Clinical Question: What is the most accurate screening approach for detecting Down syndrome during pregnancy?

Setting: Outpatient (specialty)

Study Design: Cohort (prospective)

Synopsis: Several approaches to screening for Down syndrome during pregnancy have been advocated. This is the report of the First- and Second-Trimester Evaluation of Risk (FASTER) Trial, designed to compare several approaches directly. Women (n = 38,167) were enrolled if they had singleton pregnancies with crown-rump length by study ultrasonography consistent with gestation of 10 weeks and three days to 13 weeks and six days. First-trimester risk was calculated on the basis of nuchal translucency and two serum markers, pregnancy-associated plasma protein A and the free beta subunit of human chorionic gonadotropin (i.e., combined screening). The optimal age for first-trimester screening was 11 weeks’ gestation. Second-trimester risk was calculated at 15 to 18 weeks’ gestation using serum alpha fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A, together with maternal age (i.e., quadruple test).

Biochemical markers were converted to multiples of median and adjusted for maternal weight and race. A single reviewer scored all nuchal translucency images at the main study site. Patients were given results after the second-trimester screening results were available. Screening was considered positive when the calculated risk of Down syndrome was one out of 150 for first-trimester testing and one out of 300 for second-trimester testing. Amniocentesis for karyotyping was offered if first- or second-trimester screening results were positive. Sensitivity and specificity were calculated for different test combinations. There were 117 patients with Down syndrome in the cohort. In 7 percent of patients, a satisfactory nuchal translucency image was not obtained. The costs of testing approaches were not compared.

Bottom Line: The most accurate screening approach was sequential testing, which detected 95 percent of patients with Down syndrome with a 2.5 percent false-positive rate. The process: perform combined screening during the first trimester. If the screening result is positive, offer genetic testing; if negative, perform the quadruple test in the second trimester, and then offer genetic testing if that yields a positive result. Fully integrated testing (second-trimester quadruple test plus first-trimester nuchal translucency) is almost as accurate (95 percent detection and 4 percent false-positive results). The skill of the ultrasonographer in measuring nuchal translucency is key to these approaches. (Level of Evidence: 1b)