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Performance of Common Down Syndrome Screening Methods Used in India with Construction of an Indian Normogram for Nuchal Translucency/Crown-Rump Length Measurements in 14,337 Subjects.

ABSTRACT: Background/Purpose of Study:Sonologists often lack access to the Fetal Medicine Foundation Down syndrome risk calculation software or cannot offer the combined test for aneuploidy screening because of resource constraints. Instead, sonologists use nuchal translucency (NT) measurements that rely on fixed NT cut-offs for labelling foetuses with high risks for Down syndrome. In the present study, we aimed to plot normative data for NT and the crown-rump length (CRL) in Indian foetuses and to assess the value of using the 95th/99th centiles of NT for CRL cut-offs instead of fixed NT cut-offs to calculate the risk for aneuploidies during the first trimester. Methods:We conducted a retrospective observational study measuring the NT/CRL in 14,337 Indian foetuses between 11 and 13 + 6 weeks of gestation. We used regression analysis and calculated the 95th/99th centiles of NT distribution. We compared performances of NT?>?95th/99th centiles and fixed NT cut-offs of 2.5- and 3.5-mm as screening. Results:The NT measurements increased with increasing CRL values. NT?>?95th centile for a particular CRL for detecting all aneuploidies had the maximum sensitivity of 73.9% for a false positive rate (FPR) of 4.3%. Similar values for fixed cut-off?>?2.5 mm were 63.0% FPR 3.7% (T21 68.2 FPR 3.8%) and for NT?>?3.5 mm 36.9% FPR 0.43% (T21 36.5% FPR 0.5%). Conclusion:A fixed NT cut-off point is not appropriate for the first trimester screening. The best sensitivity for assessing aneuploidies is achieved using the 95th centile, but the 99th centile achieves higher specificity for gestational age.

SUBMITTER: Kaul A

PROVIDER: S-EPMC6801244 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Performance of Common Down Syndrome Screening Methods Used in India with Construction of an Indian Normogram for Nuchal Translucency/Crown-Rump Length Measurements in 14,337 Subjects.

Kaul Anita A Radhakrishnan Prathima P

Journal of obstetrics and gynaecology of India 20190117 Suppl 2

<h4>Background/purpose of study</h4>Sonologists often lack access to the Fetal Medicine Foundation Down syndrome risk calculation software or cannot offer the combined test for aneuploidy screening because of resource constraints. Instead, sonologists use nuchal translucency (NT) measurements that rely on fixed NT cut-offs for labelling foetuses with high risks for Down syndrome. In the present study, we aimed to plot normative data for NT and the crown-rump length (CRL) in Indian foetuses and t ...[more]

PMID: 31686747

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Project description:Background: Increased nuchal translucency (NT) is an important biomarker associated with increased risk of fetal structural anomalies. It is known to be contributed by a wide range of genetic etiologies from single-nucleotide variants to those affecting millions of base pairs. Currently, prenatal diagnosis is routinely performed by karyotyping and chromosomal microarray analysis (CMA); however, both of them have limited resolution. The diversity of the genetic etiologies warrants an integrated assay such as genome sequencing (GS) for comprehensive detection of genomic variants. Herein, we aim to evaluate the feasibility of applying GS in prenatal diagnosis for the fetuses with increased NT. Methods: We retrospectively applied GS (> 30-fold) for fetuses with increased NT (?3.5?mm) who underwent routine prenatal diagnosis. Detection of single-nucleotide variants, copy number variants, and structural rearrangements was performed simultaneously, and the results were integrated for interpretation in accordance with the guidelines of the American College of Medical Genetics and Genomics. Pathogenic or likely pathogenic (P/LP) variants were selected for validation and parental confirmation, when available. Results: Overall, 50 fetuses were enrolled, including 34 cases with isolated increased NT and 16 cases with other fetal structural malformations. Routine CMA and karyotyping reported eight P/LP CNVs, yielding a diagnostic rate of 16.0% (8/50). In comparison, GS provided a twofold increase in diagnostic yield (32.0%, 16/50), including one mosaic turner syndrome, eight cases with microdeletions/microduplications, and seven cases with P/LP point mutations. Moreover, GS identified two cryptic insertions and two inversions. Follow-up study further demonstrated the potential pathogenicity of an apparently balanced insertion that disrupted an OMIM autosomal dominant disease-causing gene at the insertion site. Conclusions: Our study demonstrates that applying GS in fetuses with increased NT can comprehensively detect and delineate the various genomic variants that are causative to the diseases. Importantly, prenatal diagnosis by GS doubled the diagnostic yield compared with routine protocols. Given a comparable turnaround time and less DNA required, our study provides strong evidence to facilitate GS in prenatal diagnosis, particularly in fetuses with increased NT.

