Genetic Sonography After First-trimester Down Syndrome Screening

Abstract

Although second-trimester Down syndrome screening using maternal analytes was long accepted as the standard of care, first-trimester screening using both maternal analytes and fetal nuchal translucency measurement has become a viable alternative and may even be preferable, since it identifies approximately 90% of Down syndrome cases. This simulation study used published statistical parameters to determine whether following a first-trimester screening test with second-trimester sonography is an effective sequential screening protocol. Both stepwise screening (all patients have both a first-trimester screening and a second-trimester ultrasound exam) and contingent screening (all patients have a first-trimester screening; only those with a Down syndrome risk between 1/300 and 1/2500 have a second-trimester ultrasound exam) were evaluated. Serum analytes assessed in the first trimester included free β-human chorionic gonadotropin and pregnancy-associated plasma protein A. Ultrasound markers included nuchal translucency thickness and nasal bone in the first trimester, and nuchal fold, hyperechoic bowel, short humerus, short femur, echogenic intracardiac focus, pyelectasis, or a major abnormality in the second trimester. Combined first-trimester screening with maternal serum analytes and nuchal thickness detected 88.5% of Down syndrome cases at a false-positive rate of 4.2%. If women who were screen negative underwent a second-trimester genetic ultrasound and everyone whose fetus had at least one ultrasound marker was considered screen positive, another 8% of Down syndrome cases were identified at an additional false-positive rate of 13.2%. This protocol thus identified 96.5% of all Down syndrome cases at a total screen positive rate of 17.5%. In an alternative approach, the second-trimester ultrasound markers were converted into likelihood ratios that were used to modify the Down syndrome risk determined by the first-trimester screening test. This protocol identified a total of 94.1% cases at a total screen positive rate of 5.4%. In the contingent protocol, only women whose first-trimester risk of Down syndrome was between 1/300 and 1/2500 underwent second-trimester ultrasound, and sonographic markers were converted into likelihood ratios that were used to modify the Down syndrome risk determined by the first-trimester screening test. This yielded an overall Down syndrome detection rate of 93.3% and a total false-positive rate of 4.9%. Regardless of whether a stepwise sequential or contingent protocol is used, second-trimester genetic sonography may be considered as an alternative to second-trimester serum screening for maximizing the detection of Down syndrome at reasonable rates of false-positive findings.