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Objective: A rolling circle amplification (RCA) based commercial methodology using cell-free (cf)DNA to screen for common trisomies became available in 2018. Relevant publications documented high detection but with a higher than expected 1% false positive rate. Preliminary evidence suggested assay variability was an issue. A multi-center collaboration was created to explore this further and examine whether subsequent manufacturer changes were effective. Methods: Three academic (four devices) and two commercial (two devices) laboratories provided run date, chromosome 21, 18, and 13 run-specific standard deviations, number of samples run, and reagent lot identifications. Temporal trends and between-site/device consistency were explored. Proportions of run standard deviations exceeding pre-specified caps of 0.4%, 0.4% and 0.6% were computed. Results: Overall, 661 RCA runs between April 2019 and July 30, 2022 tested 39,756 samples. In the first 24, subsequent 9, and final 7 months, proportions of capped chromosome 21 runs dropped from 39% to 22% to 6.0%; for chromosome 18, rates were 76%, 36%, and 4.0%. Few chromosome 13 runs were capped using the original 0.60%, but capping at 0.50%, rates were 28%, 16%, and 7.6%. Final rates occurred after reformulated reagents and imaging software modifications were fully implemented across all devices. Revised detection and false positive rates are estimated at 98.4% and 0.3%, respectively. After repeat testing, failure rates may be as low as 0.3%. Conclusion: Current RCA-based screening performance estimates are equivalent to those reported for other methods, but with a lower test failure rate after repeat testing. [ABSTRACT FROM AUTHOR]

Background: Combined first‐trimester screening (cFTS) for fetal anomalies involves maternal serum screening for biochemical markers and measurement of the nuchal translucency (NT) by ultrasound. Noninvasive prenatal screening (NIPS) analyses cell‐free DNA present in a maternal blood sample for presence of fetal chromosomal aneuploidies. Aims: To compare NIPS with cFTS as frontline screening in a public hospital in Australia. Materials and methods: Women were offered NIPS in addition to the usual cFTS routinely offered to all women at a public hospital in NSW, Australia. The cFTS sample was collected at ten weeks' gestation and the NIPS sample at 12 weeks' gestation at the ultrasound appointment. Results: In a low‐risk population of 997 women, frontline NIPS had a screen‐positive rate of 0.5% (5/997) vs 4.2% (42/997) with cFTS. cFTS correctly identified one trisomy 21 case and one trisomy 18 case; however, there were two trisomy 18 false negatives. Of five positive NIPS calls, four were correctly identified as trisomy 21 (one) and trisomy 18 (three); there were no NIPS false negatives. Overall, the false‐positive rate with NIPS was 0.1% vs 4.0% by cFTS. Conclusions: The lower screen‐positive rate with NIPS for common trisomies was a result of the significantly lower false‐positive rate with NIPS. Consequently, NIPS as first‐line screening, even if funded by the hospital, may provide cost savings. We believe NIPS should be used from ten weeks' gestation in conjunction with morphology ultrasound for routine first‐trimester prenatal management. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening with cell-free DNA is now considered a first-line screening for common aneuploidies. Advancements in existing laboratory techniques now allow to interrogate the entirety of the fetal genome, and many commercial laboratories have expanded their screening panels to include screening for rare autosomal aneuploidies and copy number variants. Here, we review the currently available data on the performance of fetal cell-free DNA to detect rare autosomal aneuploidies and copy number variants that are associated with clinically significant microdeletion and microduplication syndromes and the current position of medical societies on routine screening for these syndromes. [ABSTRACT FROM AUTHOR]

Cell-free DNA (cfDNA) screening has high detection for the common fetal autosomal aneuploidies, but is not diagnostic. The positive predictive value should be utilized in counseling after a positive cell-free DNA screen, and diagnostic testing should be offered for confirmation. cfDNA screening does not report a result in ~3% of cases; nonreportable results indicate an increased risk for aneuploidy and some adverse perinatal outcomes. False-positive cfDNA screening occurs due to confined placental mosaicism, maternal copy number variants, mosaicism, and cancer. Pretest education and counseling should be provided with emphasis on the potential benefits, risks, and limitations before cfDNA screening. [ABSTRACT FROM AUTHOR]

Although nearly all noninvasive prenatal testing is currently based on analyzing circulating maternal cell-free DNA, the technical methods usedvary considerably. We review the different methods. Based on validation trials and clinical experience, there are mostly relatively small differences in screening performance for trisomies 21, 18, and 13 in singleton pregnancies. Recent reports show low no-call rates for all methods, diminishing its importance when choosing a laboratory. However, method can be an important consideration for twin pregnancies, screening for sex chromosome abnormalities, microdeletion syndromes, triploidy, molar pregnancies, rare autosomal trisomies, and segmental imbalances, and detecting maternal chromosome abnormalities. [ABSTRACT FROM AUTHOR]

The discovery of cell-free fetal DNA (cffDNA) in maternal blood and the rapid development of massively parallel sequencing have revolutionized prenatal testing from invasive to noninvasive. Noninvasive prenatal screening (NIPS) based on cffDNA enables the detection of fetal trisomy through sequencing, comparison, and bioassays. Its accuracy is better than that of traditional screening methods, and it is the most advanced clinical application of high-throughput sequencing technologies. However, the existing sequencing methods are limited by high costs and complex sequencing procedures. These limitations restrict the availability of NIPS for pregnant women. Many amplification methods have been developed to overcome the limitations of sequencing methods. The rapid development of non-sequencing methods has not been accompanied by reviews to summarize them. In this review, we initially describe the detection principles for sequencing-based NIPS. We summarize the rapidly evolving amplification technologies, focusing on the need to reduce costs and simplify the procedures. To ensure that the testing systems are feasible and that the testing processes are reliable, we expand our vision to the clinic. We evaluate the clinical validity of NIPS in terms of sensitivity, specificity, and positive predictive value. Finally, we summarize the application guidelines and discuss the corresponding quality control methods for NIPS. In addition to cffDNA, extracellular vesicle DNA, RNA, protein/peptide, and fetal cells can also be detected as biomarkers of NIPS. With the development of prenatal testing, NIPS has become increasingly important. Notably, NIPS is a screening test instead of a diagnostic test. The testing methods and procedures used in the NIPS process require standardization. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to assess the utility of ultrasound screening for pregnancies with positive noninvasive prenatal testing results for trisomy 21, trisomy 18, and trisomy 13. Methods: We performed a retrospective analysis of positive noninvasive prenatal testing results and first‐trimester ultrasound screening at our department between 2013 and 2019. Invasive genetic testing was performed if the patient had positive noninvasive prenatal testing results. Fetal ultrasound and cytogenetic data were collected. Noninvasive prenatal testing was performed in the women for advanced maternal age, nuchal translucency thickness, or history of abnormality in the previous child or relative. Results: Forty‐one pregnant women had positive noninvasive prenatal testing results for trisomy 21, trisomy 18, and trisomy 13. Twenty‐three women had positive results for trisomy 21, 13 had positive results for trisomy 18, and 5 had positive results for trisomy 13 at 11 to 14 weeks of gestation. The positive predictive value of noninvasive prenatal testing was 100% for trisomy 21, 84.6% for trisomy 18, and 100% for trisomy 13. The positive predictive value of positive noninvasive prenatal testing results and fetal morphological abnormalities was 100% for trisomy 21, trisomy 18, and trisomy 13. Conclusion: Combining an ultrasound examination with noninvasive prenatal testing resulted in a higher positive predictive value for trisomy 18. Normal ultrasound examination results can help alleviate stress caused by false‐positive noninvasive prenatal testing results. In contrast, the positive predictive value and negative predictive value for trisomy 21 were not altered by adding an ultrasound examination to noninvasive prenatal testing. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the diagnostic value of the BACs-on-Beads (BoBs) assay for the rapid diagnosis of common aneuploidies and microdeletions.Methods: A total of 4961 pregnant women admitted to the Wuxi Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University from January 2017 to March 2019 were enrolled. BoBs assay and conventional karyotyping were applied to detect amniotic fluid samples with various indications for prenatal diagnosis. Chromosomal microarray analysis (CMA) and maternal cell contamination (MCC) tests were used for further validation.Results: The overall abnormality detection rates (BoBs associated with karyotyping) were 4.25% (211/4961). The prenatal diagnosis success rate of karyotyping was 99.4% (4933/4961), compared to 100% (4961/4961) using the BoBs assays. The BoBs assay was similar to karyotyping for the detection of trisomy 21 (1.01%, 50/4961), trisomy 18 (0.40%, 20/4961), trisomy 13 (0.04%, 2/4961), and sex chromosomal aneuploidies (0.15%, 12/4961). The BoBs assay also identified sex chromosomal microduplications/microdeletions (1.73%, 86/4961), 22q11.2 microdeletions/microduplications (0.1%, 5/4961), and Cri du Chat syndrome (0.02%, 1/4961) which were missed by karyotyping. The sensitivity for the detection of numerical chromosomal abnormalities of the BoBs assay and karyotyping analysis was 100% (95/95, 95% CI: 1.0-1.0) and 98.9% (94/95, 95% CI: 0.969-1.010), respectively. The sensitivity of detecting structural chromosomal abnormalities in the BoBs assay was significantly higher than those of karyotyping (79.3%, 92/116, 95% CI: 0.718-0.868) versus 21.6% (25/116, 95% CI: 0.140-0.291) (p < .01).Conclusions: The BoBs assay is a reliable and rapid test for the detection of common aneuploidies and nine microdeletion syndromes with high sensitivity and accuracy in prenatal diagnosis. The assay can compensate for the limitations of karyotyping analysis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of implementing cell-free DNA (cfDNA) testing on gestational age (GA) at termination of pregnancy in a French perinatal network.Methods: We conducted a retrospective study. All women having undergone a termination of pregnancy between 1 January 2012 and 31 December 2017 were included. We compared the periods before and after the introduction of second-line cfDNA testing, which started on 1 January 2015. Throughout the study period, the invasive procedures were foetal karyotyping and chromosomal microarray analysis. The primary study outcome was GA at termination. The secondary outcomes were GA at termination for trisomy 21 and the frequency and GA at the time of invasive procedures.Results: During the 6-year study period, 840 women underwent termination. The median GA at termination before and after the implementation of cfDNA testing was 19.4 and 19.0 weeks, respectively (p = 0.38). Although the frequency of termination for trisomy 21 increased significantly from 23% to 32% (p < 0.01), the median GA at termination did not change significantly (p = 0.80). The implementation of cfDNA testing was associated with a decrease in the frequency of invasive procedures in general and chorionic villus sampling in particular (p = 0.04).Conclusion: The introduction of cfDNA testing does not increase the GA at termination for trisomy21. [ABSTRACT FROM AUTHOR]

