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This article, titled "Prenatal detection of Down syndrome based on second and third trimester ultrasound scan," examines the incidence of Down Syndrome suspected on late trimester scans. The study analyzed the medical records of pregnant women who gave birth to babies with confirmed Down Syndrome. Out of 126 mothers, 80 had at least one prenatal scan, and 50 of them had abnormal findings on the scans. 15 fetuses were suspected with Down Syndrome, and further genetic testing confirmed the diagnosis in some cases. The article suggests that early prenatal diagnosis through first trimester screening programs could be beneficial for counseling and support. [Extracted from the article]

Objective: To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99th centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies.Methods: This was a retrospective cohort study of 226 fetuses with NT > 99th centile at 11-14 weeks' gestation, between January 2013 and December 2017, in a clinical setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters.Results: In the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester.Conclusions: cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99th centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound will identify a major structural abnormality in 11% of the fetuses with NT > 99th centile and no genetic anomaly. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [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]

Objectives: Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Several studies have reported a significant association between ARSA and Down syndrome, as well as 22q11.2 microdeletion. The objective of this study was to assess the risk of abnormal chromosomal microarray analysis (CMA) findings in a large cohort of pregnancies with fetal ARSA as an isolated, as well as a non-isolated, sonographic anomaly. A secondary objective was to review the literature, examining the frequency of chromosomal microarray aberrations in fetuses with isolated ARSA.Methods: Data from all pregnancies referred for invasive testing and CMA due to sonographic diagnosis of fetal ARSA, between 2013 and 2017, were obtained retrospectively from the computerized database of the Israeli Ministry of Health. The rate of clinically significant CMA findings in these fetuses was compared to that in a local control population of 2752 low-risk pregnancies with normal ultrasound and serum screening results. In addition, a literature search was conducted in PubMed, from inception to February 2018, of original studies in the English language describing the frequency and nature of microscopic and submicroscopic aberrations in fetuses with isolated ARSA.Results: Of 246 pregnancies with isolated ARSA that underwent CMA analysis, a clinically significant finding was detected in one (0.4%) pregnancy (trisomy 21). This rate did not differ significantly from that in the control population (P = 0.1574). Of 22 fetuses with non-isolated ARSA, one (4.5%) additional case of trisomy 21 was noted. The frequency of trisomy 21 in this cohort also did not differ from that in the control population (relative risk, 5.5 (95% CI, 0.8-37.6)). The literature search yielded 13 additional relevant papers, encompassing 333 cases of isolated ARSA. Of 579 cases overall (including those of the present study), 13 (2.2%) cases of trisomy 21 were detected, with no cases of 22q11.2 microdeletion.Conclusion: While an association may exist between non-isolated ARSA and Down syndrome, isolated ARSA might better serve as a soft marker for Down syndrome, rather than a routine indication for invasive prenatal testing. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13, contingent on the results of the first-trimester combined test in twin pregnancy.Methods: Screening for trisomies 21, 18 and 13 was carried out in 959 twin pregnancies by assessment of a combination of maternal age, fetal nuchal translucency thickness, and serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A at 11-13 weeks' gestation in two UK NHS hospitals. Women in the high-risk group (risk ≥ 1 in 100) were offered the option of invasive testing, cfDNA testing or no further testing, and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates.Results: In 42 (4.4%) of the 959 pregnancies, there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow-up. The 917 pregnancies with known trisomic status of both twins included six that were discordant for trisomy 21, four that were discordant for trisomy 18 and 907 with no trisomy 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.1%) and 667 (72.7%) of the pregnancies were classified as high risk, intermediate risk and low risk, respectively. The high-risk group included five (83.3%) cases of trisomy 21 and three (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included six pregnancies with trisomy 21, three with trisomy 18 and 206 with no trisomy 21, 18 or 13. The cfDNA test classified correctly as screen positive all six cases of trisomy 21 and two of the three with trisomy 18, and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening led to prenatal detection of all cases of trisomy 21 and three of four with trisomy 18.Conclusion: This study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: An association between isolated, increased nuchal translucency thickness (NT) and pathogenic findings on chromosomal microarray analysis (CMA) has been reported. A recent meta-analysis reported that most studies use a NT cut-off value of 3.5 mm. However, considering NT distribution and the commonly accepted 5% false-positive rate in maternal serum screening, NT cut-off levels should be reconsidered. The aim of this study was to assess different NT cut-off levels as indication for CMA and to determine whether CMA should be recommended for mildly increased NT of 3.0-3.4 mm.Methods: This was a retrospective, multicenter study of singleton pregnancies with CMA results and either normal NT and no other finding or with increased NT as the only medical indication for CMA at the time of an invasive procedure (increased NT was considered an isolated finding in cases of advanced maternal age). Women with normal fetal NT who underwent CMA did so at their own request. A single laboratory performed all genetic analyses. Comparative genomic hybridization microarray analysis or single nucleotide polymorphism array technology was used for CMA. If combined first-trimester screening (NT and biochemistry) indicated increased risk for common aneuploidies, the case was excluded. NT was used to divide cases into three groups (≤ 2.9 mm, 3.0-3.4 mm and ≥ 3.5 mm) and their CMA results were compared.Results: CMA results were recorded in 1588 pregnancies, among which 770 fetuses had either normal NT with no other finding or isolated increased NT. Of these, 462 had NT ≤ 2.9 mm, 170 had NT of 3.0-3.4 mm and 138 had NT ≥ 3.5 mm. Pathogenic copy number variants were found in 1.7%, 6.5% and 13.8% of cases, respectively.Conclusion: Our results suggest that CMA should be recommended when fetuses have isolated, mildly increased NT (3.0-3.4 mm). Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [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]

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 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]

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]

