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Objectives: To examine the distribution of nuchal translucency thickness (NT), free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed., Methods: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and β-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated., Results: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). β-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss., Conclusions: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and β-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Background: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy., Objective: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed., Results: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate., Conclusion: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the performance of high-resolution chromosomal microarray (CMA) as the standard diagnostic approach for genomic imbalances in pregnancies with increased risk based on combined first-trimester screening (cFTS)., Methods: This was a retrospective study of genomic findings in a cohort of 575 consecutive pregnancies undergoing invasive testing because of a cFTS risk ≥ 1:300 on a publicly funded population-based screening program in the Central and Northern Regions of Denmark, between September 2015 and September 2016. Women with fetal nuchal translucency thickness ≥ 3.5 mm or opting for non-invasive prenatal testing (NIPT) were excluded. Comparative genomic hybridization was performed using a 180-K oligonucleotide array on DNA extracted directly from chorionic villus/amniocentesis samples. Genomic outcomes were reported in relation to cFTS findings., Results: Of the 575 pregnancies that underwent invasive testing, CMA detected 22 (3.8% (95% CI, 2.5-5.7%)) cases of trisomies 21, 18 and 13, 14 (2.4% (95% CI, 1.4-4.0%)) cases of other types of aneuploidy and 15 (2.6% (95% CI, 1.5-4.3%)) cases with a pathogenic or probably pathogenic copy number variant (CNV). Of the 15 CNVs, three were > 10 Mb and would probably have been detected by chromosomal analysis, but the other 12 would most probably not have been detected using conventional cytogenetic techniques; therefore, the overall detection rate of CMA (8.9% (95% CI, 6.8-11.5%)) was significantly higher than that estimated for conventional cytogenetic analysis (6.8% (95% CI, 5.0-9.1%)) (P = 0.0049). Reducing the cFTS risk threshold for invasive diagnostic testing to 1 in 100 or 1 in 50 would have led, respectively, to 60% or 100% of the pathogenic CNVs being missed., Conclusions: CMA is a valuable diagnostic technique that can identify an increased number of genomic aberrations in pregnancies at increased risk on cFTS. Limiting diagnostic testing to pregnancies with a risk above 1 in 100 or 1 in 50, as proposed in contingent NIPT/invasive testing models, would lead to a significant proportion of pathogenic CNVs being missed at first-trimester screening. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Screening tests for trisomy 21 have gradually become more refined and now involve complex statistical models that combine demographic, biophysical, and biochemical parameters to produce individualized risk estimates for pregnant women. An understanding of the evolution of the principles, methods, and statistical techniques applied to Down syndrome screening is valuable as these processes can be transferred to other, more prevalent, adverse pregnancy outcomes. First trimester ultrasound forms the foundation of this process.

The term 'Non invasive prenatal testing' is used to describe the rapidly emerging molecular technologies related to cell free DNA assessment that are being applied to prenatal screening for Down syndrome and other chromosomal abnormalities. This technology is now available to Australian women through a number of off-shore laboratories. We review the basis of this method of testing, the literature describing the effectiveness of NIPT in screening for trisomy 21 and the potential methods by which this tool could be incorporated into current screening strategies., (© 2013 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objectives: Absence of the nasal bone has been recognized to be a strong ultrasound marker for Down syndrome and its inclusion in combined first-trimester screening would increase the sensitivity and specificity of this test. We describe the development of a method of image scoring that should allow reliable assessment of practitioners submitting themselves to peer review for nasal bone imaging., Methods: Twenty sonographers submitted 20 images demonstrating the presence of the nasal bone for quality assurance audit. Image quality was compared with the criteria described by The Fetal Medicine Foundation. Three raters scored the images on four separate occasions. On the first two occasions all 400 images were assessed qualitatively and given a simple pass/fail score. On the third and fourth occasions, five images from each of the 20 sets were scored objectively for five criteria by each of the three raters, with a cut-off applied to the scores generated. The reliability of these image assessment techniques was compared statistically., Results: Through quantitative assessment, 84% of images were judged in the same manner by three raters on two separate occasions and in 94% of cases five of these six ratings drew the same conclusion. Rates of intrarater and inter-rater agreement were significantly better using quantitative rather than qualitative techniques., Conclusions: This study has shown that clearly defined assessment criteria together with a quantitative scoring method improve the reliability of expert peer review. The quantitative method is recommended as the basis for future nasal bone image audit., (Copyright 2009 ISUOG. Published by John Wiley & Sons, Ltd.)

