Maternal Serum Screening Cares About Fetal Development

Historically, maternal mortality was 6 to 9 out of 1000 live births, and 100 per 1000 live-born infants died within the first 12 months of life in the early 1900s. Maternal mortality declined to less than 0.1 out of 1000 live births, and infant mortality declined to 7 out of 1000 live births in 2000. Fetal growth and development are affected by various factors such as genetic, nutritional, environmental, uteroplacental, etc. Today, Improvements in nutrition and advances in clinical prenatal screening are key factors in the decline in mortality and morbidity.

Maternal serum screening is a critical component of prenatal care designed to assess the risk of certain genetic disorders and birth defects in a developing fetus, in particular Down's syndrome (trisomy 21 or T21), Edwards' syndrome (trisomy 18 or T18), Patau's syndrome (trisomy 13 or T13) and Neural tube defects (NTDs). This non-invasive test, often performed as the first step during the first and second trimesters of pregnancy, involves only a blood draw but provides early information to parents and health providers.

Multiple serum markers are applied in the purpose of screening, rather than diagnosis. Common practice uses the unit multiple of median (MoM)?as a gestational age-dependent expression of serum marker’s concentration. MoM is a measure of how far an individual test result deviates from the median level for the entire population at that gestational age in that laboratory, which can be calculated by the following formula:

Using MoM values, rather than absolute levels, also allows results from different laboratories to be interpreted in a consistent way. Also, racial differences are a key factor in causing differences in MoM values. It is necessary to establish MOM database algorithms for different races.

First Trimester Serum Screening?may be performed between 10 and 14 weeks. The markers used for the risk calculation are 2 serum markers: PAPP-A and free βhCG). The third marker is the fetal nuchal translucency (NT, a fluid-containing area behind the fetal neck) which is performed by ultrasound.

Here is a study of contour plots applied to Caucasian woman for free βhCG and PAPP-A MoM in trisomies 21, 18 and 13 and unaffected pregnancies (Fig. 1).

Pregnancy-Associated Plasma Protein A?(PAPP-A)?is a glycoprotein secreted in the plasma of pregnant woman and its concentration increases throughout pregnancy until delivery. Decreased levels of PAPP-A are found in association with abnormal placental function which has formed the basis for the first trimester screening of fetal T21, T18 and T13. PAPP-A is also proved to have a positive relationship with birth weight. As PAPP-A decreases, complications as intrauterine growth deficiency (IUGR), premature birth, preeclampsia and stillbirth are observed to be increasing. Elevated levels are less common but can also be indicative of other conditions.

Human chorionic gonadotropin?(hCG)?is a hormone produced by the placenta during pregnancy, and its levels in the mother’s blood can provide insights into fetal health. It peaks at 8–10 weeks and then declines to reach a plateau at 18–20 weeks. For the initiation and maintenance of pregnancy, hCG mediates multiple placental, uterine and fetal functions. hCG hormone is composed of two noncovalently linked subunits, α and β. A molecular biology studies have demonstrated that trisomy 21 trophoblasts show a marked increase in βhCG mRNA, suggesting that beta subunit production is more markedly increased. In trisomies 18 and 13, maternal serum free βhCG are decreased.

Second?Trimester Serum Screening?(also called as quad marker test) is usually done between the 15 and 20 weeks of pregnancy. The variations of multiple markers are possibly correlated with various adverse pregnancy outcomes summarized as below:

Alpha-fetoprotein screening (AFP)?is synthesized early in gestation by the fetal yolk sac and later by the fetal gastrointestinal tract and the liver. It is present in the fluid surrounding the fetus (amniotic fluid), and crosses the placenta into the mother's blood. Elevated levels of AFP can indicate an increased risk of neural tube defects. Other fetal abnormalities such as omphalocele, gastroschisis, congenital renal disease, esophageal?atresia, and other fetal-distress situations 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.?Low levels of AFP can be associated with an increased risk of Down syndrome and Edward’s syndrome. In this situation, AFP is just one of several markers used to assess the risk.

Free βhCG?serves as double screening of chromosomal abnormality in second trimester serum testing. Increased βhCG levels are associated with Down syndrome, while decreased levels may be seen in trisomy 18. Elevations of βhCG 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.

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 Unconjugated Estriol (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).

Inhibin consists of disulfide-linked α and β subunits. While the α subunits are identical in all Inhibins, the β subunits exist in 2?major forms, termed A and B. Inhibins and activins are produced by the feto-placental unit in increasing quantities, mirroring fetal growth. Only Inhibin A?is found in appreciable quantities in the maternal circulation. Therefore, Inhibin A becomes a significant marker in the maternal serum screening. Maternal Inhibin A levels are correlated with maternal hCG levels and are abnormal in the same conditions (eg,?Inhibin A levels are typically higher in Down syndrome pregnancies). 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’s syndrome.

Mayo Clinic recommends the sequential maternal serum screening as below. If screening shows positive, diagnostic testing such as amniocentesis, chorionic villus sampling?should be offered.

YHLO’s Serum Markers for Maternal Screening

To evaluate the risk of genetic disorders and birth defects?during pregnancy, blood tests are commonly requested by doctors.?These tests typically include PAPP-A, βhCG, AFP, uE3, Inhibin A, YHLO’s fertility panel supports all of these tests.

YHLO is now collecting data to build own MoM values database and developing Screening Testing Algorithm?Software. Stay tuned next year.

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