ABSTRACT Objectives The primary objective was to estimate the prevalence of aberrant right subclavian artery ( ARSA) in fetuses with Down syndrome. Secondary objectives were to assess the prevalence of ARSA in euploid fetuses, the feasibility of ultrasound evaluation of the right subclavian artery ( RSA) in the first and second trimesters of pregnancy, the performance of ARSA in screening for trisomy 21 and its association with other abnormalities. Methods Web-based databases ( PubMed, EMBASE and MEDLINE) were searched up to July 2014. The STROBE, PRISMA and QUIPS instruments were used to assess all included studies and for reporting of methodology, results and conclusions. Original studies that reported prenatal ultrasound evaluation of ARSA, assessment of its prevalence in Down-syndrome and euploid fetuses, feasibility of ultrasound evaluation of the RSA in the first and second trimesters of pregnancy and correlation of ARSA with other abnormalities were included, excluding duplications and case reports. Collected data were summarized to estimate prevalence and feasibility. A meta-analysis was performed pooling the study-specific positive and negative likelihood ratios (LR+ and LR-), detection rates and false-positive rates for trisomy 21. Results Prevalence of ARSA in Down-syndrome fetuses was 23.6% (95% CI, 19.4-27.9%), whereas in euploid fetuses it was 1.02% (95% CI, 0.86-1.10%). Ultrasound evaluation of the RSA course and origin in the first and second trimesters of pregnancy was feasible in 85% and 98% of cases (first and second trimester, respectively) and it was directly related to sonographic experience and fetal crown-rump length and inversely related to maternal body mass index. In more than 20% of fetuses with ARSA there was an association with other abnormalities but ARSA seemed to be an independent marker of trisomy 21. The meta-analysis showed that ARSA is a significant risk factor for Down syndrome (pooled LR+ = 26.93, 95% CI, 19.36-37.47, P for effect < 0.001, P for Q = 0.3, I2 = 17.3%), whereas normal RSA is a significant protective marker (pooled LR- = 0.71, 95% CI, 0.51-0.99, P for effect = 0.043, P for Q = 0.9, I2 = 0%). Conclusions ARSA appears to be a clinically useful prenatal ultrasound marker of Down syndrome. Additional testing when ARSA is diagnosed should involve evaluation of all risk factors by applying a mathematical model. There is insufficient evidence to recommend fetal karyotyping in cases with isolated ARSA. If the background risk is higher or additional markers are present, full fetal karyotyping is advisable, including analysis for 22q11 microdeletion. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives We performed a meta-analysis to examine the performance of second-trimester (14-24 weeks' gestation) isolated fetal pyelectasis as a marker for trisomy 21 and to calculate its associated weighted pooled likelihood ratios. Methods PubMed, Ovid MEDLINE and Cochrane databases were searched using the terms 'pyelectasis' and 'pelviectasis'. Studies were included if fetuses with isolated pyelectasis were reported separately from fetuses with other soft markers of aneuploidy and/or structural anomalies and if knowledge of the fetal karyotype was unknown at the time of ultrasound examination. Results Individual study statistics were pooled as weighted positive and negative likelihood ratios with 95% CIs, using a random-effects model. Ten observational studies were included (2148 cases of isolated pyelectasis). Isolated fetal pyelectasis was defined in seven out of 10 studies as a renal pelvis anteroposterior diameter of ≥ 4 mm. Isolated fetal pyelectasis was associated with pooled positive and negative likelihood ratios of 2.78 (95% CI, 1.75-4.43) and 0.99 (95% CI, 0.98-1.00), respectively. Conclusions The detection of isolated fetal pyelectasis on mid-trimester ultrasound is associated with an increased likelihood of trisomy 21. If the finding of isolated fetal pyelectasis is used to adjust the trisomy 21 risk from maternal serum screening tests, a positive likelihood ratio of 2.78 should be used in the calculation. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives To determine whether there is an association between sonographically assessed hyper- or hypocoiling of the umbilical cord and the presence of trisomy 21, to provide reference values for the antenatal umbilical coiling index ( aUCI) at a gestational age of 16-21 weeks and to determine whether these measurements are reliable and reproducible. Methods This was a prospective study of 737 pregnancies in which the aUCI was measured between 16 and 21 weeks of gestation by ultrasound at the time of amniocentesis. The aUCI was calculated as the reciprocal value of the mean length of one complete coil in centimeters. We created reference curves and studied the relationship with trisomy 21 and other chromosomal defects. In 30 pregnancies we studied the intra- and interobserver variation in measurements using Bland-Altman plots with associated 95% limits of agreement and intraclass correlation coefficients. Results aUCI was found to be non-linearly related to gestational age at 16-21 weeks and reference curves were created for the mean aUCI and the 2.3rd, 10th, 90th and 97.7th percentiles. There was no significant difference in aUCI values between the reference group (n = 714) and cases with trisomy 21 (n = 16) or other aneuploidies (n = 7) (one-way ANOVA, P = 0.716). There was good intra- and interobserver agreement in aUCI measurements. Conclusions The aUCI can be measured reliably and varies according to gestational age at 16-21 weeks. The aUCI was not significantly associated with trisomy 21 or other chromosomal defects. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Non-invasive prenatal testing ( NIPT) for aneuploidy using cell-free DNA in maternal plasma is revolutionizing prenatal screening and diagnosis. We review NIPT in the context of established screening and invasive technologies, the range of cytogenetic abnormalities detectable, cost, counseling and ethical issues. Current NIPT approaches involve whole-genome sequencing, targeted sequencing and assessment of single nucleotide polymorphism ( SNP) differences between mother and fetus. Clinical trials have demonstrated the efficacy of NIPT for Down and Edwards syndromes, and possibly Patau syndrome, in high-risk women. Universal NIPT is not cost-effective, but using NIPT contingently in women found at moderate or high risk by conventional screening is cost-effective. Positive NIPT results must be confirmed using invasive techniques. Established screening, fetal ultrasound and invasive procedures with microarray testing allow the detection of a broad range of additional abnormalities not yet detectable by NIPT. NIPT approaches that take advantage of SNP information potentially allow the identification of parent of origin for imbalances, triploidy, uniparental disomy and consanguinity, and separate evaluation of dizygotic twins. Fetal fraction enrichment, improved sequencing and selected analysis of the most informative sequences should result in tests for additional chromosomal abnormalities. Providing adequate prenatal counseling poses a substantial challenge given the broad range of prenatal testing options now available. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective To evaluate the impact of the introduction of a Down syndrome screening policy in England, including implementation of the first-trimester combined screening test, on reducing prenatal invasive diagnostic procedure rates. Methods All English cytogenetic laboratories were asked to submit data from the fiscal years 2003/2004 until 2011/2012 on all samples received from prenatal invasive procedures, including those that were undertaken following a higher-risk Down syndrome screening result. Results There was a gradual decline in the number of invasive procedures undertaken subsequent to a positive Down syndrome screening result in England, from 36?968 in 2003/2004 to 11?446 in 2008/2009, with only a relatively small subsequent decrease, to 10?215, in 2011/2012. This corresponds to a 72% reduction in the number of referrals received by the cytogenetic laboratories over a 9-year period and correlates with the national policy of implementing the combined screening test in place of second-trimester screening, which has reduced the overall screen-positive rate to 3.1% from an initial level of 6.0%. Conclusions Implementation of a national Down syndrome screening policy based on the combined screening test has significantly reduced the number of invasive tests performed. However, as the combined screening test has become the replacement for second-trimester testing and has been almost completely implemented it appears that improvements in screening using current approaches may have reached their limits. [ABSTRACT FROM AUTHOR]