Background/aim: Although cutting edge procedures such as cell-free fetal DNA isolation from maternal blood are now available, invasive prenatal tests are still being used extensively for prenatal diagnosis. The study aims to evaluate the demographic data, indications, and cytogenetic results of 9297 results of patients who underwent prenatal invasive testing for genetic analysis that were referred for the last 20 years in a University Medical Genetics Center. Materials and methods: The records of 8363 amniocenteses, 626 chorionic villus, and 308 cordocenteses samples were retrospectively evaluated and analyzed regarding referral reasons, indications and their cytogenetic results. The total numbers and the percentages of each group were recorded; Chi-square and logistic regression analyses were performed to give the statistical likelihood of different events. Results: The number of referrals decreased significantly after 2009. Risk of having trisomy 21 as well as trisomy 13 and 18 significantly increased in parallel with advanced maternal age. When the 21–25 age group was compared to the older age groups in terms of having a trisomy 21 pregnancy, the risk doubled in the 36–40, 5 times higher in 41–45 and 10-fold in 46–50 age groups. No significant linear correlation between maternal serum screening test results and trisomy 21 was found, however the difference between the pregnancies whom cut-off value above and below 1/250 in maternal serum screening test were significant. Conclusion: These data have provided useful information on the frequency of referrals to the reference genetics department, and the feasibility of genetic services. By reviewing the indications and their corresponding results, we can offer invaluable insights that will be useful in genetic counseling and also in the development of more effective genetic strategies. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal screening using cell-free DNA involves analysis of a sample of maternal blood for DNA fragments of fetal chromosomes from the fetal-placental unit to detect common chromosome abnormalities, trisomy 21, trisomy 13, trisomy 18, and sex chromosomes as early as 10 weeks' gestation when the fetal fraction is usually more than 4%. It is the most sensitive and specific prenatal screening option for these conditions. Because it is a screening test, false-positive and false-negative results can occur. Positive screen results necessitate further evaluation for diagnosis to confirm a medical condition, before critical decisions regarding pregnancy are made. Professional organizations provide clinical recommendations to providers regarding prescreen and postscreen counseling and management of results. [ABSTRACT FROM AUTHOR]

Background: Fetoplacental discrepancies occur in approximately 1–2% of analyzed prenatal cases. They are typically due to confined placental mosaicism, where an aberration is observed in the placental cells but not found in the fetal cells. Confined placental mosaicism usually involves aneuploidies and more sparsely structural chromosomal aberrations. To the best of our knowledge, this is the first reported case of a discrepancy in the analyses of chorionic villus sampling and amniocentesis involving two different structural chromosomal aberrations of chromosome 21. Case presentation: We report a 33-year-old woman who was referred for a non-invasive prenatal testing due to an increased risk of trisomy 21 gleaned from a combined ultrasound and blood test. The non-invasive prenatal testing showed an increased risk of trisomy 21 with a normalized coverage signal that did not match the fetal cell-free DNA fraction. Rapid aneuploidy detection performed on uncultured chorionic villi indicated mosaicism for trisomy 21. The follow-up analyses revealed discordant chromosomal aberrations: 46,XY,der(21)t(10;21)(p11.21;q10) in the analysis of the chorionic villus sampling and 46,XY, + 21,der(21;21)(q10;q10) in the analysis of the amniocentesis. Thus, the analyses indicated mosaicism for a cell line containing trisomy 21 and a cell line containing a partially duplicated short arm of chromosome 10 in the chorionic villi and complete trisomy 21 resulting from an isochromosome 21 in the amniotic fluid. The analyses of the lymphocytes and the fibroblasts of the woman were normal. Conclusions: We propose a multiple-step mechanism as a possible theoretical explanation for the formation of these discordant structural chromosomal aberrations in the chorionic villi and amniotic fluid. With this case report, we want to highlight the importance of understanding the possible underlying embryological mechanisms when interpreting results from different prenatal analyses. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies.Methods: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort.Results: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies.Conclusion: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations. [ABSTRACT FROM AUTHOR]

Background: Nowadays several Prenatal Tests for Chromosomal Abnormalities Detection (PTCAD) are available. In those cases in which there is not an Institutional protocol to advise women about the available PTCAD, the choice of which one to undergo is up to the woman and largely depends on her knowledge about them. Therefore, we decided to evaluate, as a primary outcome, knowledge about PTCAD among pregnant women attending our Term Clinic. As a secondary outcome we evaluated the relationship between the patient's knowledge and the subsequently chosen PTCAD. Methods: From August 2017 to August 2018 an anonymous questionnaire with multiple-choice answers was administered to all pregnant women attending our Term antenatal Clinic, a tertiary obstetric unit in Catanzaro (Italy). Results: Three hundred and twenty-five pregnant women were enrolled in the study. We observed that 28.8% of the pregnant women that chose one of the PTCAD, avoided the first trimester combined screening test; among these, 11.4% were in favour of the cell-free foetal DNA test. The latter was erroneously considered diagnostic by 34.3% of the women that had chosen it. Conclusions: This study demonstrated that women's knowledge about PTCAD is poor and that there is a potentially dangerous confusion between the words 'screening' and 'diagnostic'. Informative campaigns about PTCAD and the application of dedicated antenatal counselling appointments should be a health-care priority to avoid unnecessary risks and costs for pregnant women and possible legal issues. [ABSTRACT FROM AUTHOR]

