Search

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

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

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

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]

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

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

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

Objective: To investigate the rates of termination of pregnancy (TOP) for fetal chromosomal abnormalities and factors related to such parental decision in Japan.Methods: A multicenter retrospective cohort study of chromosomal abnormalities diagnosed before 22 weeks of gestation between April 2008 and March 2015. The pregnancy outcomes and parental decisions were investigated.Results: Among 931 fetuses with chromosome abnormalities, the total TOP rate was 75.1% (699/931). TOP rates were 89.3% (585/655) in autosomal aneuploidies and 40.8% (51/125) in sex chromosome aneuploidies. Trisomy 21 showed the highest TOP rate (93.8% [390/416]) followed by trisomy 18 (84.5% [163/193]) and trisomy 13 (71.9% [23/32]). Indications for karyotyping were related to a parental decision for TOP (p < 0.01): in cases of autosomal aneuploidy, with fetal abnormal ultrasound findings as the reference value, diagnoses made following positive results at non-invasive prenatal testing (adjusted odds ratio [OR]: 13.7, 95% confidence interval [CI] 4.07-45.9) and those because of advanced maternal age (adj. OR 2.91, 95% CI 1.15-7.35) were significantly more frequent.Conclusions: In Japan, pregnancies with fetal trisomy 21 are more likely to result in TOP when diagnosed in utero than any other chromosome anomaly. The indications for prenatal karyotyping strongly affect the decision to TOP. © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Few data exist describing laboratory related failure rates in prenatal diagnosis. The aim of this study is to assess the laboratory associated failure rate for karyotype, QF-PCR and CGH-array following amniocentesis in relation to gestation.Methods: Retrospective database study of amniocenteses performed 2004-2014 comparing laboratory failure rate for karyotype, QF-PCR and CGH-array between 16 + 0 and 40 + 0 weeks' gestation.Results: A total of 10 484 amniotic fluid test results were collected in three databases. Karyotype failed in 41/1797 (2.3%) tests; failure rate was significantly greater with advancing gestation reaching 43% at 36-40 weeks. QF-PCR failed in 132/5715 tests (2.3%) and was significantly greater with advancing gestation reaching 7% at 36-40 weeks. For CGH-array, 10/298 tests (3.4%) failed analysis. In one case, no result was obtainable by any technique.Conclusions: These data provide gestation specific laboratory failure rates for amniocentesis enabling informed decisions about the timing and laboratory technique most applicable to the clinical situation. Before 20 weeks, karyotype is least likely to fail of the three techniques. However, in the late third trimester, QF-PCR and, in particular, karyotyping are more likely to fail than CGH-array. Although there is some overlap between the three different tests, they may be preferentially offered in different clinical scenarios. © 2016 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]

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

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]

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

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]

Objectives: Clinical performance of a low coverage, low cost, massively parallel sequencing (MPS)-based assay to stratify risk of trisomy 21, 18, and 13 pregnancies was determined.Methods: The study included 1100 samples with birth outcome or karyotype results, comprising low-risk patients (84.2%) negative for risk indications from maternal age, serum screening, ultrasound, or family history, and high-risk patients (15.8%) with at least one of the aforementioned indications. Cell free DNA (cfDNA) was extracted from maternal plasma. Library preparation incorporated 96 index barcodes to enable sequencing on a HiSeq 2000 or 2500. Risk scores were calculated using chromosomal representation, fetal fraction, and maternal age at the estimated date of delivery. A risk score greater than or equal to 1 in 100 was used to stratify samples as high risk for trisomy 21, trisomy 18, or trisomy 13.Results: Sensitivity and specificity were calculated based on risk group stratification. Trisomy 21, trisomy 18, and trisomy 13 were detected with greater than 99% sensitivity and 99.9% specificity. Fetal sex classification accuracy was 99.3%.Conclusions: We conclude that simplified MPS can be used to stratify the risk of pregnancies for trisomy 21, trisomy 18, and trisomy 13 and accurately determine fetal sex. © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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

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

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 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 investigate geodemographic characteristics of women having prenatal diagnosis for Down syndrome and other fetal chromosome abnormalities in Victoria, Australia. Methods: A descriptive analysis of population-based data on all confinements, amniocenteses and chorionic villus sampling for 1998 and 2002 was undertaken. Multivariate logistic regression analysis of 2002 data investigated geographical differences, including selected maternal features and a socioeconomic status measure that may be associated with uptake of diagnostic testing. Results: After adjusting for age, parity of three or more children was associated with a significantly decreased likelihood of testing ( P < 0.001). Women from Africa were 61% less likely to have testing than women born in Australia ( P < 0.01). While overall uptake of testing was lower than average in rural regions, only the Loddon Mallee had a significantly decreased likelihood of testing (OR 0.71 (0.53, 0.95), P = 0.02). A socioeconomic index of place of residence showed no association with uptake. Metropolitan and rural women giving birth in private hospitals were 31 and 60% more likely to have a test than women giving birth in public hospitals ( P < 0.01). Conclusion: Geographical differences influence uptake of prenatal diagnosis, probably related to access to services. However, other maternal demographic factors also play a role in uptake. To ensure equity in access and autonomy in women's reproductive choices, reasons for exceptionally low uptake in certain localities or within certain subgroups of pregnant women should be investigated further, followed by appropriate changes in service provision. [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]

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]

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]

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]

A 32-year-old woman at 17 weeks of gestation had a high possibility (1:82) of having a child with Down syndrome. Fetal chromosome according to amniocentesis revealed 46,XX,del(7)(q11.23q21.2). The fetus' chromosomal defect was not inherent because the chromosome analysis of the parents did not have any abnormal findings. We were regularly monitoring the pregnant woman by routine prenatal schedule and she had a normal spontaneous delivery. The baby showed a typical facial malformation, epicanthal fold, decreased muscle tone, and cardiac abnormalities. This is the first patient prenatally diagnosed with de novo 7q deletion by positive triple marker screening test. We consider the triple test, which is the most popular examination used to clarify the risk of chromosome abnormality in obstetrics, will be used not only for trisomy 21 and 18, but also for any other chromosome abnormalities. [ABSTRACT FROM AUTHOR]