Objectives To study the ratio of prenasal thickness (PT) to nasal bone length (NBL) in normal and trisomy-21 fetuses in the second and third trimesters of pregnancy. Methods The PT and NBL were measured retrospectively in 106 normal fetuses (in three-dimensional (3D) volumes) and in 30 fetuses with trisomy 21 (10 on two-dimensional (2D) images and 20 in 3D volumes). Results In normal fetuses the mean PT and NBL increased between 15 and 33 weeks' gestation from 2.3 to 6.1 mm ( r = 0.85, P < 0.001) and from 3.3 to 9.6 mm ( r = 0.87, P < 0.001), respectively. The PT : NBL ratio was stable throughout gestation, with a mean of 0.61 (95% CI, 0.59-0.63; r = − 0.04, P = 0.7). The 5 th and 95 th percentiles were 0.48 and 0.80, respectively. In trisomy-21 fetuses the mean PT and NBL increased between 14 and 34 weeks from 3.0 to 9.2 mm ( r = 0.86, P < 0.001) and from 1.9 to 7.8 mm ( r = 0.85, P < 0.001), respectively. The PT : NBL ratio was significantly higher than in normal fetuses ( P < 0.001) but also stable throughout gestation, with a mean of 1.50 (95% CI, 1.20-1.80; r = − 0.35, P = 0.07). Twenty-three (77%) of the 30 fetuses with trisomy 21 had a PT above the 95 th percentile and 20 (67%) had an NBL below the 5 th percentile. All the trisomy-21 fetuses had a PT : NBL ratio above the 95 th percentile. When the 95 th percentile of the PT : NBL ratio was used as a cut-off value the detection and false positive rates for trisomy 21 were 100 (95% CI, 89-100)% and 5 (95% CI, 2-11)%, respectively. The positive likelihood ratio was 21.2. Conclusions The PT : NBL ratio is stable in the second and third trimesters of pregnancy in both normal and trisomy-21 fetuses, but all trisomy-21 fetuses in this series had a PT : NBL ratio above the 95 th percentile. The ratio is therefore a strong marker for trisomy 21. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective To document the incidence of congenital heart defects (CHD) that are detectable echocardiographically in the fetus with trisomy 21 and the relationship with nuchal translucency, fetal sex and ethnicity. Methods Data on fetuses with a karyotypic diagnosis of trisomy 21 were collected between January 2002 and March 2010. The data were analyzed for the gestational age at examination, maternal age, reason for referral for fetal echocardiography, cardiac diagnosis, fetal sex, ethnicity and outcome. Results Of 917 fetuses with trisomy 21, 487 had a diagnostic echocardiogram. Cardiac examination was performed before 14 weeks' gestation in 75% of cases. The main reasons for referral were increased nuchal translucency (NT) in 76% of cases, suspected cardiac abnormality in 15% and an extracardiac anomaly in 6%. Structural CHD was found in 164/487 (34%), or 98/412 (24%) if those referred for suspected CHD are removed from the analysis. The most common diagnosis was atrioventricular septal defect (AVSD) (115/487, 24%). The ratio of female to male fetuses with AVSD was 29%:18% ( P = 0.003). There was no difference in the incidence of AVSD with ethnicity. The pregnancy continued in 36 cases, but three were lost to follow-up; of the known outcomes there were 10 intrauterine deaths, six of which had structural heart disease, and 23 live births, 15 of which had CHD. Conclusion Most fetuses (66-76%) with trisomy 21 have a structurally normal heart on echocardiography. The presence of structural CHD was not associated with increased NT. The increased incidence of AVSD in females was confirmed in our study, although an ethnic difference could not be confirmed. CHD does not appear to increase the chance of spontaneous intrauterine loss in ongoing pregnancies. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives The primary aim of this study was to assess pregnant women's knowledge of first-trimester combined Down syndrome screening in a setting of required informed consent. As the secondary aim, we wanted to identify relevant differences in knowledge level among subgroups of pregnant women, including those informed in different ways about prenatal examinations. Methods Data stem from a population-based cross-sectional questionnaire study including 15 multiple-choice questions assessing knowledge of different aspects of screening. Included were 6427 first-trimester pregnant women from three Danish obstetric departments offering prenatal screening free of charge. Both participants and non-participants in the screening program were included. The results are based on 4095 responders (64%). Differences between subgroups were examined using chi-squared tests and logistic regression analysis. Estimates are stated with 95% CI. Results The majority of the participants (87.6 (86.6-88.6)% to 92.6 (91.7-93.3)%) correctly identified the test concept and the main condition being screened for. Fewer participants (16.4 (15.3-17.6)% to 43.3 (41.8-44.8)%) correctly recognized test accuracy and the potential risk of adverse findings other than Down syndrome. Knowledge level was positively associated with length of education (adjusted ORs 1.0 (0.8-1.4) to 3.9 (2.4-6.4)) and participation in the screening program (adjusted OR 0.9 (0.6-1.3) to 5.9 (3.9-8.8)). Participation in an individual information session was weakly associated with more knowledge. Conclusion The majority of the pregnant women correctly identified the test concept and the main condition being screened for. The pregnant women were found less knowledgeable on test accuracy and drawbacks. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives In Denmark a new national guideline for prenatal screening and diagnosis was issued in 2004 according to which all pregnant women should be offered a first-trimester combined risk assessment for trisomy 21 (T21). The aim of this study was to investigate whether the new screening strategy for T21 has changed the gestational age at which trisomy 18 (T18) and trisomy 13 (T13) are diagnosed prenatally, and the number of infants born with T18 or T13. Methods We collected from the Danish Cytogenetic Central Register information on all prenatal and postnatal chromosome analyses for T18 or T13, registered from 1997 to 2007. Information on first-trimester screening results was collected from each department of obstetrics and gynecology performing the nuchal translucency scans. The cut-off used for referral to invasive diagnostic testing for T21 and for T18/T13 was 1 : 300 and 1 : 150 at screening, respectively. Results In total, there were 435 cases with T18 and 168 cases with T13 between 1997 and 2007 in Denmark. The estimated incidence of T18 and T13 at the time of delivery was calculated as 2.5 and 1.6 per 10 000 deliveries, respectively. The number (proportion) of cases diagnosed before week 18 increased significantly, from 63 (59.4%) in 1997 and 1998 to 90 (80.4%) in 2006 and 2007 ( P < 0.001). In addition, the number of T18 and T13 cases diagnosed prenatally after week 22 or postnatally decreased significantly, from 34 (32.1%) in 1997 and 1998 to seven (6.3%) in 2006 and 2007 ( P < 0.0001). For women participating in first-trimester risk assessment in 2006 and 2007, the detection rate of T18 and T13 was 78.8% (95% CI, 71.0-86.7%). Conclusion The number of T18 and T13 fetuses diagnosed before week 18 increased significantly after the introduction of a combined first-trimester screening strategy for T21 in Denmark. In addition, the total number of fetuses diagnosed late in pregnancy and infants born with T18 or T13 decreased significantly. The national detection rate for T18 and T13 in the first trimester is comparable with detection rates found in modeled datasets and other prospective studies. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates a sonographic technique of predicting Down syndrome risk during the second trimester of pregnancy by measuring the iliac crest angle (ICA). Three dimensional views of fetal pelvis were obtained to measure different parameters of ICA. The study revealed that the parameters middle and coronal 2 were the most reproducible ICA measurements and iliac crest measurements can be used to monitor Down syndrome risks in the second trimester of pregnancy.