Aims: To compare the screening capability of ultrasonography in detecting trisomy 13 (T13) using a multiparameter sonographic protocol (NT+) with a classical combined screening test (CST) protocol.Methods: The project was a prospective, multicenter study based on a nonselected mixed-risk population of women referred for a first-trimester screening examination. Each subject was offered a choice between either the gold standard, traditional combined screening test (CSG arm) or the ultrasound-based screening protocol (USG arm). General and MA-based screening performances were checked.Results: The study population comprised 20,887 pregnancies: 12,933 in the CSG arm, including 27 cases of T13, and 7954 in the USG arm, including 30 cases of T13. The DR for T13 was higher in the CSG arm than in the USG arm for all tested cutoff points: 1/50 (88.5 versus 63.3%, respectively), 1/100 (88.5 versus 70%, respectively) and 1/300 (92.3 versus 83.3%, respectively). Using the ROC curves for fixed FPRs of 3 and 5%, the T13 detection rate in our study reached 90 and 93%, respectively, in the USG arm and 92 and 96%, respectively, in the CSG arm. MA influenced the T13 screening performance in the USG arm and reduced the DR in patients <31 years. Such influence was not detected in the CSG arm.Conclusions: Classic CST was more effective in detecting T13 than the ultrasound-only approach. However, the recommended cutoff of 1/50 showed unsatisfactory results for both traditional CST and the multiparameter sonographic test we proposed. [ABSTRACT FROM AUTHOR]

Aim: To investigate the epidemiology of chromosomal abnormalities (CA) in fetuses of all pregnancies based on a provincial‐wide birth defects‐monitoring system, which could provide scientific basis for making relatively policy and research. Methods: Chromosomal abnormalities cases were collected from all hospitals in Hunan Province, China, between 2016 and 2019. The prevalence of CAs was calculated to examine associations among infant sex, maternal age and region. The rates of prenatal diagnosis and termination of pregnancy (TOP) involving CA or associated anomalies were calculated as rates or proportions. Results: From 2016 to 2019, a total of 2 883 890 perinatal infants (28 weeks of gestation to postpartum 7 days) underwent prenatal screening and diagnostic tests, and 3181 fetuses were diagnosed as CA, with the prevalence of 11.03/10 000. The average prevalence of CAs was higher for male than female fetuses (11.33/10 000 vs 10.06/10 000) (OR = 1.13, 95% CI: 1.05–1.21), which was higher in urban areas than rural areas (23.03/10 000 vs 7.13/10 000) (OR = 3.23, 95% CI: 3.02–3.47), and the prevalence increased linearly with maternal age (Xtrend2 = 1821.844, P = 0.000). Among the fetuses with CAs, 3097 (97.36%) were diagnosed prenatally, and 3046 (98.35%) underwent TOP. The majority of CA were numerical abnormalities (90.18%). The main types of numerical autosomal abnormalities were trisomy 21 (6.69/10 000, 59.57%), trisomy 18 (1.13/10 000, 10.04%) and trisomy 13 (0.21/10 000, 1.88%). The main types of numerical gonosomal abnormalities were Klinefelter syndrome (0.68/10 000, 6.02%), Turner syndrome (0.49/10 000, 4.39%), Triple X syndrome (0.26/10 000, 2.29%) and 47,XYY syndrome (0.21/10 000, 1.91%). The three associated anomalies with the highest proportions were congenital heart defects (CHD) (41.06%), cleft palate or/and cleft lip (10.89%) and congenital talipes equinovarus (8.94%). Conclusion: The prevalence of CA was lower than that reported. Chromosome detection should be further promoted including test contest and coverage, especially for urban areas, older mothers and fetuses with CHD, cleft palate or/and cleft lip or congenital talipes equinovarus. [ABSTRACT FROM AUTHOR]

Objective: Maternal characteristics and neonatal outcomes associated with cell-free DNA (cfDNA) results were analysed retrospectively to assess the details of false-positive and false-negative results after initial blood sampling in non-invasive prenatal testing (NIPT).Study Design: A multicentre retrospective study was performed for women undergoing NIPT who received discordant cfDNA results between April 2013 and March 2018. The NIPT data obtained using massive parallel sequencing were studied in terms of maternal background, fetal fraction, z-scores, invasive procedure results and neonatal outcomes after birth.Results: Of the 56,545 women who participated in this study, 54 false-positive (0.095 %) and three false-negative (0.006 %) cases were found. Seven of the 54 false-positive cases (13.0 %) had vanishing twin on ultrasonography. Among the 18 false-positive cases of trisomy 18, confined placental mosaicism (CPM) was confirmed in three cases (16.7 %), while CPM was present in one of the three false-negative cases of trisomy 21.Conclusion: These data suggest that the incidence of women with false-positive or false-negative results is relatively low, that such false results can often be explained, and that vanishing twin and CPM are potential causes of NIPT failure. Genetic counselling with regard to false results is important for clients prior to undergoing NIPT. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the cisterna magna (CM) width measured in first-trimester fetuses is a useful marker for aneuploidy detection.Methods: This was a prospective study in 2 different cohorts in a tertiary referral center. The first cohort comprised 913 fetuses from the general pregnancy population during the period 2012-2016 and was used to construct the CM reference ranges applying the λ-μ-σ (LMS) method. The second cohort included 714 high-risk fetuses undergoing chorionic villus sampling during the period 2012-2016. Mean detection rates using the 95th percentile for CM width observed in chromosomal anomaly groups were compared with those obtained in chromosomally normal fetuses.Results: The 50th percentile for CM ranged from 1.66 to 2.75 mm when crown-rump length (CRL) increased from 45 to 84 mm. Among high-risk fetuses, the following chromosomal anomalies were diagnosed in 125 (17%) fetuses: trisomy 21 (n = 63), trisomy 18 or 13 (n = 21), monosomy X (n = 9), submicroscopic anomalies (n = 11), and other anomalies (n = 22). The mean CM width for euploid fetuses was 2.4 mm (1.13 multiples of the median, MoM). While CM width was significantly increased in trisomy 21 (mean 2.7 mm; 1.23 MoM; p > 0.05), no differences were found in the other anomaly groups. Among the 63 fetuses with trisomy 21, a CM width above the 99th percentile was observed in 23 fetuses (37%).Conclusions: The new reference range for CM width at 11-13 weeks of gestation did not differ from previous studies. In first-trimester fetuses with trisomy 21, CM width appears to be increased, although its value as an ultrasound marker is limited, because of its detection rate of 37%. [ABSTRACT FROM AUTHOR]

Objectives: To examine multiples of the median (MoM) values of serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a large series of pregnancies with a vanishing twin, determine the association of these values with the interval between embryonic death and blood sampling, and develop a model that would allow incorporation of these metabolites in first-trimester combined screening for trisomy.Methods: This was a retrospective study comparing maternal serum free β-hCG and PAPP-A levels at 11-13 weeks' gestation in 528 dichorionic pregnancies with a vanishing twin, including 194 (36.7%) with an empty gestational sac and 334 (63.3%) with a dead embryo, with those in 5280 normal singleton pregnancies matched for method of conception and date of examination. In vanishing-twin pregnancies with a dead embryo, marker levels were examined in relation to the estimated time between embryonic death and maternal blood sampling.Results: First, in pregnancies with a vanishing twin, median free β-hCG MoM was not significantly different from that in normal singleton pregnancies (1.000; 95% CI, 0.985-1.016 vs 0.995; 95% CI, 0.948-1.044; P = 0.849). Second, PAPP-A MoM was higher in vanishing-twin pregnancies than in normal singleton pregnancies (1.000; 95% CI, 0.985-1.015), both in the group with an empty gestational sac (1.165; 95% CI, 1.080-1.256; P = 0.0001) and in that with a dead embryo (1.175; 95% CI, 1.105-1.249; P < 0.0001). Third, in vanishing-twin pregnancies with a dead embryo, PAPP-A MoM was related inversely to the interval between estimated gestational age at embryonic demise and blood sampling (P < 0.0001). Fourth, in first-trimester screening for trisomy 21 in singleton pregnancies, the estimated detection rate, at a 5% false-positive rate, was 82% in screening by a combination of maternal age and fetal nuchal translucency thickness, and this increased to 86% with the addition of serum free β-hCG and to 91% with the addition of serum PAPP-A. Fifth, similar performance of screening can be achieved in pregnancies with a vanishing twin, provided the appropriate adjustments are made to the level of PAPP-A for the interval between estimated gestational age at embryonic demise and blood sampling.Conclusions: First-trimester screening for trisomy in pregnancies with a vanishing twin should rely on a combination of maternal age, fetal nuchal translucency thickness and serum free β-hCG, as in singleton pregnancy, without the use of serum PAPP-A. Alternatively, PAPP-A can be included but only after appropriate adjustment for the interval between estimated gestational age at fetal demise and blood sampling. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

