening modalities. However, NIPT has limitations and complexities that requesting clinicians and their patients should understand., Objective: This review article will briefly describe the technical basis of NIPT assays and compare the performance characteristics of NIPT with existing screening tests. The clinical use of NIPT will also be discussed., Discussion: NIPT is now an established option for antenatal screening for trisomy 21, 18, 13 and other selected chromosomal abnormalities. If used appropriately, it increases the detection rate for fetal chromosomal abnormalities, while decreasing the number of invasive tests required. An understanding of the scientific basis of NIPT, and the appropriate clinical use and limitations, will enable medical practitioners to provide optimal antenatal screening.

Objective: To evaluate the clinical validity of a new ultrahigh-throughput non-invasive prenatal test (NIPT) based on combinatorial probe-anchor ligation (cPAL) sequencing of cell-free fetal DNA (cffDNA) using centralized testing., Methods: Maternal plasma samples were obtained from 10 594 singleton pregnancies in high-risk populations at 20 centers in China, including 8155 that were collected retrospectively and 2439 prospectively. Fetal outcome data and karyotyping results were documented as gold standard and were double blinded during NIPT. The clinical performance of the ultrahigh-throughput sequencing method, cPAL, for NIPT was validated by evaluating its sensitivity, specificity and positive predictive value (PPV) in detecting trisomies 21, 18 and 13 as the centralized testing mode in the reference laboratory. To ensure stable and reproducible performance of centralized cPAL-based NIPT in detecting trisomies, a series of quality-control systems, including sequencing of two sets of artificial samples, were employed and evaluated., Results: Ten prospective cases were excluded from the study because of incomplete clinical data. Four prospective samples failed to generate a NIPT result due to assay failure, presenting a failure rate of 0.16% (4/2429). A total of 168 retrospective cases and 47 prospective cases had a positive NIPT result for trisomy, giving respective positive rates of 2.06% and 1.94%. Four false-positive and no false-positive cases were observed in the retrospective and prospective groups, respectively, resulting in PPV of 97.62% (95% CI, 94.02-99.35%) and 100% (95% CI, 92.45-100%), respectively. In the retrospective group, sensitivity and specificity were, respectively, 100% (95% CI, 97.07-100%) and 99.98% (95% CI, 99.94-100%) for trisomy 21, 100% (95% CI, 97.75-100%) and 99.98% (95% CI, 99.94-100%) for trisomy 18, and 100% (95% CI, 15.81-100%) and 100% (95% CI, 99.95-100%) for trisomy 13. In the prospective group, sensitivity and specificity were, respectively, 100% (95% CI, 90.75-100%) and 100% (95% CI, 99.85-100%) for trisomy 21, 100% (95% CI, 63.06-100%) and 100% (95% CI, 99.85-100%) for trisomy 18, and 100% (95% CI, 2.50-100%) and 100% (95% CI, 99.85-100%) for trisomy 13., Conclusion: In this multicenter study with a full quality-control system, NIPT by centralized cPAL-based testing showed high stability and performance comparable to those of previous validation studies in high-risk populations. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.)

Massively parallel sequencing (MPS) technology has become increasingly available and has been widely used to screen for trisomies 21, 18, and 13 in singleton pregnancies. This study assessed the performance of MPS testing of cell-free fetal DNA (cffDNA) from maternal plasma for trisomies 21, 18, and 13 in twin pregnancies. Ninety-two women with twin pregnancies were recruited. The results were identified through karyotypes of amniocentesis or clinical examination and follow-up of the neonates. Fluorescent in-situ hybridization was used to examine the placentas postnatally in cases of false-positive results. The fetuses with autosomal trisomy 21 (n = 2) and trisomy 15 (n = 1) were successfully detected via MPS testing of cffDNA. There was one false-positive for trisomy 13 (n = 1), and fluorescence in-situ hybridization (FISH) identified confined placental mosaicism in this case. For twin pregnancies undergoing second-trimester screening for trisomy, MPS testing of cffDNA is feasible and can enhance the diagnostic spectrum of non-invasive prenatal testing, which could effectively reduce invasive prenatal diagnostic methods. In addition to screening for trisomy 21, 18, and 13 by cffDNA, MPS can detect fetal additional autosomal trisomy. False-positive results cannot completely exclude confined placental mosaicism.

Purpose: Cell-free DNA (cfDNA) prenatal screening tests have been rapidly adopted into clinical practice, due in part to positive insurance coverage. We evaluated the framework payers used in making coverage decisions to describe a process that should be informative for other sequencing tests., Methods: We analyzed coverage policies from the 19 largest US private payers with publicly available policies through February 2016, building from the University of California San Francisco TRANSPERS Payer Coverage Policy Registry., Results: All payers studied cover cfDNA screening for detection of trisomies 21, 18, and 13 in high-risk, singleton pregnancies, based on robust clinical validity (CV) studies and modeled evidence of clinical utility (CU). Payers typically evaluated the evidence for each chromosomal abnormality separately, although results are offered as part of a panel. Starting in August 2015, 8 of the 19 payers also began covering cfDNA screening in average-risk pregnancies, citing recent CV studies and updated professional guidelines. Most payers attempted, but were unable, to independently assess analytic validity (AV)., Conclusion: Payers utilized the standard evidentiary framework (AV/CV/CU) when evaluating cfDNA screening but varied in their interpretation of the sufficiency of the evidence. Professional guidelines, large CV studies, and decision analytic models regarding health outcomes appeared highly influential in coverage decisions.Genet Med advance online publication 22 September 2016.