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.

The article presents a study which examines the possible effect to the autonomy of patient with health professionals non-respect to ethical principles during Down syndrome screening. The study was conducted at the medical population in Eastern France with the questionnaire attempting to evaluate the health professionals medical knowledge and their attitudes concerning their patients. It suggests that the health professional knowledge and opinion have influence over the patient's autonomy.

The article presents a prospective study that combines maternal age, fetal nuchal translucency (NT) and maternal serum freeβ-human chorionic gonadotropin (β-hCG) , and pregnancy-associated plasma protein-A (PAPP-A) in screening for trisomy 21. It presents the characteristics of 19, 614 pregnancies with normal delivery and 122 cases of trisomy 21, which comprise the study population. It reveals that the capability of the combine method to detect 90% for trisomy 21.

The article presents a retrospective study which evaluates the effectivity of the second-trimester genetic sonogram to detect Down syndrome and other chromosomal abnormalities in a community-based antenatal testing unit. 660 fetal ultrasound examinations were analyzed to identify the detection rate for fetal Down syndrome and other chromosomal abnormalities. The results reveal that 32 among the study population have chromosomal abnormalities but only 12 were noted as Down Syndrome.

Objectives: Two methods have been proposed for standardizing measures of nuchal translucency thickness (NT) for risk calculation in first-trimester screening for chromosomal defects: differential delta NT (delta-NT) and multiples of the median (MoM) of NT. There is currently some debate as to which of these is more appropriate. The aims of this study were to determine whether delta-NT could be extrapolated successfully from one center-specific NT reference curve to another and thus to empirically calculate the likelihood ratios (LRs) of delta-NT. Methods: This was a retrospective analysis of a database of 4248 singleton pregnancies, including 13 cases of Down syndrome. The delta-NT was extrapolated to the reference curve of the NT values of the original group of patients for whom the LRs were calculated empirically, using a scale factor. The Down syndrome risk was calculated by standardizing the NT, using both extrapolated delta-NT and MoM methods, both for the screening based on maternal age and NT alone, and for the combined screening, in which biochemical markers are also taken into account. We analyzed detection rates and false positives, the precision of the risk prediction obtained by each of the methods and the effectiveness when each of the methods was used with a cut-off point based on a fixed post-test risk. Results: The risk calculation using extrapolated delta-NT presented an effectiveness profile that was similar to that obtained using MoMs, both when NT was used as the sole marker and when it was used in combination with biochemical markers. The precision of the risk prediction was similar with both methods. Conclusions: Delta-NT can be extrapolated for use in risk calculation between two populations with different distributions and medians of NT values. The precision of the risk estimate obtained is similar to that derived using MoMs. [ABSTRACT FROM AUTHOR]

Objective To assess the effects of sociodemographic and health-provider factors of women's understanding of abnormal results on measurement of nuchal translucency (NT) and maternal serum screening (MSS), 18 months after the implementation of a policy aimed at increasing women's awareness regarding MSS. Methods A representative sample of women (n = 734) who gave birth in Parisian maternity units in 1999 were asked about their understanding o fan abnormal result on MSS and NT. We assessed the effects of sociodemographic and health-provider factors on the probability, of women interpreting an abnormal result correctly, misinterpreting it as a definitive diagnosis, or declaring that they did not know how to interpret the result. Response rate was 92 % and the analyses included multinomial models. Results For both MSS and NT measurement, the majority of women interpreted an abnormal result correctly. However, there were substantial sociodemographic differences in the probability of women interpreting an abnormal result correctly, and more so in the probability of their declaring not to know how to interpret the result. The probability of correct interpretations was substantially higher, and that of declaring not to know how to interpret the result substantially lower, for MSS than NT measurement. However, for several sociodemographic groups, the proportion of women who misinterpreted an abnormal result on screening as indicative of a definitive diagnosis was also higher for MSS as compared with NT measurement. Conclusions These findings underscore the need for additional efforts, along with alternative strategies, to inform women about the implications of prenatal screening, particularly in the case of measurement of NT. [ABSTRACT FROM AUTHOR]

Objectives To compare levels of anxiety and depression during pregnancy and puerperium between women who are offered nuchal translucency (NT) screening routinely and those who are not, and to compare levels between women accepting and those declining screening. Methods In 12 midwife practices in three different health districts an experimental NT screening program was offered to pregnant women between 1 June 1999 and 1 January 2001. As part of this implementation study, questionnaires including the Hospital Anxiety and Depression Scale (HADS) were completed: after the patient was informed but before screening (T1), at 20 weeks of gestation (T2), and 6 weeks after delivery (T3). A control group of women receiving routine prenatal care (i.e. no screening offered) also completed the HADS questionnaire at 12 and 20 weeks and after delivery. Results Five hundred and twenty-seven questionnaires were analyzed. There was a screening uptake of 87% in the intervention group (i.e. those offered screening). Women in this group differed significantly in the percentage of previous miscarriages and religious background compared with the control group. We adjusted for these differences in the analysis. There were no significant differences in HADS scores between the intervention and the control groups at T1, suggesting that women receiving information on screening were not more anxious compared with women who were not informed. Women who were offered screening (acceptors as well as decliners) had significantly lower HADS levels at 20 weeks and after delivery. There were no demographic differences between women accepting and those declining screening. Conclusion Informing women and offering them NT screening for Down syndrome does not increase anxiety or depression levels in pregnancy. In fact, women undergoing or declining screening seem less anxious compared with those who are not offered screening. It is possible that informing women and offering them the chance to decide autonomously whether to participate in screening reduces anxiety levels. [ABSTRACT FROM AUTHOR]

The author comments on the use of ultrasonic imaging to perform prenatal diagnosis of Down syndrome. According to the author, detection of Down syndrome remain to be one of the main challenges of prenatal medicine. He cited thoracic vascular malformation as another possible prenatal marker of Down syndrome.

