Clinical Information

Maternal serum screening is used to identify pregnancies that may have an increased risk for certain birth defects, including neural tube defects (NTD), trisomy 21 (Down syndrome), and trisomy 18 (Edwards syndrome). The screen is performed by measuring analytes in maternal serum that are produced by the fetus and the placenta. The analyte values along with maternal demographic information such as age, weight, gestational age, diabetic status, and race are combined in a mathematical model to derive a risk estimate. A specific cutoff for each condition is used to classify the risk estimate 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 rather indicates that further evaluation should be considered.

Analytes:

Alpha-Fetoprotein:

Alpha-fetoprotein (AFP) is a fetal protein that is initially produced in the fetal yolk sac and liver. A small amount is produced by the gastrointestinal tract. By the end of the first trimester, nearly all of the AFP is produced by the fetal liver. The concentration of AFP peaks in fetal serum between 10 to 13 weeks. Fetal AFP diffuses across the placental barrier into the maternal circulation. A small amount also is transported from the amniotic cavity.

The AFP concentration in maternal serum rises throughout pregnancy, from a non-pregnancy level of 0.2 ng/mL to about 250 ng/mL at 32 weeks gestation. If the fetus has an open NTD, AFP is thought to leak directly into the amniotic fluid causing unexpectedly high concentrations of AFP. Subsequently, the AFP reaches the maternal circulation, thus producing elevated serum levels. Other fetal abnormalities such as omphalocele, gastroschisis, congenital renal disease, esophageal atresia, and other fetal distress situations (eg, threatened abortion and fetal demise) also may result in maternal serum AFP elevations. Increased maternal serum AFP concentrations also may be seen in multiple pregnancies and in unaffected singleton pregnancies in which the gestational age has been underestimated.

Lower maternal serum AFP concentrations have been associated with an increased risk for genetic conditions such as trisomy 21 and trisomy 18.

Estriol:

Estriol (E3), the principal circulatory estrogen hormone in the blood during pregnancy, is synthesized by the intact feto-placental unit. E3r exists in maternal blood as a mixture of the unconjugated form and a number of conjugates. The half-life of unconjugated estriol (uE3) in the maternal blood system is 20 to 30 minutes because the maternal liver quickly conjugates E3 to make it more water soluble for urinary excretion. E3 levels increase during the course of pregnancy. Decreased uE3 has been shown to be a marker for trisomy 21 and trisomy 18. Low levels of E3 also have been associated with pregnancy loss, Smith-Lemli-Opitz, and X-linked ichthyosis (placental sulfatase deficiency).

Decreased second trimester uE3 has been shown to be a marker for Down and trisomy-18 syndromes. uE3 is a part of multiple marker prenatal biochemical screening, together with alpha-fetoprotein, human chorionic gonadotropin, and inhibin-A measurements. Low levels of uE3 also have been associated with pregnancy loss, Smith-Lemli-Opitz syndrome (defect in cholesterol biosynthesis), X-linked ichthyosis and contiguous gene syndrome (placental sulfatase deficiency disorders), aromatase deficiency, and primary or secondary fetal adrenal insufficiency.

Human Chorionic Gonadotropin:

Human chorionic gonadotropin (hCG) is a glycoprotein consisting of 2 noncovalently bound subunits. The alpha subunit is identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyrotropin (TSH, formerly thyroid-stimulating hormone), while the beta subunit has significant homology to the beta subunit of LH and limited similarity to the FSH and TSH beta subunits. The beta subunit determines the unique physiological, biochemical, and immunological properties of 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 trisomy 21, while decreased levels may be seen in trisomy 18. Elevations of hCG also can be seen in multiple pregnancies, unaffected singleton pregnancies in which the gestational age has been overestimated, triploidy, fetal loss, and hydrops fetalis.

Inhibin A:

Inhibins are a family of heterodimeric glycoproteins, primarily secreted by ovarian granulosa cells and testicular Sertoli cells, which consist of disulfide-linked alpha and beta subunits. While the alpha subunits are identical in all inhibins, the beta subunits exist in 2 major forms, termed A and B, each of which can occur in different isoforms. Depending on whether an inhibin heterodimer contains a beta A or a beta B chain, they are designated as inhibin A or inhibin B, respectively. Together with the related activins, which are homodimers or heterodimers of beta A and B chains, the inhibins are involved in gonadal-pituitary feedback and in paracrine regulation of germ cell growth and maturation. During pregnancy, inhibins and activins are produced by the feto-placental unit in increasing quantities, mirroring fetal growth. Their physiological role during pregnancy is uncertain. They are secreted into the coelomic and amniotic fluid, but only inhibin A is found in appreciable quantities in the maternal circulation during the first and second trimesters.

Maternal inhibin A levels are correlated with maternal hCG levels and are abnormal in the same conditions that are associated with abnormal hCG levels (eg, inhibin A levels are typically higher in trisomy 21 pregnancies). However, despite their similar behavior, measuring maternal serum inhibin A concentrations in addition to maternal serum hCG concentrations further improves the sensitivity and specificity of maternal multiple marker screening for trisomy 21.