Project description:INTRODUCTION:Currently fetal nuchal translucency (NT) ≥3.5 mm is an indication for invasive testing often followed by chromosomal microarray. The aim of this study was to assess the risks for chromosomal aberrations in fetuses with an NT 3.0-3.4 mm, to determine whether invasive prenatal testing would be relevant in these cases and to assess the residual risks in fetuses with normal non-invasive prenatal test (NIPT) results. MATERIAL AND METHODS:A retrospective study and meta-analysis of literature cases with NT between 3.0 and 3.4 mm and 2 cohorts of pregnant women referred for invasive testing and chromosomal microarray was performed: Rotterdam region (with a risk >1:200 and NT between 3.0 and 3.4 mm) tested in the period July 2012 to June 2019 and Central Denmark region (with a risk >1:300 and NT between 3.0 and 3.4 mm) tested between September 2015 and December 2018. RESULTS:A total of 522 fetuses were referred for invasive testing and chromosomal microarray. Meta-analysis indicated that in 1:7.4 (13.5% [95% CI 8.2%-21.5%]) fetuses a chromosomal aberration was diagnosed. Of these aberrant cases, 47/68 (69%) involved trisomy 21, 18, and 13 and would potentially be detected by all NIPT approaches. The residual risk for missing a (sub)microscopic chromosome aberration depends on the NIPT approach and is highest if NIPT was performed only for common trisomies-1:21 (4.8% [95% CI 3.2%-7.3%]). However, it may be substantially lowered if a genome-wide 10-Mb resolution NIPT test was offered (~1:464). CONCLUSIONS:Based on these data, we suggest that the NT cut-off for invasive testing could be 3.0 mm (instead of 3.5 mm) because of the high risk of 1:7.4 for a chromosomal aberration. If women were offered NIPT first, there would be a significant diagnostic delay because all abnormal NIPT results need to be confirmed by diagnostic testing. If the woman had already received a normal NIPT result, the residual risk of 1:21 to 1:464 for chromosome aberrations other than common trisomies, dependent on the NIPT approach, should be raised. If a pregnant woman declines invasive testing, but still wants a test with a broader coverage of clinically significant conditions then the genome-wide >10-Mb resolution NIPT test, which detects most aberrations, could be proposed.

Project description:BackgroundTo investigate the association of crown-rump length (CRL) during the first trimester of pregnancy with neonatal outcomes.MethodsA total of 15,524 women with a reliable first day of the last menstrual period and a regular menstrual cycle (28 ± 4 days) were included from January 2015 to November 2016. CRL was measured by ultrasound from 7+0 to 13+6 weeks during pregnancy and transformed to a standard deviation score (SDS) adjusted for gestational age. Linear regression was used to explore risk factors for CRL. A generalised linear model was used to evaluate the association between CRL and neonatal outcomes.ResultsIn the multivariate analysis, maternal age (0.25 mm, 95% CI = [0.22-0.28], P < 0.001; 0.04 SDS, 95% CI = [0.03-0.04], P < 0.001), multipara (0.30 mm, 95% CI = [0.08-0.52], P = 0.007; 0.04 SDS, 95% CI = [0.00-0.07], P = 0.031) and folic acid supplement use (0.78 mm, 95% CI = [0.49-1.08], P < 0.001; 0.05 SDS, 95% CI = [0.01-0.10], P < 0.019) were positively associated with CRL, while pre-pregnancy BMI (-0.17 mm, 95% CI = [-0.21 to -0.13], P < 0.001; -0.02 SDS, 95% CI = [-0.03 to -0.02], P < 0.001) was negatively related to CRL. For neonatal outcomes, CRL was negatively associated with small for gestational age (SGA) ([risk ratio] (RR) = 0.733, 95% [CI] = 0.673-0.8004, Padjusted < 0.001) and neonatal intensive care unit (NICU) admission ([RR] = 0.928, 95% [CI] = 0.883-0.976, Padjusted = 0.003), and preterm birth ([RR] = 1.082, 95% [CI] = 1.008-1.162, Padjusted = 0.029), but positively related to large for gestational age (LGA) ([RR] = 1.241, 95% [CI] = 1.184-1.301, Padjusted = 0.012). When stratified by pre-pregnancy BMI, the risk of SGA and LGA remained significant in all groups, while the increased risk of preterm birth was only observed in the lean group (BMI < 18.5 kg/m2) and decreased risk of NICU admission rate in the normal group (BMI 18.5-24 kg/m2).ConclusionsMaternal characteristics were independently associated with CRL in the first trimester, which was negatively related to foetal size, SGA, preterm birth, and admission rate to the NICU, but positively related to LGA.

Dataset Information

Performance of Common Down Syndrome Screening Methods Used in India with Construction of an Indian Normogram for Nuchal Translucency/Crown-Rump Length Measurements in 14,337 Subjects.

Publications

Performance of Common Down Syndrome Screening Methods Used in India with Construction of an Indian Normogram for Nuchal Translucency/Crown-Rump Length Measurements in 14,337 Subjects.

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