Maternal Triple Screen and Maternal Quad Screens are groups of tests that are provided to pregnant women in early pregnancy as a screening test to identify potential birth defects or serious chromosomal/genetic abnormalities.
In the past, maternal screening tests have been offered to pregnant women who were considered to be at increased risk for birth defects (e.g., women over the age of 35 years, or women who have previously delivered children with birth defects). These screening tests may indicate the potential for the presence of fetal defects (particularly trisomy 21 [Down syndrome] or trisomy 18). They may also indicate increased risk for neural tube defects (e.g., myelomeningocele, spina bifida) or abdominal wall defects (omphalocele or gastroschisis).
The incidence of these abnormalities is directly related to maternal age. The risk for having a child with trisomy 21 increases in a gradual, linear fashion until about age 30 and increases exponentially thereafter. That is, the risk for having a child with trisomy 21 is 1 in 1300 for a 25-year-old woman; at age 35, the risk increases to 1 in 365. At age 45, the risk for a having a child with trisomy 21 increases to 1 in 30. It is important to note that women younger than 35 years, however, give birth to about 70% of infants with trisomy 21. In the United States, maternal screening is now routinely offered to all pregnant women—usually in their second trimester of pregnancy. Patients must understand that this is a “screening” test, not a “diagnostic” test. If the screening tests are positive, more accurate diagnostic testing, such as chorionic villus sampling (CVS) in early pregnancy or amniocentesis in mid–pregnancy, is performed. Most pregnant women over 35 years of age routinely have CVS or amniocentesis without maternal screening.
There are several variations of this test available:
• Double Test: Measures two markers, Human Chorionic Gonadotropin (hCG) and Alpha-Fetoprotein (AFP).
• Triple Test (Maternal Triple Screen Test): Measures three markers, Human Chorionic Gonadotropin, AFP, and Estriol. AFP is produced in the yolk sac and fetal liver. Unconjugated Estriol and hCG are produced by the placenta.
• Quadruple Test: Measures four markers, hCG, AFP, Estriol, and inhibin A
• Fully Integrated Screen Test: Measures AFP, estriol, Fetal Nuchal Translucency, beta and total hCG, and Pregnancy-Associated Plasma Protein-A (PAPP-A).
The maternal triple screen test has become the standard. Combination of these three markers offers a 50% to 80% chance of detecting pregnancies with trisomy 21 as compared to AFP alone, with only a 30% chance of detection. These tests are most accurately performed during the second trimester of pregnancy—more specifically between the 14th and 20th weeks. The use of ultrasound to accurately indicate gestational age improves the sensitivity and specificity of maternal serum screening.
First-trimester screening for genetic defects is now an option for pregnant women. This testing would include Fetal Nuchal Translucency combined with the beta subunit of hCG (beta-hCG), and pregnancy-associated plasma protein-A (PAPP-A). A low level of PAPP-A may indicate an increased risk for having a stillborn baby. These tests have detection rates comparable to standard second-trimester triple screening.
First-trimester screening offers several potential advantages over second-trimester screening. When test results are negative, it may help reduce maternal anxiety earlier. If results are positive, it allows women to take advantage of first-trimester prenatal diagnosis by chorionic villus sampling (CVS) at 10 to 12 weeks or early pregnancy amniocentesis.
Detecting problems earlier in the pregnancy may allow women to prepare for a child with health problems. It also affords women greater privacy and less health risk if they elect to terminate the pregnancy.
With trisomy 21, second-trimester absolute maternal serum levels of AFP and unconjugated estriol are about 25% lower than normal levels and maternal serum hCG is approximately two times higher than the normal hCG level. The results of the screening are expressed in “multiples of median” (MoM). AFP and uE3 values during pregnancies with trisomy 21 are lower than those associated with normal pregnancies, which means that values below the mean are below 1 MoM. The hCG value for trisomy 21 is above 1 MoM. The MoM, fetal age, and maternal weight are used to calculate the possible risk for chromosomal abnormalities, such as trisomy 21. Specific computer programs used for this calculation have been developed. A composite estimate of the risk for trisomy 21 is reported to the clinician. A standard risk cutoff is used to determine when the screening test is considered “positive.” Most laboratories use a risk cutoff of 1 in 270, which is equal to the second-trimester risk for trisomy 21 in a 35-year-old woman.
All of the above-named maternal screening tests are discussed elsewhere in this book. For the sake of thoroughness, Inhibin A and PAPP-A are discussed below:
Inhibin A is normally secreted by the granulosa cells in the ovaries and inhibits the production of follicle-stimulating hormone (FSH) by the pituitary gland. Inhibin A is a glycoprotein of placental origin in pregnancy similar to hCG. Levels in maternal serum remain relatively constant through the 15th to 18th week of pregnancy. Inhibin A is important in the control of fetal development. Maternal serum levels of inhibin A are twice as high in pregnancies affected by trisomy 21 as in unaffected pregnancies. The discovery of this fact led to the inclusion of inhibin A in the above-noted serum screening tests for trisomy 21. Inhibin A concentrations are significantly lower in women with normal pregnancies than in women with pregnancies that result in spontaneous abortions. Furthermore, circulating concentrations of inhibin A appear to reflect tumor mass for certain forms of ovarian cancer. More accurate diagnostic testing is required if screening tests are abnormal.
Pregnancy-associated plasma protein-A (PAPP-A) is a product of the placenta and the endometrium. It is secreted into the maternal circulation during human pregnancy. Women with low blood levels of PAPP-A at 8 to 14 weeks of gestation have an increased risk for intrauterine growth restriction, trisomy 21, premature delivery, preeclampsia, and stillbirth. This protein rapidly rises in the first trimester of normal pregnancy. However, in a trisomy 21–affected pregnancy, serum levels are half that of unaffected pregnancies. Furthermore, low first-trimester levels of PAPP-A in maternal serum are associated with adverse fetal outcomes, including fetal death in utero and intrauterine growth restriction.
Tieple Screen and Quad Screen Role in Diagnoses
Increased serum markers are associated with potential for birth defects. AFP markers are decreased in trisomy chromosomal defects, however. Low levels of PAPP-A may be associated with stillbirths. By the aid of maternal screen testing, the following birth defects can be diagnosed:
- Trisomy 21 (Down Syndrome).
- Trisomy 18 (Edwards Syndrome).
- Neural Tube Defects.
- Abdominal Wall Defects.