The debate over the application of nuchal translucency measurement in Down's syndrome screening is still unresolved in some clinicians' minds. Although different authors report a range of sensitivities for Down's syndrome, none question the validity of the association between increased nuchal translucency and fetal aneuploidy. The published literature reveals a lack of congruence over a standard, reproducible method for measuring nuchal translucency. Only with the adoption of uniform methodology, and the establishment of international standards for nuchal translucency measurement, is the true potential of this test likely to be realized. The increasing use of first trimester ultrasound has focused attention on the value of this investigation in confirming fetal viability, estimation of gestational age, and screening for congenital abnormality. This review summarizes the role of ultrasound and maternal serum biochemistry in first trimester screening.

This study examines GATA-4 gene expression in cardiac tissue from fetuses with trisomy 21 presenting with increased nuchal translucency thickness at 10-14 weeks of gestation. mRNA was extracted from cardiac tissue after termination of pregnancy at 10-18 weeks of gestation in ten trisomy 21 fetuses and 29 normal controls. Northern and slot blots were performed and densitometric analysis of slot blots was used to determine the steady-state levels of expression of GATA-4. GATA-4 transcript levels were also compared with ANP and BNP, which have previously been measured in the same panel of samples. GATA-4 expression increased significantly with gestation but there was no significant difference between fetuses with trisomy 21 and controls. There was no significant association between GATA-4 expression and the steady-state level of transcripts for the natriuretic peptides.

At 10-14 weeks of gestation about 80% of fetuses with chromosomal defects have abnormal accumulation of subcutaneous fluid in the nuchal region that is visualized by ultrasonography as nuchal translucency. A possible cause for this translucency is cardiac dysfunction due to the associated defects in the heart and great arteries. The aim of this study was to investigate whether in cardiac tissue from trisomic fetuses, compared to normals, there is an alteration in the steady state levels of expression of the genes encoding sarcoplasmic reticulum calcium ATPase (calcium ATPase), which is known to be downregulated in postnatal heart failure. After termination of pregnancy at 10-18 weeks of gestation, mRNA was extracted from cardiac tissue in 11 trisomy 21 and 4 trisomy 18 fetuses. Densitometric analysis of the Northern and slot blots was used to determine the steady state levels of expression of calcium ATPase and the values from the trisomic fetuses were compared to those of 30 normal controls at 10-18 weeks. Calcium ATPase gene expression did not change significantly with gestation at 10-18 weeks. In trisomic fetuses there was no significant decrease in calcium ATPase expression and expression levels of calcium ATPase were not related to increased nuchal translucency. However, the levels expressed in fetuses are already very low and cardiac dysfunction as a potential etiological factor cannot be excluded.

Objective: To investigate whether the increased nuchal translucency of trisomic fetuses is the consequence of heart failure by examining cardiac expression of atrial natriuretic peptide and brain natriuretic peptide genes., Methods: Cardiac atrial natriuretic peptide and brain natriuretic peptide messenger RNA (mRNA) levels were measured in fetal hearts from 15 pregnancies affected by trisomy 21 or 18 at 12-16 weeks' gestation and from 30 normal controls at 10-20 weeks., Results: In normal fetuses, mRNA levels of atrial natriuretic peptide decreased, but levels of brain natriuretic peptide did not change significantly with gestation. In trisomic fetuses, mRNA levels of both atrial natriuretic peptide and brain natriuretic peptide were significantly higher than in gestational age-matched normal controls., Conclusion: These data demonstrate that atrial natriuretic peptide and brain natriuretic peptide genes are transcribed prenatally, and the findings in trisomic fetuses suggest that the increased translucency of trisomic fetuses may be the consequence of heart failure.

