LAUSR

BACKGROUND The American College of Obstetricians and Gynecologists and the Society for Maternal Fetal Medicine recently recommended offering genetic counselling and diagnostic testing for enlarged NT at > 3.0mm, regardless of prior negative screening with noninvasive prenatal testing (NIPT). OBJECTIVES To perform a population-based, individual record-linkage study to determine the optimal definition of an enlarged NT for the detection of atypical chromosome abnormalities. STUDY DESIGN Retrospective study of women resident in Victoria, Australia, undergoing combined first trimester screening (CFTS) during the 24 month period from Jan 2015 to Dec 2016. Linkage between state-wide results for CFTS, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain frequency and type of chromosome abnormality by gestation and NT 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 CFTS, 491 (0.60%) had an NT > 3.5mm, 534 (0.66%) had an NT 3.0-3.4 mm, and 80,219 (98.74%) had an NT less than 3.0mm. When grouped by NT MoM, 192 (0.24%) had NT ≥3.0 MoM, 513 (0.63%) had NT 1.9-2.9 MoM, and 80,539 (99.13%) had NT less than 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 NT > 3.5mm (147/491, 29.94%) compared with NT 3.0-3.4mm, (21/534, 3.93%) or NT < 3.0mm (71/80219, 0.09%) (P< 0.001) respectively. There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95%CI 2.51-6.22%), 0.37% (95%CI 0.05-1.35%), and 0.09% (95%CI 0.07-0.11%) in the groups with NT > 3.5mm, 3.0-3.4mm and < 3.0mm respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% CI 2.17-8.71%), 2.53% (95% CI 1.36-4.29%) and 0.09% (95% CI 0.07-0.11%) in the groups with NT > 3.0MoM, 1.9-2.9 MoM and < 1.9 MoM respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11-13 weeks, both an NT threshold of 1.9MoM and a fixed threshold of 3.0mm captured 22/93 (23.7%) of fetuses with an atypical chromosome abnormality. Of these, 50.0% had a co-existing fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had better specificity than 3.0 mm. The positive predictive value of an enlarged NT for any atypical chromosome abnormality was 1 in 47 for NT > 3.0mm and 1 in 32 for NT > 1.9 MoM. Our NT threshold of 1.9MoM captured 0.87% of fetuses, thus approximating the 99th centile. CONCLUSIONS A gestational-age adjusted NT threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged NT is more than tripled in the presence of an additional ultrasound abnormality.