This is the fourth in a series of papers. The previous papers inform midwifery practice by providing insight into whether, to what extent and how cognitive status influences understanding of Down syndrome screening information, the importance of tailoring information, and highlighting areas of communication that are effective in facilitating understanding. These findings led to the development of recommendations to inform a 'best practice' model for midwifery communication of screening information within a conceptual framework that recognises the importance of accurate facts, empathic communication and support for decision-making in a woman-centred approach. These recommendations may have wider relevance beyond midwife communication of Down syndrome screening and may impact upon the communication of other screening information provided within antenatal and neonatal screening. It is important that screening information is communicated effectively in light of changes to screening programmes, such as the introduction of non-invasive prenatal testing. [ABSTRACT FROM AUTHOR]

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)—96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13—were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up. [ABSTRACT FROM AUTHOR]

Background: The ductus venosus agenesis (DVA) is a rare condition with a variable prognosis that relies partly on the presence of associated conditions. The purpose of our study was to analyze the literature regarding the post-natal outcome of fetuses with DVA associated with fetal malformations, in order to discuss the best management options for couples. Methods: We performed a systematic review of the literature of MEDLINE and SCOPUS electronic databases in a 25-year period from 1992 to September 2017. Methods: We found 340 cases of DVA associated with fetal abnormalities. The most common chromosomal abnormalities were: monosomy X (12/48, 25%), trisomy 21 (11/48, 22.9%) and trisomy 18 (6/48, 12.5%). From the 340 cases with DVA, in 31 cases the umbilical venous shunt type was not reported. Of the fetuses, 60.8% (188/309) had an extrahepatic umbilical venous drainage while 39.2% (121/309) presented an intrahepatic connection. The DVA was associated in 71 cases (23.0%) with cardiac abnormalities, in 82 cases (26.5%) with extracardiac abnormalities and in 85 cases (27.5%) with both cardiac and extracardiac abnormalities. Conclusion: DVA associated with both cardiac and extracardiac malformations may confer a poorer fetal outcome, a clinically relevant fact that should clarify what can be expected from this entity and help prenatal counseling. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To report the experience on the clinical use of noninvasive cell-free (cf) DNA testing at late pregnancy.Study Design: A cohort of 1539 women with singleton gestations of ≥23 weeks receiving cfDNA testing in a 3-year period were included for this study. Maternal characteristics and data on cfDNA testing, confirming diagnostic testing and pregnancy outcome were reviewed.Results: During the study period, 1539 patients had cfDNA testing although they had a normal first-trimester screening. Of these, 7 cases had a positive result, including 5 for chromosome 21, one for chromosome 18, and one for chromosome 13. The most common indication was soft markers on ultrasound, followed by polyhydramnios. Cytogenetic testing was done for the 5 trisomy 21 positive cases, and confirmed the cfDNA results. Confirmative testing was declined in the two cases with positive cfDNA for trisomy 18/13, and postnatal placental investigation showed confined placental mosaicism with normal karyotype in the cord blood of newborns. There were no confirmed false negatives reported. The cfDNA screening achieved a positive predictive value of 71.4 % and a negative predictive value of 100 % in late pregnancy for common trisomies.Conclusions: There is no gestational age upper limit for cfDNA use in the clinical practice. Most of the time, cfDNA was used in late gestation for reassurance in patients who is at low risk for aneuploidies but had second-trimester soft markers on ultrasound. [ABSTRACT FROM AUTHOR]

Objective: To examine the diagnostic accuracy of a previously developed model for the first-trimester combined test in screening for trisomies 21, 18 and 13.Methods: This was a prospective validation study of screening for trisomies 21, 18 and 13 by assessment of a combination of maternal age, fetal nuchal translucency, fetal heart rate and serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation in 108 982 singleton pregnancies undergoing routine care in three maternity hospitals. A previously published algorithm was used to calculate patient-specific risks for trisomy 21, 18 and 13 in each patient. The detection rate (DR) and false-positive rate (FPR) at estimated risk cut-offs from 1 in 2 to 1 in 1000 were determined. The proportions of trisomies detected were compared to their expected values in different risk groups.Results: In the study population, there were 108 112 (99.2%) cases with normal fetal karyotype or birth of a phenotypically normal neonate and 870 (0.8%) cases with abnormal karyotype, including trisomy 21 (n = 432), trisomy 18 (n = 166), trisomy 13 (n = 56), monosomy X (n = 63), triploidy (n = 35) or other aneuploidy (n = 118). The screen-positive rates, standardized according to the maternal age distribution in England and Wales in 2011, of fetuses with abnormal or normal karyotype were compatible with those predicted from the previous model; at a risk cut-off of 1 in 100, the FPR was about 4% and the DRs for trisomies 21, 18 and 13 were 90%, 97% and 92%, respectively. There was evidence that the algorithm overestimated risk. This could, to some degree, reflect under-ascertainment in pregnancies ending in miscarriage or stillbirth.Conclusion: In a prospective validation study, the first-trimester combined test detected 90%, 97% and 92% of trisomies 21, 18 and 13, respectively, as well as > 95% of cases of monosomy X and triploidies and > 50% of other chromosomal abnormalities, at a FPR of 4%. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Introduction: The aim was to investigate the parental decisions about prenatal screening and diagnosis among infants with trisomy 21 (T21) in a national cohort with high uptake of combined first-trimester screening (cFTS).Material and Methods: This was a nationwide population-based study including infants born in 2009-2012. Information from the cFTS, fetal karyotype results and pregnancy outcome was obtained from the Danish Fetal Medicine Database on all women with a cFTS risk assessment. Cut-off for referral for invasive testing was ≥1:300. Karyotype results from pregnancies with no cFTS were obtained from the Danish Cytogenetic Central Registry.Results: The uptake rate of cFTS was 91.6%, and 82.8% (8,032/9,704) of the screen-positive women opted for invasive testing. Overall, 82.2% (454/552) chose to terminate an affected pregnancy. In the 4-year period, 102 of 232,962 singletons were born alive with T21. The cFTS risk was true-positive, false-negative or not obtained in 21.6, 48.0 and 30.4%, respectively, of these pregnancies.Discussion: In this large national cohort, 4.4 per 10,000 live-born infants had T21. Of 102 infants with T21 from 2009 to 2012, 52.0% were born after the women had not opted for cFTS or were true-positive but declined invasive testing or termination, and 48.0% were born after a false-negative risk assessment. [ABSTRACT FROM AUTHOR]

