First-trimester combined screening for trisomy 21 at 7-14 weeks' gestation.

To establish an algorithm for first-trimester combined screening for trisomy 21 with biochemical testing from 7 to 14 weeks' gestation and ultrasound testing at 11-13 weeks. This was a multicenter study of 886 pregnancies with trisomy 21 and 222 475 unaffected pregnancies with measurements of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. Multiple regression modeling of log-transformed marker values was used to produce log multiples of the median (MoM) values for PAPP-A and free β-hCG. The models included terms for the center attended and the machine used for biochemical analysis, gestational age, maternal racial origin, maternal weight, smoking status and method of conception. Bivariate Gaussian distributions were fitted to log MoM PAPP-A and log MoM free β-hCG in trisomy 21 and in unaffected pregnancies. In each case the patient-specific risk for trisomy 21 was estimated by multiplying the individual maternal age-related risk with the likelihood ratio (LR) for fetal nuchal translucency (NT) according to the mixture model and the combined LR for maternal serum free β-hCG and PAPP-A. Estimates of detection rates for trisomy 21 and false-positive rates were calculated for combined screening with measurements of NT at 12 weeks together with measurements of free β-hCG and PAPP-A from 8 to 13 weeks. In trisomy 21 pregnancies the mean log MoM free β-hCG increased linearly with gestation between 7 and 14 weeks, whereas the relation between log MoM PAPP-A and gestation was fitted by a quadratic equation such that the maximum separation between trisomy 21 and unaffected pregnancies occurs at 9-10 weeks. At a false-positive rate of 3% the detection rate of combined screening at 12 weeks was 86% and this increased to 90% by biochemical testing at 9 weeks and ultrasound scanning at 12 weeks. The detection rate increased to 92% by measuring PAPP-A at 9 weeks and free β-hCG at the time of the scan at 12 weeks. The performance of first-trimester biochemical screening for trisomy 21 is best at 9-10 weeks rather than at 7-8 or 11-14 weeks.

Wright D ，Spencer K ，Kagan K K ，Tørring N ，Petersen OB ，Christou A ，Kallikas J ，Nicolaides KH ... -  《-》

Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A.

Kagan KO ，Wright D ，Baker A ，Sahota 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》

Impact of bias in serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A multiples of the median levels on first-trimester screening for trisomy 21.

To examine the effect of bias in median multiples of the median (MoM) levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG) on first-trimester combined screening for trisomy 21. The effects of deviations in the MoM levels of free β-hCG and PAPP-A were investigated by simulating nuchal translucency (NT) at 12 weeks and MoM values for PAPP-A and free β-hCG for 500 000 euploid and 500 000 trisomy 21 pregnancies at 9 and at 12 weeks of gestation. Likelihoods were calculated using the mixture model for NT and the standard Gaussian model for log MoM PAPP-A and free β-hCG values. Deviations in MoM marker levels were simulated by applying percentage changes of 5% to 20% to MoM values. Detection and false-positive rates were calculated with and without adjustments of the maternal serum marker levels by taking the proportion of euploid and aneuploid cases above given thresholds for each maternal age and then taking a weighted average with respect to the maternal age distribution. With median MoM levels on target, the modeled detection and false-positive rates in combined screening for trisomy 21 at 12 weeks of gestation with a fixed risk cut-off of 1 in 100 were 85% and 2.5%, respectively. For median MoM levels of free β-hCG and PAPP-A between 0.8 and 1.2 MoM, detection rates ranged from 77% to 91%, with corresponding false-positive rates ranging from 1.0% to 6.1%. In first-trimester screening for trisomy 21, biases in the serum marker MoM levels of 10% can increase false-positive rates by over 50%, whilst biases of 20% can more than double false-positive rates.

Wright D ，Abele H ，Baker A ，Kagan KO ... -  《-》

First-trimester combined screening for trisomy 21 with different combinations of placental growth factor, free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A.

To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11-13 weeks' gestation and to model the impact on first-trimester combined screening. PlGF was measured in 509 (409 euploid and 100 trisomic) fetal serum samples derived from prospective first-trimester combined screening for trisomy 21 at 11-13 weeks' gestation. The serum samples were stored at -80°C, following the measurement of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels, for median time spans of 0.9 and 4.1 years in the euploid and trisomy 21 pregnancies, respectively. The effect of additional PlGF measurement at the time of combined screening was investigated by simulating fetal nuchal translucency (NT) measurements and multiples of the median (MoM) values for PAPP-A, free β-hCG and PlGF for 20,000 euploid and 20,000 trisomy 21 pregnancies. Patient-specific combined risks were calculated based on maternal age and fetal NT in addition to free β-hCG, PAPP-A and PlGF, PAPP-A and PlGF or free β-hCG and PlGF, and detection and false-positive rates were calculated. Median PlGF-MoM was 1.0 (95% confidence interval (CI), 0.96-1.04) in euploid fetuses and significantly lower, at 0.73 (95% CI, 0.70-0.76), in trisomy-21 fetuses (P < 0.0001). There was no significant dependency between PlGF-MoM and either gestational age at the time of blood sampling (r = 0.087, P = 0.392) or sample storage time (r = 0.028, P = 0.785). Modeled detection and false-positive rates for first-trimester combined screening (based on maternal and gestational age, fetal NT and maternal serum biochemistry) without PlGF were 85% and 2.7% for a fixed risk cut-off of 1:100. The addition of PlGF increased the detection rate to 87% and reduced the false-positive rate to 2.6%. Screening by maternal age and fetal NT in combination with PlGF and PAPP-A or in combination with PlGF and free β-hCG provided detection rates of 82% and 79%, with false-positive rates of 2.7% and 3.0%, respectively. In pregnancies with trisomy 21 PlGF is reduced. The impact on the overall screening performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21 screening. However, as PlGF is measured with the aim of assessing the risk for pre-eclampsia, further improvement in screening for trisomy 21 can be considered as an added benefit.

Kagan KO ，Hoopmann M ，Abele H ，Alkier R ，Lüthgens K ... -  《-》