First-Trimester Screening for Trisomy 21 by Free Beta-Human Chorionic Gonadotropin and Pregnancy-Associated Plasma Protein-A: Impact of Maternal and Pregnancy Characteristics

Abstract

In pregnancies complicated by fetal trisomy 21, maternal serum levels of free-human chorionic gonadotropin (free β-hCG) are about twice as high as in pregnancies with a euploid fetus, while levels of pregnancy-associated plasma protein-A (PAPP-A) are reduced by about half. Screening for trisomy 21 using these markers in addition to fetal nuchal translucency thickness has been reported to detect about 90% of affected pregnancies at a false-positive rate of 5%. However, currently the only variables for which adjustments are made are maternal weight and gestational age. To determine if other maternal variables influence screening test results, the present multicenter trial prospectively screened women in the first-trimester of pregnancy for trisomy 21, using multiple regression analysis to learn how maternal factors, particularly ethnic origin, influenced measured levels of β-hCG and PAPP-A. Gaussian distributions were fitted to the distribution of log multiples of the median values in 491 cases of trisomy 21 and 96,803 euploid pregnancies. Compared with Caucasian women who were parous, nonsmokers, and conceived spontaneously, PAPP-A levels were 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 women who conceived by in vitro fertilization (IVF). Maternal serum levels of free β-hCG were 12% higher in women of Afro-Caribbean origin, 9% lower in South Asian women, 8% higher in East Asians, 2% higher in nulliparous women, 4% lower in smokers, and 9% higher in women who conceived by IVF. If no adjustments were made for variables other than maternal age and gestational age, integrated first-trimester screening based on maternal age-related risk and serum PAPP-A and free β-hCG levels resulted in the detection of 51% of all cases of trisomy at a false-positive rate of 1.4% in Afro-Carribean women; after adjustment for race, the detection increased to 68% at a false-positive rate of 4.6%. Similar changes in the detection and false-positive rates occurred after adjustment for smoking, conception by IVF, and parity. In addition, screening was considerably more sensitive when carried out at 11-12 weeks' gestation rather than at 13 weeks. These results indicate that numerous maternal and pregnancy-related factors must be taken into account when screening in the first-trimester of pregnancy for trisomy 21.