Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study.

BACKGROUND: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. OBJECTIVE: This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. STUDY DESIGN: This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. RESULTS: Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of ≥3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of ≥3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of ≥3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm (21 of 534, 3.93%) or a nuchal translucency of <3.0 mm (71 of 80,219, 0.09%) (P<.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.5 mm, 3.0 to 3.4 mm, and <3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.0 MoM, 1.9 to 2.9 MoM, and <1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of >3.0 mm and 1 in 32 for nuchal translucency of >1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile. CONCLUSION: A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort.

STUDY QUESTION: What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births? SUMMARY ANSWER: The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.3% to 15.6% of tests in the miscarriage, prenatal and postnatal cohorts, respectively. WHAT IS KNOWN ALREADY: Over the past decade, technological advances have revolutionized genomic testing at every stage of reproduction. Chromosomal microarrays (CMAs) are now the gold standard of chromosome assessment in prenatal diagnosis and pediatrics. STUDY DESIGN, SIZE, DURATION: A population-based cohort study including all chromosome analysis was performed in the Australian state of Victoria during a 24-month period from January 2015 to December 2016. All samples obtained via invasive prenatal diagnosis and postnatal samples from pregnancy tissue and infants ≤12 months of age were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: A research collaboration of screening and diagnostic units in the Australian state of Victoria was formed (the Perinatal Record Linkage collaboration), capturing all instances of prenatal and postnatal chromosome testing performed in the state. Victoria has over 73 000 births per annum and a median maternal age of 31.5 years. We analyzed our population-based diagnostic data set for (i) chromosome assessment of miscarriage, prenatal diagnosis and postnatal samples; (ii) testing indications and diagnostic yields for each of these cohorts; (iii) and the combined prenatal/infant prevalence of 22q11.2 deletion syndrome (DS) as a proportion of all births ≥20 weeks gestation. MAIN RESULTS AND THE ROLE OF CHANCE: During the 24-month study period, a total of 8826 chromosomal analyses were performed on prenatal and postnatal specimens in Victoria. The vast majority (91.2%) of all chromosome analyses were performed with CMA.The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826). There was a significant decreasing trend in the percentage of chromosome abnormalities with later developmental stage from 50.9% to 21.3% to 15.6% in the miscarriage, prenatal and postnatal cohorts, respectively (χ2 trend = 790.0, P < 0.0001). The total frequency of abnormalities in the live infant subgroup was 13.4% (244/1816). The frequencies of pathogenic copy number variants (CNVs) detected via CMA for the miscarriage, prenatal and postnatal cohorts were 1.9% (50/2573), 2.2% (82/3661) and 4.9% (127/2592), respectively. There was a significant increasing trend in the frequency of pathogenic CNVs with later developmental stage (χ2 trend = 39.72, P < 0.0001). For the subgroup of live infants, the pathogenic CNV frequency on CMA analysis was 6.0% (109/1816). There were 38 diagnoses of 22q11.2 DS, including 1 miscarriage, 15 prenatal and 22 postnatal cases. After excluding the miscarriage case and accounting for duplicate testing, the estimated prevalence of 22q11 DS was 1 in 4558 Victorian births. LIMITATIONS, REASONS FOR CAUTION: Clinical information was missing on 11.6% of postnatal samples, and gestational age was rarely provided on the miscarriage specimens. We were unable to obtain rates of termination of pregnancy and stillbirth in our cohort due to incomplete data provided by clinical referrers. We therefore cannot make conclusions on pregnancy or infant outcome following diagnostic testing. Childhood and adult diagnoses of 22q11 DS were not collected. WIDER IMPLICATIONS OF THE FINDINGS: Our study marks a complete transition in genomic testing from the G-banded karyotype era, with CMA now established as the first line investigation for pregnancy losses, fetal diagnosis and newborn/infant assessment in a high-income setting. Integration of prenatal and postnatal diagnostic data sets provides important opportunities for estimating the prevalence of clinically important congenital syndromes, such as 22q11 DS. STUDY FUNDING/COMPETING INTEREST(S): L.H. is funded by a National Health and Medical Research Council Early Career Fellowship (1105603); A.L. was funded by a Mercy Perinatal Research Fellowship; J.H. was funded by a National Health and Medical Research Council Senior Research Fellowship (10121252). The funding bodies had no role in the conduct of the research or the manuscript. Discretionary funding from the Murdoch Children's Research Institute has supported the prenatal diagnosis data collection and reporting over the years.Dr Ricardo Palma-Dias reports a commercial relationship with Roche Diagnostics, personal fees from Philips Ultrasound, outside the submitted work. Debbie Nisbet reports a commercial relationship with Roche Diagnostics, outside the submitted work. TRIAL REGISTRATION NUMBER: NA.

Association between timing of diagnosis of trisomy 21, 18, and 13 and maternal socio-economic status in Victoria, Australia: A population-based cohort study from 2015 to 2016.

OBJECTIVES: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES). DESIGN: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage. RESULTS: Among 160 230 total births were 571 diagnoses of T21 and 246 of T18/T13. The overall and live birth prevalences of T21 were 3.56 and 0.47 per 1000 births, respectively. Compared with women from disadvantaged SES regions, women from high SES regions were more likely to have a prenatal diagnosis of a trisomy before 17 weeks than after (P < .01) and less likely to have a live-born T21 infant than a prenatal diagnosis (P < .01). There was a significant trend to higher live birth rates of T21 with lower SES (P = .004). The majority (68.5%) of women who gave birth to a live infant with T21 did not utilise prenatal testing. CONCLUSION: There is a significant relationship between lower SES, later prenatal diagnosis of trisomy, and higher live birth rate of T21 in Victoria.

Antenatal screening - the first and second trimester.

Antenatal screening is performed in the first or second trimester to determine whether a pregnant woman's baby has an increased risk of having Down syndrome (a chromosomal abnormality affecting one in 500 pregnancies), Edward syndrome (one in 3000) or open neural tube defects (one in 750). First trimester screening combines results from a blood test with a nuchal translucency and nasal bone obstetric scan during the first trimester of pregnancy. Second trimester screening requires only a blood test. The screening approach varies across Australia; this article primarily describes the Victorian protocol.