Objective: Atrioventricular septal defect is associated with a high risk of a chromosomal abnormality, particularly trisomy 21. The aim of this study is to assess the rate of trisomy 21 in fetuses diagnosed with an atrioventricular septal defect and to examine the influence of prior screening on the rate of trisomy 21.Methods: Electronic ultrasound database was searched to identify fetuses diagnoses with an atrioventricular septal defect from 2002 to 2014. Rate of trisomy 21 and other aneuploidies was calculated among fetuses with normal situs. The prevalence of trisomy 21 and other aneuploidies was assessed in women with low and high first trimester risk for trisomy 21, using a cut-off value of 1:150 and 1:250.Results: A total 110 fetuses with a diagnosis of atrioventricular septal defect were identified. Among the 98 fetuses with normal situs, the prevalence of trisomy 21 was 46% (95% CI: 36-56%). Using a 1:150 threshold, the rate of trisomy 21 within the low-risk group was 41% (95% CI: 27-57%) while in the high-risk group it was 70% (95% CI: 52-83%), significantly higher than in the low risk group (p=0.028). Similar results were obtained when the 1:250 threshold was applied (66% versus 41%, p=0.055).Conclusions: The rate of trisomy 21 among fetuses identified with an atrioventricular septal defect in the second trimester is high even in those that undergo first trimester combined screening. Some fetuses with a high-risk screening result show a normal karyotype. Therefore, an offer of an invasive procedure to check fetal karyotyping is indicated. Knowledge of these rates may be helpful for parents in the decision making process. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to review the performance of non-invasive prenatal testing (NIPT) for detection of trisomy 21, 18 and 13 (T21, T18 and T13) in a general pregnant population as well as to update the data on high-risk pregnancies.Material and Methods: Systematic review and meta-analysis. PubMed, Embase and the Cochrane Library were searched. Methodological quality was rated using QUADAS and scientific evidence using GRADE. Summary measures of diagnostic accuracy were calculated using a bivariate random-effects model.Results: In a general pregnant population, there is moderate evidence that the pooled sensitivity is 0.993 (95% CI 0.955-0.999) and specificity was 0.999 (95% CI 0.998-0.999) for the analysis of T21. Pooled sensitivity and specificity for T13 and T18 was not calculated in this population due to the low number of studies. In a high-risk pregnant population, there is moderate evidence that the pooled sensitivities for T21 and T18 are 0.998 (95% CI 0.981-0.999) and 0.977 (95% CI 0.958-0.987) respectively, and low evidence that the pooled sensitivity for T13 is 0.975 (95% CI 0.819-0.997). The pooled specificity for all three trisomies is 0.999 (95% CI 0.998-0.999).Conclusions: This is the first meta-analysis using GRADE that shows that NIPT performs well as a screen for trisomy 21 in a general pregnant population. Although the false positive rate is low compared with first trimester combined screening, women should still be advised to confirm a positive result by invasive testing if termination of pregnancy is under consideration. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated the influence of changes in the age at which women give birth, and of developments in prenatal screening and diagnosis on the number of pregnancies diagnosed and terminated with chromosomal anomalies. However, we are unaware of any population studies examining pregnancy terminations after diagnosis of chromosomal anomalies that has included all aneuploidies and the influence of maternal factors. The aims of this study were to examine the association between results of prenatal tests and pregnancy termination, and the proportion of foetuses with and without chromosomal anomalies referred for invasive diagnostic tests over time. Diagnostic information of 26,261 prenatal invasive tests from all genetic service laboratories in Scotland from 2000 to 2011 was linked to Scottish Morbidity Records to obtain details on pregnancy outcome. Binary logistic regression was carried out to test the associations of year and type of diagnosis with pregnancy termination, while controlling for maternal age, neighbourhood deprivation and parity. There were 24,155 (92.0%) with no chromosomal anomalies, 1,483 (5.6%) aneuploidy diagnoses, and 623 (2.4%) diagnoses of anomaly that was not aneuploidy (including translocations and single chromosome deletions). In comparison with negative test results, pregnancies diagnosed with trisomy were most likely to be terminated (adjusted OR 437.40, 95% CI 348.19–549.46) followed by other aneuploid anomalies (adjusted OR 95.94, 95% CI 69.21–133.01). During the study period, fewer pregnancies that were diagnosed with aneuploidy were terminated, including trisomy diagnoses (adjusted OR 0.44, 95% CI 0.26–0.73). Older women were less likely to terminate (OR 0.35, 95% CI 0.28, 0.42), and parity was also an independent predictor of termination. In keeping with previous findings, while the number of invasive diagnostic tests declined, the proportion of abnormal results increased from 6.09% to 10.88%. Systematic advances in prenatal screening have improved detection rates for aneuploidy. This has been accompanied by a reduction in the rate of termination for aneuploidy. This may reflect societal changes with acceptance of greater diversity, but this is speculation, and further research would be needed to test this. [ABSTRACT FROM AUTHOR]

In the last 15 years, major advances have been made in prenatal screening. Cohort studies have led to an understanding of the causes of many common diseases that are determined by the combined effects of genetic and phenotypic factors. Non-invasive prenatal testing (NIPT) is a technology used to isolate deoxyribonucleic acid (DNA) placental fragments from the mother's blood at as early as 10 weeks of gestation, using cell free fetal DNA technology. NIPT screens for trisomy 13,18 and 21 for sex chromosome abnormalities with a high detection rate. Cohort studies have shown a high detection rate and a low false positive rate for NIPT, but it is still considered a screening test and not diagnostic. It is recommended confirmation in case of a positive test, with a diagnostic procedure as chorionic villus sampling or amniocentesis. It is essential that NIPT be used ethically and effectively. Because of its high sensitivity (true positive rate) and its specificity (true negative rate) many recommend that NIPT should be used as a diagnostic method. However, today NIPT is used as a screening method, an attractive alternative to the serum screens and invasive test currently in use. There is a continuing decline in sequencing costs and hopefully, soon, the cost will be reduced. [ABSTRACT FROM AUTHOR]

Purpose: To determine correlations between macrophage colony-stimulating factor (MCSF) levels in maternal blood during first trimester screening with respect to normal and pathological pregnancies.Methods: This was a prospective single centre study. First trimester screening was performed according to FMF London certificates. Nuchal translucency, PAPP-A and free β-HCG were obtained as well as M-CSF serum levels in maternal blood. Fetal karyotyping was achieved by chorionic villi sampling.Results: 125 patients were enrolled in this study. 21 pregnancies had confirmed aberrant karyotypes. Trisomy 21 cases showed significantly elevated M-CSF levels of 270 ± 91 pg/ml (p = 0.032), whereas cases of trisomy 13 (183 ± 68 pg/ml) and trisomy 18 (143 ± 40 pg/ml) had low M-CSF levels. Furthermore M-CSF levels tended to be low in preterm deliveries, placental insufficiency and nicotine consumption. In cases with gestational diabetes M-CSF tended to be elevated. Furthermore we found a positive correlation between high free β-human chorionic gonadotropin (hcg) and MCSF values. There was no correlation between pregnancy associated plasma protein (PAPP-A) and M-CSF.Conclusions: M-CSF is a cytokine promoting placental growth and differentiation. M-CSF is known to be involved in the process of implantation in pregnancy. The role of M-CSF with respect to disturbed pregnancy outcomes such as placental insufficiency in normal or aberrant karyotypes, for example, is yet subject to further research. [ABSTRACT FROM AUTHOR]

