Prospective validation of first-trimester combined screening for trisomy 21.

To examine the performance of the new algorithm in 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). This was a prospective screening study for trisomy 21 in singleton pregnancies at 11 + 0 to 13 + 6 weeks of gestation using an algorithm combining maternal age, fetal NT thickness based on the mixture model for the assessment of NT, and maternal serum free beta-hCG and PAPP-A based on a multiple regression model for the assessment of serum biochemistry. The NT measurements were performed by 60 operators who had obtained The Fetal Medicine Foundation certificate of competence in the 11-13-week scan. The study population consisted of 19 614 pregnancies with a normal karyotype or delivery of a phenotypically normal baby (euploid group) and 122 cases of trisomy 21. In the euploid fetuses the NT was above the previously defined 50(th), 95(th) and 99(th) centiles in 10 033 (51.2%), 618 (3.2%) and 123 (0.6%) cases and the respective values for trisomy 21 were 117 (95.9%), 94 (77.0%) and 57 (46.7%). The median fetal NT was within 0.1 mm of the expected in 47 (78.3%) of the 60 sonographers and within 0.2 mm in all. In the euploid fetuses the median free beta-hCG was 1.0 (range, 0.1-29.4) multiples of the median (MoM) and the median PAPP-A was 1.0 (range, 0.2-3.3) MoM. The median MoM values were 1.0 or close to 1.0 MoM for each subgroup of pregnancy characteristics, including gestations of 11, 12 and 13 weeks, maternal weight of < 60 kg, 60-80 kg and > 80 kg, different ethnic origins, cigarette smokers and non-smokers, natural conception and in vitro fertilization. For a false-positive rate of 3%, the detection rate of trisomy 21 in screening by maternal age and fetal NT was 81% (95% CI, 73-89%), by maternal age and maternal serum biochemistry it was 63% (95% CI, 56-72%) and by combined screening based on maternal age, fetal NT and maternal serum biochemistry it was 90% (95% CI, 84-96%). This study has validated the new risk algorithm and demonstrated that in combined screening for trisomy 21 based on maternal age, fetal NT and free beta-hCG and PAPP-A the detection rate is about 90% for a 3% false-positive rate.

Kagan KO ，Etchegaray A ，Zhou Y ，Wright D ，Nicolaides KH ... -  《-》

Screening for trisomy 21 by fetal tricuspid regurgitation, nuchal translucency and maternal serum free beta-hCG and PAPP-A at 11 + 0 to 13 + 6 weeks.

To examine whether in pregnancies with fetal trisomy 21 the level of maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation is independent of the presence or absence of tricuspid regurgitation and to estimate the performance of a screening test that combines tricuspid regurgitation with fetal nuchal translucency (NT) thickness and serum free beta-hCG and PAPP-A. The study population comprised 77 trisomy 21 and 232 chromosomally normal fetuses from singleton pregnancies at 11 + 0 to 13 + 6 weeks of gestation. In all cases the fetal karyotype was determined by chorionic villus sampling (CVS), which was carried out at the request of the parents after first-trimester screening for trisomy 21 by fetal NT and maternal serum free beta-hCG and PAPP-A. Immediately before chorionic villus sampling, fetal echocardiography was performed and the presence or absence of tricuspid regurgitation was determined by pulsed wave Doppler ultrasonography. The distribution of fetal NT, maternal serum free beta-hCG and PAPP-A in trisomy 21 fetuses with absent and present tricuspid regurgitation was examined. We examined two screening strategies: first, integrated first-trimester screening in all patients and second, first-stage screening of all patients using fetal NT and maternal serum free beta-hCG and PAPP-A followed by second-stage assessment of tricuspid regurgitation only in those with an intermediate risk of 1 in 101 to 1 in 1000 after the first stage. Tricuspid regurgitation was observed in 57 (74.0%) of the trisomy 21 fetuses and in 16 (6.9%) of the chromosomally normal fetuses. There were no significant differences in median maternal age, median gestational age, free beta-hCG multiples of the median (MoM) and PAPP-A MoM in trisomy 21 fetuses with and without tricuspid regurgitation. The modeled detection rates of trisomy 21 for fixed false positive rates of 1%, 2% and 5% in screening by maternal age, fetal NT thickness and maternal serum free beta-hCG and PAPP-A and assessment of tricuspid flow in all cases were 87%, 90% and 95%. In the two-stage approach, the estimated detection rate was 91% and the false positive rate was 2.6%. There is no relationship between tricuspid regurgitation and the levels of maternal serum free beta-hCG and PAPP-A in cases with trisomy 21. An integrated sonographic and biochemical test at 11 + 0 to 13 + 6 weeks can potentially identify about 90% of trisomy 21 fetuses for a false-positive rate of 2-3%.

Falcon O ，Auer M ，Gerovassili A ，Spencer K ，Nicolaides KH ... -  《ULTRASOUND IN OBSTETRICS & GYNECOLOGY》

Screening for trisomy 18 by maternal age, fetal nuchal translucency, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A.

Kagan KO ，Wright D ，Maiz N ，Pandeva I ，Nicolaides KH ... -  《-》

First-trimester screening for trisomy 21 by free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A: impact of maternal and pregnancy characteristics.

To use multiple regression analysis to define the contribution of maternal variables that influence the measured concentration of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), and the interaction between these covariates, in first-trimester biochemical screening for trisomy 21. This was a multicenter study of prospective screening for trisomy 21 by a combination of fetal nuchal translucency thickness, and maternal serum free beta-hCG and PAPP-A at 11 + 0 to 13 + 6 weeks of gestation. In the pregnancies subsequently found to have trisomy 21 and in those with no obvious chromosomal abnormality, we used multiple regression analysis to account for pregnancy characteristics that influence the measured concentrations of free beta-hCG and PAPP-A. We fitted Gaussian distributions to the distribution of log multiples of the median (MoM) values in trisomy 21 and in unaffected pregnancies. There were 491 cases of trisomy 21 and 96 803 chromosomally normal pregnancies. Compared with values in Caucasian women, those who were parous, non-smokers and those who conceived spontaneously, PAPP-A was 57% higher in women of Afro-Caribbean origin, 3% higher in South Asians, 9% higher in East Asians, 2% higher in nulliparous women, 17% lower in smokers and 10% lower in those conceiving by in-vitro fertilization (IVF). Free beta-hCG was 12% higher in women of Afro-Caribbean origin, 9% lower in South Asians, 8% higher in East Asians, 2% higher in nulliparous women, 4% lower in smokers and 9% higher in those conceiving by IVF. In screening for trisomy 21 by maternal age and serum free beta-hCG and PAPP-A the estimated detection rate was 65% for a false-positive rate of 5%. In first-trimester biochemical screening for trisomy 21 it is essential to adjust the measured values of free beta-hCG and PAPP-A for maternal and pregnancy characteristics.

Kagan KO ，Wright D ，Spencer K ，Molina FS ，Nicolaides KH ... -  《-》

One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks: a prospective study of 15 030 pregnancies.

Bindra R ，Heath V ，Liao A ，Spencer K ，Nicolaides KH ... -  《ULTRASOUND IN OBSTETRICS & GYNECOLOGY》