Clinical Information

Multiple marker serum screening has become a standard tool used in obstetric care to identify pregnancies that may have an increased risk for certain birth defects such as Down syndrome (trisomy 21) and trisomy 18 (Edward syndrome). Since early 2000s, first-trimester screening has been established as an alternative option of equal or better performance when compared to second-trimester screening programs.

The first-trimester screen is performed by measuring analytes human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) in maternal serum that are produced by the fetus and the placenta. Additionally, the nuchal translucency (NT) measurement, a sonographic marker shown to be effective in screening fetuses for Down syndrome and trisomy 18, is included in the risk calculation. A mathematical model is used to calculate a risk estimate by combining serum concentrations to hCG and PAPP-A, NT measurement, and maternal demographic information. The laboratory establishes a specific cutoff for each condition, which classifies each screen as either screen-positive or screen-negative. A screen-positive result indicates that the value obtained exceeds the established cutoff. A positive screen does not provide a diagnosis but indicates that further evaluation should be considered.

hCG:

hCG is synthesized by placental cells starting very early in pregnancy and serves to maintain the corpus luteum and, hence, progesterone production during the first trimester. Thereafter, the concentration of hCG begins to fall as the placenta begins to produce steroid hormones and the role of the corpus luteum in maintaining pregnancy diminishes. Increased total hCG levels are associated with an increased risk for Down syndrome. Low levels of hCG are associated with an increased risk for trisomy 18.

PAPP-A:

PAPP-A is a 187 kDa protein comprised of 4 subunits: 2 PAPP-A subunits and 2 pro-major basic protein subunits. PAPP-A is a metalloproteinase that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4), dramatically reducing IGFBP-4 affinity for IGF1 and IGF2, thereby regulating the availability of these growth factors at the tissue level. PAPP-A is highly expressed in first-trimester trophoblasts, participating in regulation of fetal growth. Levels in maternal serum increase throughout pregnancy. Low PAPP-A levels before the 14th week of gestation are associated with an increased risk for Down syndrome and trisomy 18.

NT:

The NT measurement, an ultrasound marker, is obtained by measuring the fluid-filled space within the nuchal region (back of the neck) of the fetus. While fetal NT measurements obtained by ultrasonography increase in normal pregnancies with advancing gestational age, Down syndrome fetuses have larger NT measurements than gestational age-matched normal fetuses. Increased fetal NT measurements can therefore serve as an indicator of an increased risk for Down syndrome and trisomy 18.