Objectives: First, to examine in twin pregnancies the performance of first-trimester screening for fetal trisomies 21, 18 and 13 by cell-free (cf) DNA testing of maternal blood and, second, to compare twin and singleton pregnancies regarding the distribution of fetal fraction of cfDNA and rate of failure to obtain a result.Methods: This was a prospective study in 438 twin and 10 698 singleton pregnancies undergoing screening for fetal trisomies by cfDNA testing at 10 + 0 to 13 + 6 weeks' gestation. Chromosome-selective sequencing of cfDNA was used and, in twin pregnancies, an algorithm was applied that relies on the lower fetal fraction contributed by the two fetuses. Multivariate regression analysis was used to determine significant predictors of fetal fraction and a failed result.Results: In twin pregnancies, the median fetal fraction was lower (8.0% (interquartile range (IQR), 6.0-10.4%) vs 11.0% (IQR, 8.3-14.4%); P < 0.0001) and failure rate after first sampling was higher (9.4% vs 2.9%; P < 0.0001) compared to in singletons. Multivariate logistic regression analysis demonstrated that the risk of test failure increased with increasing maternal age and body mass index and decreased with fetal crown-rump length. The risk was increased in women of South Asian racial origin and in pregnancies conceived by in-vitro fertilization (IVF). The main contributor to the higher rate of failure in twins was conception by IVF which was observed in 9.5% of singletons and 56.2% of twins. In the 417 twin pregnancies with a cfDNA result after first or second sampling, the detection rate was 100% (8/8) for trisomy 21 and 60% (3/5) for trisomies 18 or 13, at a false-positive rate (FPR) of 0.25% (1/404). In the 10 530 singleton pregnancies with a cfDNA result after first or second sampling, the detection rate was 98.7% (156/158) for trisomy 21 and 80.3% (49/61) for trisomies 18 or 13, at a FPR of 0.22% (23/10 311).Conclusions: In twin pregnancies undergoing first-trimester screening for trisomies by cfDNA testing, the fetal fraction is lower and failure rate higher compared to in singletons. The number of trisomic twin pregnancies examined was too small for an accurate assessment of performance of screening, but it may be similar to that in singleton pregnancies. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objectives: First, to report the distribution of the fetal fraction of cell-free (cf) DNA and the rate of a failed cfDNA test result in trisomies 21, 18 and 13, by comparison with pregnancies unaffected by these trisomies, second, to examine the possible effects of maternal and fetal characteristics on the fetal fraction, and third, to consider the options for further management of pregnancies with a failed result.Methods: This was a cohort study of 10 698 singleton pregnancies undergoing screening for fetal trisomies 21, 18 and 13 by cfDNA testing at 10-14 weeks' gestation. There were 160 cases of trisomy 21, 50 of trisomy 18, 16 of trisomy 13 and 10 472 were unaffected by these trisomies. Multivariate regression analysis was used to determine significant predictors of fetal fraction and a failed cfDNA test result amongst maternal and fetal characteristics.Results: Fetal fraction decreased with increasing body mass index and maternal age, was lower in women of South Asian racial origin than in Caucasians and in assisted compared to natural conceptions. It increased with fetal crown-rump length and higher levels of serum pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin. The median fetal fraction was 11.0% (interquartile range (IQR), 8.3-14.4%) in the unaffected group, 10.7% (IQR, 7.8-14.3%) in trisomy 21, 8.6% (IQR, 5.0-10.2%) in trisomy 18 and 7.0% (IQR, 6.0-9.4%) in trisomy 13. There was a failed result from cfDNA testing after first sampling in 2.9% of the unaffected group, 1.9% of trisomy 21, 8.0% of trisomy 18 and 6.3% of trisomy 13. In the cases with a failed result, 7% of women had invasive testing, mainly because of high risk from the combined test and/or presence of sonographic features suggestive of trisomies 18 and 13. All cases of trisomies were detected prenatally.Conclusions: In cases of a failed cfDNA test, the rate of trisomies 18 and 13, but not trisomy 21, is higher than in those with a successful test. In the management of such cases, the decision in favor of invasive testing should depend on the risk of prior screening and the results of detailed ultrasound examination. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To estimate the cost-effectiveness of fetal aneuploidy screening in the general pregnancy population using non-invasive prenatal testing (NIPT) as compared to first trimester combined screening (FTS) with serum markers and NT ultrasound.Methods: Using a decision-analytic model, we estimated the number of fetal T21, T18, and T13 cases identified prenatally, the number of invasive procedures performed, corresponding normal fetus losses, and costs of screening using FTS or NIPT with cell-free DNA (cfDNA). Modeling was based on a 4 million pregnant women cohort, which represents annual births in the U.S.Results: For the general pregnancy population, NIPT identified 15% more trisomy cases, reduced invasive procedures by 88%, and reduced iatrogenic fetal loss by 94% as compared to FTS. The cost per trisomy case identified with FTS was $497,909. At a NIPT unit, cost of $453 and below, there were cost savings as compared to FTS. Accounting for additional trisomy cases identified by NIPT, a NIPT unit cost of $665 provided the same per trisomy cost as that of FTS.Conclusions: NIPT in the general pregnancy population leads to more prenatal identification of fetal trisomy cases as compared to FTS and is more economical at a NIPT unit cost of $453. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical accuracy of the IONA® test for aneuploidy screening.Methods: This was a multicenter blinded study in which plasma samples from pregnant women at increased risk of trisomy 21 underwent cell-free DNA analysis utilizing the IONA test. For each sample, the IONA software generated a likelihood ratio and a maternal age-adjusted probability risk score for trisomies 21, 18 and 13. All results from the IONA test were compared against accepted diagnostic karyotyping.Results: A total of 442 maternal samples were obtained, of which 437 had test results available for analysis and assessment of clinical accuracy. The IONA test had a detection rate of 100% for trisomies 21 (n = 43; 95% CI, 87.98-100%), 18 (n = 10; 95% CI, 58.72-100%) and 13 (n = 5; 95% CI, 35.88-100%) with cut-offs applied to likelihood ratio (cut-off > 1 considered high risk for trisomy) and probability risk score incorporating adjustment for maternal age (cut-off ≥ 1/150 considered high risk for trisomy). The false-positive rate (FPR) was 0% for trisomies 18 and 13 with both analysis outputs. For trisomy 21, a FPR of 0.3% was observed for the likelihood ratio, but became 0% with adjustment for maternal age.Conclusion: This study indicates that the IONA test is suitable for trisomy screening in a high-risk screening population. The result-interpretation feature of the IONA software should facilitate wider implementation, particularly in local laboratories, and should be a useful addition to the current screening methods for trisomies 21, 18 and 13. [ABSTRACT FROM AUTHOR]

Objective: To assess the potential performance of screening for fetal trisomies 21, 18 and 13 by cell-free DNA (cfDNA) analysis of maternal blood using the IONA® test.Methods: This was a nested case-control study of cfDNA analysis of maternal plasma using the IONA test. Samples were obtained at 11-13 weeks' gestation, before chorionic villus sampling, from 201 euploid pregnancies, 35 with trisomy 21, four with trisomy 18 and two with trisomy 13. Laboratory personnel were blinded to the fetal karyotype.Results: Probability scores for trisomies 21, 18 and 13 were given for 241/242 samples analyzed. No probability score was provided for one (0.5%) euploid pregnancy because of low fetal fraction. In all 35 cases of trisomy 21 the probability score for trisomy 21 was > 95% and the scores for trisomies 18 and 13 were ≤ 0.0001%. In all four cases of trisomy 18, the probability score for trisomy 18 was > 77% and the scores for trisomies 21 and 13 were ≤ 0.0001%. In the two cases of trisomy 13, the probability score for trisomy 13 was > 59% and the scores for trisomies 21 and 18 were ≤ 0.0001%. In the 200 euploid pregnancies with a test result, the probability score was < 0.08% for trisomy 21, < 0.001% for trisomy 18 and < 0.002% for trisomy 13. Therefore, the IONA test detected 100% of all three trisomies, with a false-positive rate of 0%.Conclusion: The IONA test successfully differentiated all cases of trisomies 21, 18 and 13 from euploid pregnancies. [ABSTRACT FROM AUTHOR]

Background There are limited data regarding noninvasive prenatal testing ( NIPT) in low-risk populations, and the ideal aneuploidy screening model for a pregnant population has yet to be established. Aims To assess the implementation of NIPT into clinical practice utilising both first- and second-line screening models. Materials and Methods Three private practices specialising in obstetric ultrasound and prenatal diagnosis in Australia offered NIPT as a first-line test, ideally followed by combined first-trimester screening ( cFTS), or as a second-line test following cFTS, particularly in those with a calculated risk between 1:50 and 1:1000. Results NIPT screening was performed in 5267 women and as a first-line screening method in 3359 (63.8%). Trisomies 21 and 13 detection was 100% and 88% for trisomy 18. Of cases with known karyotypes, the positive predictive value ( PPV) of the test was highest for trisomy 21 (97.7%) and lowest for monosomy X (25%). Ultrasound detection of fetal structural abnormality resulted in the detection of five additional chromosome abnormalities, two of which had high-risk cFTS results. For all chromosomal abnormalities, NIPT alone detected 93.4%, a contingent model detected 81.8% ( P = 0.097), and cFTS alone detected 65.9% ( P < 0.005). Conclusions NIPT achieved 100% T21 detection and had a higher DR of all aneuploidy when used as a first-line test. Given the false-positive rate for all aneuploidies, NIPT is an advanced screening test, rather than a diagnostic test. The benefit of additional cFTS was the detection of fetal structural abnormalities and some unusual chromosomal abnormalities. [ABSTRACT FROM AUTHOR]

Objectives: Cell-free DNA (cfDNA) analysis of maternal blood for detection of trisomies 21, 18 and 13 is superior to other methods of screening but is expensive. One strategy to maximize performance at reduced cost is to offer cfDNA testing contingent on the results of the first-trimester combined test that is used currently. The objectives of this study were to report the feasibility of implementing such screening, to examine the factors affecting patient decisions concerning their options for screening and decisions on the management of affected pregnancies and to report the prenatal diagnosis of fetal trisomies and outcome of affected pregnancies following the introduction of contingent screening.Methods: We examined routine clinical implementation of contingent screening in 11,692 singleton pregnancies in two National Health Service (NHS) hospitals in the UK. Women with a risk ≥ 1 in 100 (high-risk group) were offered options of invasive testing, cfDNA testing or no further testing, and those with a risk between 1 in 101 and 1 in 2500 (intermediate-risk group) were offered cfDNA testing or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or by examination of the neonates.Results: In the study population of 11,692 pregnancies, there were 47 cases of trisomy 21 and 28 of trisomies 18 or 13. Screening with the combined test followed by invasive testing for all patients in the high-risk group potentially could have detected 87% of trisomy 21 and 93% of trisomies 18 or 13, at a false-positive rate of 3.4%; the respective values for cfDNA testing in the high- and intermediate-risk groups were 98%, 82% and 0.25%. However, in the high-risk group, 38% of women chose invasive testing and 60% chose cfDNA testing; in the intermediate-risk group 92% opted for cfDNA testing. A prenatal diagnosis was made in 43 (91.5%) pregnancies with trisomy 21 and all pregnancies with trisomies 18 or 13. In many affected pregnancies the parents chose to avoid testing or termination and 32% of pregnancies with trisomy 21 resulted in live births.Conclusions: Screening for fetal trisomies by cfDNA analysis of maternal blood, contingent on the results of the combined test, can be implemented easily in routine clinical practice. In the high-risk group from the combined test, most but not all women chose cfDNA testing rather than invasive testing. Performance of screening for trisomy 21 was superior by the cfDNA test than by the combined test. However, prenatal detection of trisomies and pregnancy outcome depend not only on performance of screening tests but also on parental choice. [ABSTRACT FROM AUTHOR]