Fetal heart rate was measured routinely as part of a prospective study examining the efficacy of screening for trisomy 21 by fetal nuchal translucency thickness and maternal age. In 6903 normal singleton pregnancies the fetal heart rate decreased from a mean of 171 bpm at 10 weeks of gestation to 156 bpm at 14 weeks (r = 0.413, p < 0.0001). In 85 trisomy 21 pregnancies, the mean heart rate was significantly higher than in the normal group (mean difference 0.67 SD, 95% confidence interval 0.42-0.92, t = 5.3, p < 0.001). The fetal heart rate in trisomy 18 and triploid fetuses was significantly lower and in trisomy 13 and Turner syndrome was higher than normal. There was no significant association between delta fetal heart rate and delta nuchal translucency thickness in either the normal (r = -0.018) or the trisomy 21 (r = -0.031) pregnancies. Consequently, the risk for chromosomal defects can be derived by combining data from maternal age, fetal nuchal translucency and fetal heart rate. The effectiveness of screening by this method was examined in a self-selected population with completed pregnancies that had undergone first-trimester scanning. This population contained 6903 normal and 29 trisomy 21 fetuses. For a false-positive rate of about 5%, the sensitivity for trisomy 21 was 48% by maternal age, 26% by fetal heart rate, 72% by nuchal translucency thickness, 59% by maternal age and fetal heart rate, 76% by maternal age and nuchal translucency thickness and 83% by a combination of maternal age, nuchal translucency thickness and fetal heart rate.

This study investigates whether first-trimester screening for trisomy 21 by fetal nuchal translucency thickness preferentially identifies those fetuses destined to die in utero and examines the potential impact of such a method of screening on the live birth incidence of trisomy 21. In 70 pregnancies, trisomy 21 was diagnosed at 12 (range 11-14) weeks of gestation and the parents opted for elective termination which was carried out at 14 (12-20) weeks. In all cases, viability was established by ultrasound scan at the time of chorion villus sampling (CVS) and just before termination of pregnancy. Eight (11.4%) fetuses died in the interval between CVS and termination of pregnancy and this rate of lethality was higher than the 6.9% estimated rate for an unselected population of trisomy 21 fetuses. This 4.5% increase may, in part, be attributed to the effects of CVS and may also be due to patient selection on the basis of increased nuchal translucency. The rate of lethality increased with translucency thickness from 5.3% for those with translucency of 1-3 mm to 23.5% for translucency of > 7 mm. In trisomy 21, the rate of intrauterine lethality is associated with nuchal translucency thickness. Nevertheless, a policy of screening by maternal age and fetal nuchal translucency followed by selective termination of affected fetuses would still result in a more than 70% reduction in the live birth incidence of trisomy 21.

Pathological examination of the great vessels was performed in 34 trisomy 21 fetuses after surgical termination of pregnancy at 11-16 weeks of gestation. In each case, the external diameters of eight segments of the great vessels were measured. The aortic valve and the ascending aorta were wider than in normal fetuses, whilst the aortic isthmus was narrower. The degree of narrowing of the isthmus was significantly greater in fetuses with high nuchal translucency thickness and it is possible that there is a causal association between the two.

Objective: Our purpose was to determine the incidence of cardiac septal defects in fetuses with trisomy 21 diagnosed by increased nuchal translucency thickness at 10 to 13 weeks' gestation., Study Design: Pathologic examination of the fetal heart was performed in 36 fetuses with trisomy 21 after suction termination of pregnancy at 12 to 15 weeks' gestation. The diagnosis of trisomy 21 was made by chorion villus sampling because of increased (> or = 3 mm) fetal nuchal translucency thickness detected at routine first-trimester ultrasonographic examination., Results: Perimembranous ventricular and atrioventricular septal defects were detected in 20 of 36 fetal hearts. A septal defect was observed in 1 of the 11 fetuses with nuchal translucency thickness of 3 mm and in 19 of the 25 with translucency > or = 4 mm (p < 0.001)., Conclusion: The incidence of ventricular and atrioventricular septal defects is much higher in fetuses with trisomy 21 and increased nuchal translucency thickness at 10 to 13 weeks' gestation than in live-born infants with this chromosomal abnormality. The incidence of cardiac septal defects increases with nuchal translucency thickness.

The article offers information on the cell-free fetal DNA (cffDNA) screening and its increasing use in Australia. Topics discussed include a study in Denmark which reported a 50% reduction in live-born prevalence of Down syndrome and 50% reduction in invasive testing following the introduction of combined first tri-mester screening, and another study in Victoria which found a high positive predictive value for cffDNA.

An abstract of the article "Screen-positive for Trisomy 21 at combined first trimester screening: how many do not have a prenatal karyotype?" by O. Petersen and others, is presented.