Objective To determine whether the prevalence of fetal echogenic intracardiac foci (ElF) differs according to maternal ethnicity. Methods We performed a retrospective cohort study of all women undergoing second-trimester diagnostic ultrasound examination and amniocentesis at a prenatal diagnosis referral center from January 1 2000 to July 1 2003. Data were collected on the presence of ElF, gestational age at time of ultrasound scan, karyotype results, maternal age and ethnicity. Univariate and multivariate analyses of ElF, ethnicity and presence of aneuploidy were conducted. Results Among the 7480 women qualifying for the study, ElF were found in 309 (4.1%). When maternal ethnicity was subdivided into Caucasian, African-American, Hispanic, Asian-American, Native American, Asian Indian, and Middle Eastern, the highest rates of ElF were found in fetuses of African-American (6.7%), Asian-American (6.9%), and Middle Eastern (8.1%) mothers compared to a rate of 3.3% in Caucasians (P < 0.001). In all ethnic groups except Hispanics, ElF was associated with an increased risk for Down syndrome (odds ratio range from 1.8 to 15.7). Conclusions African-American, Asian-American, and Middle Eastern patients are more likely than patients of other ethnicities to have a fetus with an ElF. Even controlling for ethnicity, fetuses with an ElF still have an increased risk for Down syndrome. As more data accumulate, the prevalence of EIF and its association with Down syndrome among different ethnic groups can be incorporated into patient counseling. [ABSTRACT FROM AUTHOR]

Objectives Nuchal translucency (NT) screening increases antenatal detection of Down syndrome (DS) compared to maternal age-based screening. We wanted to determine if a change in policy for prenatal diagnosis would result in fewer babies born with DS. Methods A total of 39572 pregnant women were randomized to a scan at 12–14 gestational weeks including NT screening for DS (12-week group) or to a scan at 15–20 weeks with screening for DS based on maternal age (18-week group). Fetal karyotyping was offered if risk according to NT was ≥ 1:250 in the 12-week group and if maternal age was ≥ 35 years in the 18-week group. Both policies included the offer of karyotyping in cases of fetal anomaly detected at any scan during pregnancy or when there was a history of fetal chromosomal anomaly. The number of babies born with DS and the number of invasive tests for fetal karyotyping were compared. Results Ten babies with DS were born alive with the 72- week policy vs. 16 with the 18-week policy (P = 0.25). More fetuses with DS were spontaneously lost or terminated in the 12-week group (45/19796) than in the 18-week group (27/19 776; p = 0.04). All women except one with an antenatal diagnosis of DS at <22 weeks terminated the pregnancy. For each case of DS detected at <22 weeks in a living fetus there were 16 invasive tests in the 12-week group vs. 89 in the 18-week group. NT screening detected 71% of cases of DS for a 3.5% test-positive rate whereas maternal age had the potential of detecting 58% for a test-positive rate of 18%. Conclusions The number of newborns with DS differed less than expected between pregnancies that had been screened at 12–14 weeks' gestation by NT compared with those screened at 15–20 weeks by maternal age. One explanation could be that NT screening - because it is performed early in pregnancy - results in the detection and termination of man pregnancies with a fetus with DS that would have resulted in miscarriage without intervention, and also by many cases of DS being detected because of a fetal anomaly seen on an 18-week scan. The major advantage of the 12-week scan policy is that many fewer invasive tests for fetal karyotyping are needed per antenatally detected case of DS. [ABSTRACT FROM AUTHOR]

Objective To determine the potential value of measuring the gestational sac volume (GSV) at 11 to 13 + 6 weeks of gestation in screening for chromosomal defects. Methods The GSV was measured using three-dimensional (3D) ultrasound in 500 consecutive singleton pregnancies immediately before chorionic villus sampling (CVS) for fetal karyotyping at 11 to 13 + 6 (median 12) weeks of gestation. Results The fetal karyotype was normal in 417 pregnancies and abnormal in 83. In the chromosomally normal group, the mean GSV increased significantly with gestational age from a mean of 69 mL at 11 weeks to 144 mL at 13 + 6 weeks (the standard deviation was 27 mL). In the chromosomally abnormal group, the mean GSV for gestational age was not significantly different from normal in fetuses with trisomy 21, trisomy 18 and Turner syndrome, but it was smaller in those with triploidy and trisomy 13. However, the mean GSV for crown-rump length (CRL) was significantly larger in trisomy 18, smaller in triploidy and trisomy 13, and not different from normal in trisomy 21 and Turner syndrome. The mean CRL for gestational age was significantly smaller than normal in trisomy 18, triploidy and trisomy 13. Conclusions The measurement of the GSV at 11 to 13 + 6 weeks of gestation is unlikely to provide useful prediction of the major chromosomal defects. In trisomy 13 and triploidy, the small GSV may be due to early onset fetal growth restriction and reduced amniotic fluid volume. In trisomy 18, the increase in GSV is probably due to the presence of associated fetal abnormalities that interfere with fetal swallowing. [ABSTRACT FROM AUTHOR]

