Clinical Information

Maternal serum screening is used to identify pregnancies that may have an increased risk for certain birth defects, such as trisomy 21 (Down syndrome), neural tube defect (NTD) and trisomy 18. Various options for maternal serum screening are available and include: first trimester, second trimester, and cross-trimester.

Sequential screening is a type of cross-trimester screening, which has an improved detection rate as compared to either first- or second-trimester screening. Sequential screening combines biochemical and ultrasound markers (nuchal translucency: NT) measured in both trimesters of the pregnancy.

SEQA / Sequential Maternal Screening, Part 1, Serum involves an ultrasound and a blood collection. The ultrasound measurement, referred to as the NT measurement, is difficult to perform accurately. Therefore, NT data is accepted only from NT-certified sonographers. Along with the NT measurement, a maternal serum specimen is collected to measure pregnancy-associated plasma protein A. The results of the ultrasound measurement and blood work along with the maternal age and demographic information are used to calculate Down syndrome and trisomy 18 risk estimates.

If the result from part 1 indicates a risk for Down syndrome that is higher than the screen cutoff, the screen is completed, and a report is issued. In that event, the patient is typically offered counseling and diagnostic testing. When the part 1 screen is completed, a NTD risk is not provided. For a stand-alone NTD-risk assessment, order MAFP1 / Alpha-Fetoprotein (AFP), Single Marker Screen, Maternal, Serum.

If the risk from the first trimester is below the established cutoff, an additional serum specimen is collected in the second trimester for this test. The blood sample is tested for AFP, unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A. The information from both trimesters is combined and a report is issued. If results are positive, the patient is typically offered counseling and diagnostic testing.

AFP:

AFP is a fetal protein that is initially produced in the fetal yolk sac and liver. A small amount also 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 nonpregnancy level of 0.2 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 such as threatened abortion and fetal demise, may also show AFP elevations. Additionally, increased maternal serum AFP values may be seen in pregnancies with multiple fetuses and in unaffected singleton pregnancies in which the gestational age has been underestimated. Lower maternal serum AFP values have been associated with an increased risk for genetic conditions such as Down syndrome and trisomy 18.

uE3:

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

hCG:

hCG is a glycoprotein consisting of 2 noncovalently-bound subunits. The alpha subunit is identical to the alpha subunits 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.

The CGA gene (glycoprotein hormones, alpha polypeptide) is thought to have developed through gene duplication from the LH gene in a limited number of mammalian species. hCG only plays an important physiological role in primates (including humans), where it 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 beta hCG levels are associated with Down syndrome, while decreased levels may be seen in trisomy 18. Elevations of hCG also can be seen in pregnancies with multiple fetuses, 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 Down syndrome 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 Down syndrome.