Objective: To analyse population-based trends over the entire history of prenatal testing for aneuploidy.Design: Retrospective analysis of state-wide data sets.Setting: Australian state of Victoria with ~70 000 annual births.Population: All pregnant women undergoing invasive prenatal testing at <25 weeks' gestation from 1976 to 2013.Methods: Analysis of three state-wide data sets: (1) Prenatal diagnosis data set of 119 404 amniocenteses and chorionic villus samplings from 1976 to 2013; (2) central serum screening laboratory data set from 1996 to 2013; (3) government birth statistics from 1976 to 2013.Main Outcome Measures: Annual numbers and uptake rates of invasive prenatal tests and serum screening, indications for invasive prenatal testing, prenatal diagnoses of aneuploidy, diagnostic yield of invasive tests.Results: Annual numbers of invasive prenatal tests climbed steadily from 1976, then declined from 2000. In 2013, the number of invasive prenatal tests was the lowest in 25 years, while the number of trisomy 21 diagnoses was the highest ever recorded. Annual uptake of serum screening climbed from 1.6 to 83% over 1996-2013. Results from 2013 showed a high diagnostic yield (15.8%) for a low rate of invasive testing (3.4% of births). Over four decades, the number of invasive procedures performed for each diagnosis of major chromosome abnormality declined from 100 to six.Conclusions: This study demonstrates historic reductions in the proportion of women undergoing invasive testing and dramatic improvements in diagnostic yield. Monitoring the impact of new prenatal technologies on this progress remains an important research priority.Tweetable Abstract: Invasive prenatal testing has reached historic lows due to dramatic improvements in Down syndrome screening. [ABSTRACT FROM AUTHOR]

Study Question: How does a national prenatal screening program for Down syndrome (DS) perform in detecting sex chromosome abnormalities (SCAs)-Turner syndrome (TS), Klinefelter syndrome, 47,XXX and 47,XYY syndromes.Summary Answer: The SCA detection rate resulting from DS screening was below 50% for all four groups of SCAs.What Is Known Already: The detection rates of SCAs are higher in countries with DS screening. TS is associated with greater nuchal translucency (NT) and lower pregnancy-associated plasma protein-A (PAPP-A). However, specific detection rates of SCAs using prenatal DS screening have not been determined. No clear trend in PAPP-A, free beta human chorionic gonadotropin (β-hCG) and NT has been found in the remaining SCAs. Several lines of inquiry suggest that it would be advantageous for individuals with SCA to be detected early in life, leading to prevention or treatment of accompanying conditions. There is limited information about pre- and perinatal status that distinguishes SCA embryogenesis from normal fetal development.Study Design, Size, Duration: A register-based case-control study from the Danish Central Cytogenetic Register (DCCR), cross-linked with the Danish Fetal Medicine Database (DFMD), was performed from 2008 to 2012. Groups of SCAs were compared with DS and then matched with non-SCA controls to assess differences between these groups in prenatal markers and birth outcomes.Participants/materials, Setting, Methods: We included cases with prenatal and post-natal SCA karyotypes (n = 213), DS (n = 802) and 168 056 controls. We screened 275 037 individuals examined prenatally. We retrieved information regarding maternal age, NT, β-hCG and PAPP-A, as well as details regarding maternal and newborn characteristics.Main Results and the Role Of Chance: The DS screening procedure detected 87 per 100 000 TS (42% of expected), 19 per 100 000 Klinefelter syndrome (13% of expected), 16 per 100 000 47,XXX (16% of cases) and 5 per 100 000 47,XYY (5% of expected) SCAs, with an overall detection rate of 27%. Compared with controls, all four SCA groups showed significantly higher NT and lower PAPP-A compared with controls (all P < 0.01) and similar to DS. The legal abortion rate was high for all four syndromes (47,XXX: 24%; 47,XYY: 29%; Klinefelter syndrome: 48%, TS: 84%). For SCA fetuses carried to term, only TS fetuses had consistently lower birthweights and placenta weights than non-SCA controls (both P = 0.0001). A few SCA cases localized in DCCR could not be found in DFMD (n = 16).Limitations, Reason For Caution: Controls were matched on sex of the fetus of cases, meaning that all electively aborted fetuses (before week 12) were excluded, possibly reducing the diversity in the control group. We were not able to localize all diagnosed cases of SCA and DS in DFMD. Although these cases were present in DCCR, we were not able to account for the discrepancy. In addition, we suspect that several SCA children have not been diagnosed yet and future post-natal diagnosis of these cases would reduce the diagnostic yield reported here even further.Wider Implications Of the Findings: The prenatal detection rate is below 50% for all SCAs. The approach used for detecting DS cannot be extended to also include SCAs. In addition, all SCAs have low PAPP-A and increased NT, thus probably reflecting an abnormal embryogenesis. Growth retardation of TS fetuses is if anything more pronounced than previously reported, both when evaluating fetus and placenta.Study Funding/competing Interests: This study received support from Aarhus University and the Novo Nordisk Foundation. The authors have no competing interests that may be relevant to the study. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate how many additional chromosomal abnormalities can be detected by diagnostic testing compared with noninvasive prenatal testing in a high-risk prenatal population. METHODS: All karyotype results of invasive prenatal testing in singleton pregnancies performed in response to a positive prenatal screen through the California Prenatal Screening Program from April 2009 through December 2012 were examined. Abnormal karyotypes were categorized as to whether the abnormality is detectable by current noninvasive prenatal testing methods. RESULTS: Of 1,324,607 women who had traditional screening during the study period, 68,990 (5.2%) were screen-positive. Of screen-positive women, 26,059 (37.8%) underwent invasive diagnostic testing and 2,993 had an abnormal result (11.5%). Of these, 2,488 (83.1%) were predicted to be detectable with current noninvasive prenatal testing methods, and 506 (16.9%) were considered not currently detectable. Trisomy 21 accounted for 53.2% of the abnormal results (n = 1,592). Common aneuploidies, detectable by noninvasive prenatal testing, comprised a higher percentage of abnormal results in older women (P<01). CONCLUSION: For pregnant women with a positive aneuploidy screen who pursued diagnostic testing, 16.9% of chromosome abnormalities are not currently detectable by noninvasive prenatal testing. Undetectable aneuploidies range from relatively mild to those associated with significant disability. This is important information to be considered by patients, health care providers, and screening programs in evaluating the use of traditional screening and invasive prenatal diagnosis compared with noninvasive prenatal testing. [ABSTRACT FROM AUTHOR]

Objectives: To analyze trends in screening and invasive prenatal diagnosis over a 13-year period in relation to changes in the national prenatal screening policy. Methods: Fetal karyotypes obtained following 11 045 prenatal invasive procedures between January 1999 and December 2011 were retrospectively reviewed. Referral indications were classified as medical and non-medical (anxiety). The number of tests per relevant chromosomal abnormalities (CA) detected in both groups adjusted for indication was calculated. Results: A total of 414 CA were detected (3.8%), 355 of which were considered clinically significant. The percentage of invasive procedures has declined from 49% to 12%, although cases referred by anxiety have increased from 22% to 55%. A total of 3129 invasive procedures did not have any medical indication (28%) and 13 relevant CA (0.42%) were found in this group. In this low-risk series, the index "number of invasive testing needed to detect 1 relevant CA" adjusted for indication was 241. Conclusions: Changes in our national prenatal policy through this 13-year period show an increasing efficiency of prenatal detection of CA. However, despite the intensifying screening policies, low-risk pregnant women show a growing demand for prenatal invasive testing and a baseline risk for cytogenetic abnormality of 1/241. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 40-year-old pregnant woman, who was referred to clinic at 32 weeks' gestation because of oligohydramnios and severe intrauterine growth restriction (IUGR). The patient was diagnosed for confined placental mosaicism (CPM) of double trisomies 9 and 21. The article discusses that CPM of trisomy 9 have been reported with features of skeletal abnormalities and neurodevelopmental impairment.