Objective To ascertain, by means of a questionnaire, women's preferences for four different approaches to prenatal screening for Down syndrome. Methods Women attending antenatal clinics at six UK maternity units were asked to put in order of preference four different approaches to screening for Down syndrome all of which had the same false positive rate of 5%. The options were: (1) first-trimester testing, 90% detection of Down syndrome with results available in 1 h at one-stop clinics for the assessment of risk (OSCAR); (2)first-trimester testing, 90% detection and results available within 2–3 days (combined screening); (3) first-trimester testing plus second-trimester testing, 93% detection and results available within 2–3 days of second test (integrated testing); (4)second-trimester testing, 75% detection and results available within 2–3 days. Results Over 1100 women attending antenatal clinics at six maternity units across the UK returned the questionnaire. A total of 75% of women selected a first-trimester test (option 1 or option 2) as their first choice with 68.2% expressing a preference for the OSCAR approach and a further 6.8% for combined screening. Twenty-four percent of women opted for integrated testing as their first choice with only 1% expressing a preference for second-trimester screening. Conclusions A first-trimester test is preferred by the majority of women over a test with marginally higher detection rate that delivers results later in pregnancy. Timing and rapid reporting of results appear to influence women's choice of test. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the natural course of enlarged nuchal translucency (NT) and to determine if its disappearance before 14 weeks' gestation is a favorable prognostic sign in relation to fetal karyotype and pregnancy outcome. Methods A total of 147 women with increased NT (> 95th centile) at first measurement were included in this study. A second measurement was performed in all cases, at an interval of at least 2 days. Both measurements were taken between 10 + 3 and 14 + 0 weeks. All women underwent chorionic villus sampling or amniocentesis for subsequent karyotyping. In those women with a normal karyotype, a fetal anomaly scan was performed at 20 weeks' gestation. Pregnancy outcome was recorded in all cases. The finding of persistent or disappearing NT enlargement was analyzed in relation to fetal karyotype and pregnancy outcome. Results Of the 147 paired measurements, NT remained enlarged at the second measurement in 121 (82%) cases. An abnormal karyotype was found in 35% of these cases. In 26 (18%) fetuses the NT measurement was found to be below the 95th percentile at the second measurement and in only two of them an abnormal karyotype was found (8%). In the 103 chromosomally normal fetuses an adverse outcome (i.e. fetal loss or structural defects) was recorded in 22 fetuses with persistent enlargement (28%) and in four fetuses with disappearing enlargement (17%). Conclusions Disappearance of an enlarged NT before 14 weeks' gestation is not a rare phenomenon and seems to be a favorable prognostic sign with respect to fetal karyotype. Overall, no significant difference in pregnancy outcome was found between chromosomally normal fetuses with persisting or disappearing NT enlargement. [ABSTRACT FROM AUTHOR]

Leukemia in a hydropic fetus with hepatosplenomegaly and Down syndrome was diagnosed at 25 weeks' gestation. Spontaneous demise occurred 10 days after the cordocentesis. A review of the literature of the seven cases described antenatally and 10 cases described in the immediate neonatal period or on examination of the stillborn baby is presented. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To investigate the feasibility and repeatability of nuchal translucency thickness measurement using three-dimensional ultrasound. Methods Forty consecutive women with uncomplicated singleton pregnancies attending for Down syndrome screening at 11–14 weeks’ gestation were included in this prospective crossover trial. Nuchal translucency thickness was measured using both two-dimensional and three-dimensional ultrasound. In each case two three-dimensional volumes were recorded and then examined by using the technique of planar reformatted sections. The initial plane of the first volume always contained a clear image of the nuchal region (‘sagittal volume’), whilst the initial plane of the second volume was selected randomly regardless of fetal position (‘random volume’). The repeatability of nuchal translucency measurement was examined by constructing a scatter diagram of the difference between the measurements plotted against the mean of two readings. Results Nuchal translucency measurements could be repeated in 38/40 (95%) sagittal volumes and 24/40 (60%) random volumes. The mean difference between two-dimensional measurements and those obtained by reslicing of sagittal three-dimensional volumes was -0.097 mm (95% limits of agreement from -0.481 to 0.675) and 0.225 mm (95% limits of agreement from -0.369 to 0.819) when random volumes were examined. Conclusions Reslicing of stored three-dimensional volumes can be used to replicate nuchal translucency measurements only when nuchal skin can also be clearly seen on two-dimensional ultrasound. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Fetal nuchal translucency measurement has been introduced as a screening test for the calculation of risk of chromosomal abnormalities. The purpose of this study was to investigate: (1) the feasibility of obtaining nuchal translucency measurements using three-dimensional ultrasound; (2) whether three-dimensional ultrasound could improve and facilitate the required repeated measurements of nuchal translucency; (3) the correlation between two- and three-dimensional nuchal translucency measurement values. Subjects and methods Between September 1999 and May 2000, in a prospective cohort study, 229 unselected pregnant women with a mean age of 34.6 (range, 20–46) years were examined. The mean fetal crown–rump length was 64.3 (range, 45–84) mm. Nuchal translucency thickness was measured first by two- and then by three-dimensional ultrasound in two planes (three-dimensional mid-sagittal and three-dimensional transverse). An attempt was made to repeat each nuchal translucency measurement three times (totalling nine measurements per patient) and the means of the two- and three-dimensional measurements were compared. The majority (95%) of the measurements were made transabdominally and 5% were made transvaginally. The time limit for each examination was 20 min. Results With the two-dimensional method, nuchal translucency could be measured in 96.8% of cases. Of these, three measurements could be obtained in 51.7%, two in 23.2% and only one in 25.1%. The three-dimensional examination was successful in 98.6% of cases. Of these, three measurements could be obtained in 60%, two in 22.8% and one in 17.2%. Transvaginally, all examinations were successful. The main reason for the failure of two-dimensional ultrasound was the fetal position, which in some cases precluded the distinction between fetal skin and amnion or the uterine wall. Using two-dimensional ultrasound, 6.3% of the cases of measurement failure were due to an inability to differentiate clearly between fetal skin and amnion, whilst the equivalent value for the three-dimensional method was only 3.3%. For the three-dimensional technique, fetal movement was the main reason for failure. The mean time for both methods was similar (9 min and 10 min for two- and three-dimensional ultrasound, respectively) and the correlation between the measurements obtained by the two- and three-dimensional techniques was very high (r = 0.97). Conclusion The number of fetuses in which nuchal translucency could be measured tended to be higher with three-dimensional ultrasound, although the difference was not statistically significant. The possibility of rotating a stored volume and inspecting it in three orthogonal planes makes three-dimensional ultrasound a useful tool for nuchal translucency measurements, especially in doubtful cases. [ABSTRACT FROM AUTHOR]

AbstractObjectiveTo determine the technical reliability of fetal iliac angle measurements by three-dimensional sonography as a prenatal marker for Down syndrome. MethodsThree-dimensional multiplanar views of the fetal pelvis were used to standardize iliac angle measurements from 35 normal second-trimester pregnancies. Measurement reliability for a single examiner and between two different examiners were analyzed by intraclass correlation. Normal iliac angle measurements were compared to those obtained from 16 fetuses with trisomy 21. ResultsThe mean axial angle for normal fetuses was 79 ± 5.5°, which was significantly less than that observed in fetuses with trisomy 21 (87.7 ± 4.9°) (P < 0.001). Iliac angles did not correlate with gestational age. Axial angles were reproducible between two examiners who measured the same multiplanar view of the pelvis. Inter- and intraobserver reliability were also acceptable after a standardized multiplanar view was independently obtained by each examiner (intraclass correlation = 0.91 for both). Coronal angles were unreliable because of difficulties with finding a reproducible measurement plane. For a false-positive rate of 5%, an axial angle threshold of 87° correctly identified 56% of fetuses with trisomy 21. ConclusionAxial iliac angle measurements are reliable by standardized three-dimensional multiplanar views of the pelvis and can be used to identify some fetuses at increased risk for trisomy 21. [ABSTRACT FROM AUTHOR]

