Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening

Abstract

Objectives: To evaluate the performance of first-trimester screening for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). In addition, the potential impact of a new individual risk-orientated two-stage approach to first-trimester screening was examined.

Methods: First-trimester combined screening for trisomy 21 was carried out in 75 821 singleton pregnancies with live fetuses at 11 + 0 to 13 + 6 gestational weeks. The detection and false-positive rates for different risk cut-offs were calculated. To examine the potential impact of an individual risk-orientated two-stage approach to first-trimester screening it was assumed that, after first-trimester combined screening, chorionic villus sampling (CVS) would be performed in all patients with a risk estimate of 1 in 100 or more and in none of those with a risk estimate of less than 1 in 1000. Those in the intermediate-risk category, with a risk estimate of between 1 in 101 and 1 in 1000, would have further assessment of risk by first-trimester ultrasound examination to determine presence/absence of the nasal bone, presence/absence of tricuspid regurgitation or normal/abnormal Doppler velocity waveform in the ductus venosus, and CVS would be performed if their adjusted risk became 1 in 100 or more.

Results: Fetal NT and maternal serum free beta-hCG and PAPP-A were successfully measured in all cases. The median maternal age was 31 (range, 13-49) years, the median gestation at screening was 12 (range, 11 + 0 to 13 + 6) weeks and the median fetal crown-rump length was 62 (range, 45-84) mm. Chromosomal abnormalities were identified in 544 pregnancies, including 325 cases of trisomy 21. The estimated risk for trisomy 21 was 1 in 300 or greater in 5.2% of normal pregnancies, in 92.6% of those with trisomy 21, in 88.5% of those with trisomy 18 or 13 and in 85.6% of those with other chromosomal defects. The detection rates for trisomy 21 were about 75% and 80% for respective false-positive rates of 1% and 2%. In the proposed individual risk-orientated two-stage screening for a risk cut-off of 1 in 100 the total false-positive rate would vary with the method used for the second stage of screening from 2.1% for absence of the nasal bone to 2.7% for increased impedance in the ductus venosus and 2.7% for tricuspid regurgitation and the respective detection rates would be 92.0%, 94.2% and 91.7%.

Conclusions: First-trimester combined screening for trisomy 21 is associated with a detection rate of about 90% for a false-positive rate of 5%. Individual risk-orientated two-stage screening for trisomy 21 can potentially identify, in the first trimester of pregnancy, more than 90% of affected fetuses for a false-positive rate of 2-3%.