Objective To investigate the prevalence of soft markers identified at second trimester ultrasound in a low-risk population and the association of these markers with trisomies and invasive testing. Design Prospective observational study. Setting Swedish University Hospital. Population All women with fetuses examined by ultrasound at 15+0-22+0 weeks gestation between July 2008 and March 2011. Methods Cases with soft markers were compared with non-cases with regard to trisomies and invasive testing. Main outcome measures Prevalence of soft markers, likelihood ratio for trisomies and risk ratio for invasive tests after detection of soft markers. Results Second trimester ultrasound was performed on 10 710 fetuses. Markers were detected in 5.9% of fetuses. 5.1% were isolated, 0.7% were multiple and 0.1% were combined with an anomaly. Presence of markers showed a positive likelihood ratio for Down syndrome, but the association (likelihood ratio = 7.1) was only statistically significant for the combined category of any marker (isolated, multiple or combined with anomaly). The risk ratio for invasive testing after the second trimester ultrasound was 24.0 in pregnancies with isolated soft markers compared with those without markers. Conclusion In a low-risk population, soft markers were found in 5.9% of fetuses at second trimester ultrasound. The likelihood ratio for Down syndrome was significant only for any marker (isolated, multiple or combined with anomaly). The presence of soft markers increased the incidence of invasive procedures substantially. Soft markers should be noted when information on second trimester ultrasound is formulated, and all units performing fetal ultrasound examinations should have established routines concerning information management when soft markers are identified. [ABSTRACT FROM AUTHOR]

Objective:The objective of this study was to investigate whether women who screened positive for both trisomy 18 (T18) and trisomy 21 (T21) yet had euploid karyotypes were at increased risk for adverse pregnancy outcomes.Study Design:This was a retrospective cohort study of women who had first trimester aneuploidy screening. Double-positive subjects had risks greater than screening cutoffs for T21 and T18 and confirmed euploid karyotypes. Singleton subjects were matched 1:2 by maternal age to controls with normal screening. Perinatal outcomes were investigated using t-tests and χ2-tests; statistical significance was set at P<0.05.Result:Of 9733 women who had first trimester screening, 33 euploid pregnancies screened positive for both T21 and T18. Compared with controls, these study subjects were more likely to have abnormalities identified by prenatal ultrasounds, including renal, fetal membrane and fluid, as well as multiple anomalies (P=0.01). In addition, double-positive subjects had a lower mean gestational age at birth (P=0.02) and lower mean birth weight (P=0.03) than controls. Maternal outcomes were not significantly different.Conclusion:Pregnancies with double false-positive first trimester aneuploidy screening were associated with pregnancy/fetal abnormalities. [ABSTRACT FROM AUTHOR]

Aim To establish reference values for the nuchal translucency ( NT) thickness in Japanese fetuses. Material and Methods Ultrasonographic measurements of the crown-rump length ( CRL) and NT were performed from 11 to 13 + 6 weeks of gestation in consecutive Japanese fetuses examined during prenatal visits between February 2011 and January 2012. The median, 5th and 95th percentiles of the NT thickness with 5 mm intervals of the CRL were confirmed. Results A total of 970 cases were enrolled in the study. The median NT thickness for a CRL between 45 and 80 mm ranged from 1.2 mm to 1.9 mm, and the 95th percentile of these values ranged from 2.1 mm to 3.2 mm, respectively. Conclusion The reference values for the NT thickness in Japanese fetuses were determined. These values should be useful for fetal biometry, morphological assessment and first trimester screening for chromosomal abnormalities in Japan. [ABSTRACT FROM AUTHOR]

Objective: To screen for chromosomal defects on the basis of maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. Method: Fetal nuchal translucency thickness was measured by ultrasound examination at 10-14 weeks of gestation in living singleton pregnancies in women attending routine antenatal care at Prince Ali Bin Hussein. Amman Jordan. The risks for trisomy 21 and other chromosomal defects by ultrasound measurment of fetal nuchal translucency thickness and maternal age were calculated, using the software provided by The Fetal Medicine Foundation. Results: Chromosomal defects were diagnosed in 10 cases, including 4 cases of trisomy 21 and 6 cases with other chromosomal abnormalities (trisomy 18, 13, triploidy, Turner). The estimated risk based on maternal age and fetal NT was 1 in 300 .Conclusion: The combination of maternal age and fetal nuchal translucency thickness was an effective method of screening for chromosomal defects. [ABSTRACT FROM AUTHOR]

Ütine GE, Boduroğlu K. (Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey). Prevention of congenital anomalies. Çocuk Sağlığı ve Hastalıkları Dergisi 2013; 56: 28-37. Major congenital anomalies affect 2-3% of neonates. Anomalies may be detected in another 2-3% during the first five years of life, thereby affecting 4-6% of all children. Congenital anomalies may be genetic or environmental in origin. The underlying etiology is undetermined in 50-60% of all major anomalies, multifactorial in 20-25%, genetic in 7-8%, chromosomal in 6-7%, and teratogenic in 6%. Primary prevention is of major importance, since treatment for most anomalies is either impossible or difficult. Major preventive goals for our population are: (1) decreasing the frequency of consanguineous marriages, which increase the incidence of rare autosomal recessive disorders, (2) decreasing the frequency of births among >35-year-old women, which increase chromosomal disorders, mainly Down syndrome, and (3) improving the socioeconomic and environmental factors that affect the frequency of multifactorial diseases. Antenatal maternal factors, including dietary folate intake, smoking, caffeine and alcohol consumption, rubella infection, and uncontrolled diabetes, may also affect the frequency of major anomalies. [ABSTRACT FROM AUTHOR]

Objective: To analyze trends in screening and invasive prenatal diagnosis of chromosome abnormalities (CA) over a 13-year period and correlate them to changes in the national prenatal screening policy. Methods: We retrospectively reviewed Down syndrome (DS) screening tests and fetal karyotypes obtained by prenatal invasive testing (IT) in our fetal medicine unit between January 1999 and December 2011. Results: A total of 24,226 prenatal screening tests for DS and 11,045 invasive procedures have been analyzed. Over a 13-year period, utilization of non-invasive screening methods has significantly increased from 57% to 89%. The percentage of invasive procedures has declined from 49% to 12%, although the percentage of IT performed for maternal anxiety has increased from 22% to 55%. The percentage of detected CA increased from 2.5% to 5.9%. Overall, 31 invasive procedures are needed to diagnose 1 abnormal case, being 23 procedures in medical indications and 241 procedures in non-medical indications. Conclusions: Our experience on screening and invasive prenatal diagnostic practice shows a decrease of the number of IT, with a parallel decline in medical indications. There is an increasing efficiency of prenatal screening program to detect CA. Despite the increasing screening policies, our population shows a growing request for prenatal IT. The a priori low risk population shows a not negligible residual risk for relevant CA. This observation challenges the current prenatal screening strategy focused on DS; showing that the residual risk is higher than the current cut-off used to indicate an invasive technique. [ABSTRACT FROM AUTHOR]

Abstract: Nuchal translucency (NT) identified at the time of the 11–14week scan has been established as one of the best tools for screening for Down syndrome. It has also proven to be of value in screening for other conditions such as cardiac defects and extra-cardiac structural abnormalities. In this article, we present data from our fetal medicine unit that highlight the importance of using NT measurement as a stratifying tool when referring for early scans. We propose that, whenever possible, in selected cases with increased NT, provision should be made for additional early scans at 14–18weeks of gestation with a view to providing information on fetal structural integrity well ahead of the routine scheduled appointments. Early scans should incorporate detailed assessment of the fetal cardiac as well as extra-cardiac anatomy to diagnose or rule out major structural defects. This strategy will provide reassurance to a large number of prospective parents. [Copyright &y& Elsevier]