Abstract Objective To demonstrate the relationship between fetal hydrops and/or hepatosplenomegaly in the second half of pregnancy with a myeloproliferative disorder in fetuses with trisomy 21 or mosaic trisomy 21. Design A retrospective case series. Subjects Cases were selected from 79 cases of trisomy 21 diagnosed in our prenatal unit between 1993 and 1999. Methods All fetuses had a detailed sonographic anatomic survey and biometry. Doppler of the umbilical and middle cerebral arteries, ductus venosus, inferior vena cava and umbilical vein was performed whenever possible. Two-dimensional echocardiography supplemented by color Doppler flow mapping and spectral pulsed wave Doppler was performed in all cases of fetal hydrops. Fetal karyotyping was obtained by amniocentesis, chorionic villus sampling or fetal blood sampling. In the presence of fetal hydrops a cordocentesis was performed for fetal hematology, biochemistry and TORCH serology. In cases with diagnosis of myeloproliferative disorder, peripheral blast cells were characterized by microscopy, cytochemistry and determination of surface markers. All cases with myeloproliferative disorder were stillborn and subsequently had a postmortem examination performed. Results During the study period 79 cases of trisomy 21 were diagnosed. Eleven of these had fetal hydrops. Three of these fetuses presented with hepatosplenomegaly and myeloproliferative disorder in the second and third trimesters. In addition, one fetus with sonographic markers of trisomy 21, where karyotyping was unfortunately unsuccessful, presented with hepatosplenomegaly, hydrops and myeloproliferative disorder. In the four fetuses with hepatosplenomegaly and hydrops, serology was negative for congenital infection. The characteristics of blast cells in the peripheral blood smear revealed a myeloproliferative disorder. Conclusion Fetal hydrops and/or hepatosplenomegaly in the second half of pregnancy, although suggestive of infectious etiology, may be a sign of myeloproliferative disorder in fetuses with trisomy 21 or mosaic trisomy 21. There is a possibility that a transient myeloproliferative disorder is a more common cause of mid or late-trimester hydrops in cases of trisomy 21 than previously thought. In these hydropic fetuses the prognosis seems to be poor. On the other hand we can speculate that a myeloproliferative disorder and the associated hepatosplenomegaly and/or hydrops may show spontaneous remission or that the transient myeloproliferative disorder may be without any detectable ultrasonographic signs and therefore may be more frequent in utero than realized. [ABSTRACT FROM AUTHOR]

AbstractObjectivesAlthough prenatal ultrasound is broadly used to detect abnormal fetuses, the variability in the interpretation of second-trimester prenatal ultrasound examinations is unknown. We sought to evaluate the consistency of the interpretation of prenatal ultrasound examinations. DesignPhysicians who perform prenatal ultrasound and who participate in the California Maternal Serum Expanded AFP program were asked to interpret a series of test ultrasound examinations. The series of cases was selected to include a random sample of fetal structural abnormalities, ultrasound markers that have been associated with chromosomal abnormalities, and normal cases. Interobserver agreement was evaluated using a κ statistic for each organ system. The sensitivity and false-positive rate were calculated for detecting specific anatomic abnormalities within each organ system. ResultsOf the 210 sonologists eligible for inclusion in the study, completed responses were received from 148 (70%). There was moderate to substantial agreement between physicians in reporting the presence of fetal abnormalities for all organ systems (κ range 0.40–0.88, P < 0.001). The consistency was highest for the central nervous system (CNS), neck, and face. Within each organ system, the consistency was similar for major structural abnormalities and ultrasound markers of chromosomal abnormalities. The sensitivity ranged from 62% (95% confidence interval (CI) 58–66%) for major renal abnormalities to 91% (95% CI 88–94%) for CNS abnormalities, with corresponding false-positive rates of 7% (95% CI 6–9%) for renal abnormalities and 9% (95% CI 7–11%) for CNS abnormalities. For most organ systems, the sensitivity for detecting ultrasound markers of chromosomal abnormalities was similar to the sensitivity for detecting structural abnormalities. ConclusionThere is moderate to substantial agreement in the interpretation of second-trimester prenatal ultrasound examinations. Whether the identification of specific ultrasound abnormalities and markers is overall beneficial to patients remains to be determined. [ABSTRACT FROM AUTHOR]

Abstract Objective Traditional chromosome preparation from amniotic fluid samples often involves lengthy culture procedures in order to obtain cells for analysis. Multiplex quantitative fluorescent polymerase chain reaction (PCR) is a new molecular biological technique capable of quantifying in-situ DNA without the need for cell culture. Our objective was to test the reliability of PCR using fetal DNA from amniotic fluid (amnio-PCR) for the rapid prenatal diagnosis of the common trisomies. Design This was a large prospective study of 5000 amniocentesis specimens. Multiplex quantitative fluorescent PCR was performed specifically for short tandem repeat sequences within chromosomes 21, 18, 13, X and Y. All amniocentesis samples were subsequently analyzed by traditional karyotyping methods. Results Amnio-PCR detected all 89 major autosomal trisomies in this cohort. Diagnosis of sex chromosome anomalies was accurate for cases involving first meiotic division nondisjunction. However, further markers were necessary to detect sex chromosome anomalies arising from second meiotic division nondisjunction, highlighting the importance of using specific markers that enable the quantification of both the X and the Y chromosomes simultaneously. Conclusions Rapid prenatal diagnosis of trisomies 21, 18, and 13 and the sex chromosome anomalies using amnio-PCR is a reliable technique that aids the clinical management of pregnancy. The speed of the methodology will help to minimize the period of parental anxiety in the wait for a diagnostic test result. [ABSTRACT FROM AUTHOR]