Background: To evaluate the impact of the introduction of prenatal screening on time of detection and pregnancy outcome for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13)., Methods: We performed a retrospective, population-based cohort study in the Northern Netherlands including 503 trisomy cases born between 2005 and 2012. Screening tests and invasive procedures, timing of diagnosis and pregnancy outcome were compared between the period before (2005-2006) and after introduction (2007-2012) using X 2 tests., Results: There was an increase in proportion of women who had a prenatal screening and/or invasive test, from 62% in 2005-2006 to 84% in 2010-2012 (p < 0.01), while the proportion of prenatally diagnosed cases did not change (60% overall). In women < =35 years 47% of the cases were diagnosed prenatally vs 73% in women >35 years (p < 0.01). More T13/T18 cases were diagnosed <24 weeks after introduction (62% vs 84%; p < 0.01). In T13/T18 intra-uterine death decreased (26% vs 15%), while terminations increased: 55% vs 72%., Conclusion: The introduction of prenatal screening had limited impact on the time of detection and outcome of the most common trisomies. The introduction of the 20-week anomaly scan has resulted in more trisomy cases diagnosed <24 weeks and a shift from fetal death to terminations.

Objective: Antenatal reflex DNA screening for Down's syndrome has a high screening performance. We aimed to determine the performance of trisomy 18 and trisomy 13 reflex DNA screening when added to Down's syndrome screening., Methods: In our modelled screening protocol, women provide two samples: a serum sample for a Combined test and a plasma sample for a possible DNA test. Women with Down's syndrome, trisomy 18, or trisomy 13 Combined test risks above a single cut-off have a reflex DNA test using the plasma sample, without the need to recall them to collect another sample and provide counselling. Women with a failed DNA test (after a second attempt using a fresh plasma sample) have an Integrated test, and are classified as positive if any of the Down's syndrome, trisomy 18, or trisomy 13 Integrated test risks are greater than 1 in 25., Results: At 1 in 800 term risk cut-offs for Down's syndrome, trisomy 18, and trisomy 13, an estimated 10% of women are reflexed to DNA screening, yielding a 91% Down's syndrome detection rate, an 89% trisomy 18 detection rate, and a 79% trisomy 13 detection rate for a 0.05% false-positive rate. At a 1 in 1900 term risk cut-off for Down's syndrome, trisomy 18, or trisomy 13, an estimated 20% of women are reflexed to DNA screening, and this yields a 94% Down's syndrome detection rate, a 92% trisomy 18 detection rate, and an 84% trisomy 13 detection rate for a 0.10% false-positive rate., Conclusion: Reflex DNA screening for trisomies 18 and 13 can be usefully added to reflex DNA screening for Down's syndrome., (© The Author(s) 2016.)

Objective The objective of this study was to describe antenatal/intrapartum management and survival of liveborn infants with known trisomy 13 (T13) or trisomy 18 (T18) based on planned neonatal care. Study Design This is a retrospective cohort study of singleton pregnancies complicated by T13/T18 at a tertiary center from 2004 to 2015. We included pregnancies with antenatal or neonatal cytogenetic T13/T18 diagnosis and excluded those which were terminated or had a fetal demise < 20 weeks. We compared antenatal/intrapartum management and neonatal survival by planned neonatal care, defined as either neonatal intervention (INT), including neonatal cardiopulmonary resuscitative measures or comfort care (CC) without resuscitative measures. Results In this study, 32 women (10 with T13 and 22 with T18) met study criteria; 12 (38%) elected INT and 20 (62%) CC. Compared with those who elected INT, women who elected CC were more likely to undergo elective induction (40 vs. 0%, p = 0.01), have an intrapartum stillbirth (0 vs. 32%, p = 0.14), and deliver vaginally (25 vs. 63%, p < 0.01). In neonatal survival analysis (n = 26), median survival was longer in the INT group compared with CC group (64 days [interquartile range, IQR: 2, 155) vs. 3 days [IQR]: 0.3, 42), p = 0.28), but survival to hospital discharge was similar (53 vs. 57%, p = 0.95). Conclusion Regardless of desired level of neonatal INT, many women who continue pregnancies complicated by T13/18 have infants who survive beyond hospital discharge., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To estimate the performance of antenatal sequential Integrated screening for Down's syndrome (DS), trisomy 18 (T18) and trisomy 13 (T13), in which women have first trimester testing for each disorder; those above specified risk cut-offs are screen-positive, and the remainder continue to Integrated testing, using first and second trimester screening markers together., Methods: Published screening marker parameters and Monte Carlo simulation were used to calculate detection rates (DR's) and risk cut-off levels for specified false-positive rates (FPR's), and DR's and FPR's for specified risk cut-offs. We compared this screening performance with that based on all women having Integrated tests., Results: Sequential Integrated DS screening detects 71% of DS pregnancies at the first trimester stage at a 0.5% FPR. For an overall 2% FPR, the DS DR is 92%, the same screening performance as the Integrated test performed on all women. Sequential Integrated T18 and T13 screening detects 70% of T18 and 53% of T13 pregnancies at the first trimester stage at a 0.05% FPR for each. The overall T18 and T13 DR's are 96% and 72% respectively at 0.2% FPR, the same screening performance as with Integrated tests performed on all women. Increasing the overall FPR's does not materially increase the DR's for any of the three disorders., Conclusion: The performance of sequential Integrated screening is similar to the performance if all women have an Integrated test, but has the advantage of identifying most DS, T18, and T13 pregnancies a few weeks earlier., (© The Author(s) 2015.)