Screening markers are used to calculate a pregnant woman’s risk of having a child with Down syndrome, thereby allowing her to make an informed choice about invasive diagnostic testing, which is costly and associated with some risk of pregnancy loss. A variety of serum markers are used to screen for Down syndrome in the first and/or second trimesters. The quad test is performed in the second trimester (optimally at fifteen to eighteen weeks of gestation) and consists of alpha fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (beta-hCG), and inhibin A (inhA) measurements. Each patient should be given the specific numerical risk of Down syndrome (eg, 1 in 100) calculated for her based on her age and screening test results. The risk cut-off chosen for test interpretation (ie, identifying patients as screen negative or screen positive) determines the detection and false positive rates for Down syndrome. For a given test, as the risk cut-off gets higher, fewer women are screen positive and fewer affected pregnancies will be identified. If less stringent risk cut-offs are chosen, a greater number of affected pregnancies will be identified, but there will be more false positive tests leading to a larger number of couples experiencing parental anxiety and having to consider costly and potentially risky diagnostic procedures. Thus, there is always a trade-off between an optimal detection rate and a tolerable screen positive rate.