This study assesses two methods used to define relatively short femur in screening for trisomy 21 and examines changes in performance of screening with gestational age. Retrospective analysis of data on menstrual age, femur length (FL) and biparietal diameter (BPD) in 49 trisomy 21 pregnancies and 6069 normal controls. Reference ranges were derived for BPD/FL versus menstrual age and for FL versus BPD. Two methods of defining short femur (BPD/FL and observed-to-expected FL ratio) were examined for false-positive rates and detection rates for trisomy 21 at different gestational ages. In the control group the BPD/FL ratio and its standard deviation decreased with menstrual age. Trisomy 21 was associated with a significantly higher BPD/FL ratio (P < 0.001) and the deviation increased significantly with menstrual age (P < 0.05). Eleven percent of 28 fetuses examined at 15–17 weeks had a BPD/FL above the 95th centile compared with 24% of 21 fetuses examined at 18–20 weeks (P = 0.40). The median observed-to-expected FL ratio in the control group was 1.0 throughout the gestational age range but the standard deviation decreased significantly with menstrual age (P < 0.01). Trisomy 21 was associated with a significantly reduced observed-to-expected FL ratio (P < 0.001) and the deviation increased significantly with menstrual age (P < 0.05). A fixed cut-off of 0.91 for observed-to-expected FL ratio provided a false-positive rate of 12% at 15–17 weeks compared with 6% at 18–20 weeks of gestation (P < 0.001) with detection rates of 29 and 38%, respectively (P = 0.73). Irrespective of the definition used to define the condition, relatively short femur is a poor marker for trisomy 21 particularly when the assessment takes place before 18 weeks of gestation. [ABSTRACT FROM AUTHOR]

To examine cardiovascular and non-cardiovascular prenatal ultrasound markers and determine which markers physicians of varying skill levels could use to identify fetuses with trisomy 21. Eighty second-trimester fetuses with trisomy 21 and 2000 controls underwent real-time plus color Doppler examination of cardiovascular and non-cardiovascular systems followed by amniocentesis. Non-cardiac markers were central nervous system malformations (CNS); choroid plexus cysts (CPC); abnormal nuchal skin fold (NSF); hyperechoic bowel (HB); and pyelectasis (PY). Cardiac markers consisted of ventricular septal defect, right-to-left chamber disproportion (RL); tricuspid regurgitation; mitral regurgitation (MR); pericardial effusion; and outflow tract abnormalities (OFT). Multinomial logistic regression was used to identify interactivity between the markers. Logistic regression was utilized to identify which combinations of markers significantly contributed to the identification of fetuses with trisomy 21 and to compute the likelihood ratio. All but three markers (CPC, MR, OFT) contributed significantly to the identification of 91% of fetuses with trisomy 21 with a false-positive rate of 14%. When only non-cardiovascular markers were examined, all but CPC contributed to the identification of 60% of fetuses with trisomy 21 with a false-positive rate of 5.9%. Combining right-to-left chamber disproportion with CNS, NSF, HB and PY identified 75% of fetuses with trisomy 21 with a false-positive rate of 6.4%. All markers were independent predictors of trisomy 21 except RL and NSF. Ultrasound can detect between 60 and 91% of fetuses with trisomy 21 depending upon which markers are selected for evaluation. [ABSTRACT FROM AUTHOR]

The purpose of our study was to investigate the knowledge, attitudes, and practices of the staff in prenatal diagnosis toward expanded non-invasive prenatal testing (NIPT) in China. Participants in the study included specialists in prenatal diagnosis, obstetricians and gynecologists, nurses in obstetrics and gynecology, obstetric ultrasound doctors, and prenatal diagnosis laboratory technicians. VP28.13: Knowledge, attitudes and practices of staff in prenatal diagnosis toward expanded non-invasive prenatal testing in China. [Extracted from the article]

Objective To examine the discriminative capacity of nuchal translucency measurement in the detection of trisomy 21 and other chromosomal anomalies. Design Prospective cohort study. Subjects A total of 2247 women with viable singleton pregnancies between 10 and 14 weeks' gestation attending a prenatal diagnosis center for fetal karyotyping. Methods The fetal nuchal translucency was measured transabdominally in all women before invasive prenatal testing. Results Chromosomal abnormalities were found in 63 fetuses, including 36 with Down's syndrome. The likelihood of the presence of chromosomal abnormalities increased with larger nuchal translucency thickness. A nuchal translucency of 3 mm or more identified 25 out of 36 fetuses (69%) with trisomy 21 at the expense of a 4.0% false-positive rate. Correction of nuchal translucency measurements for differences due to variation of the measurement with gestational age, either by using the ‘delta-value’ or multiples of the median (MoM), did not improve the detection rate in our patient data set. Conclusions The discriminative capacity of nuchal translucency measurement makes it a useful tool in screening for trisomy 21 and other chromosomal anomalies. [ABSTRACT FROM AUTHOR]

Objective To evaluate the outcome of fetuses with isolated borderline, unilateral ventriculomegaly. Design A retrospective survey was conducted at four perinatal centers in Israel. Subjects and methods Only fetuses with one ventricular width of ≥ 11 mm and the other < 10 mm were included in the study. In all cases, the difference of the ventricular width between the two ventricles was > 2.4 mm (two standard deviations). Fetuses with other malformations, chromosomal abnormalities, or those with evidence of in utero infection, were not included in the study. Results Unilateral ventriculomegaly was found in 27 subjects (after excluding one case with unilateral ventriculomegaly and Down's syndrome). The mean width of the enlarged ventricle was 11.7 ± 0.9 mm, while the other normal ventricle was 7.2 ± 0.9 mm. The mean gestational age at diagnosis of the unilateral ventriculomegaly was 23.6 ± 2.7 weeks. In one case, pregnancy was terminated, and pathological examination of the fetal brain failed to detect any structural abnormality. Twenty-five patients delivered at term and only one at 34 weeks' gestation. The neurological development in all 25 fetuses was normal, and one fetus had petit mal seizures. Conclusion Fetuses with isolated, borderline unilateral ventriculomegaly, but without other abnormalities, have a good neurological outcome. [ABSTRACT FROM AUTHOR]

The aim of this study is to describe the prenatal diagnosis and perinatal outcomes in fetuses with agenesis of the ductus venosus (ADV) and to perform a systematic review of literature. As for perinatal results, of 36 patients 9 died; 30 had some anomaly (aneuploidy or major abnormality associated), and 6 were healthy. [Extracted from the article]

OC02.02: Performance of a genome-wide PCR-free, paired-end sequencing-based non-invasive prenatal screening test, VeriSeq NIPT Solution v2 Frozen plasma samples from pregnant women with a gestational age of >=10 weeks were tested using VeriSeq™ NIPT Solution v2, which has two reporting options: basic and genome wide analysis. The paired-end sequencing-based VeriSeq NIPT Solution v2, with basic and genome-wide reporting options, showed high sensitivities and high specificities with a low failure rate. [Extracted from the article]