Quad Fetal Risk Assessment

Measurement of multiple maternal serum markers have routinely been offered to women for the prenatal identification of pregnancies at-risk for open neural tube defects and for Down’ syndrome. The objective of this screening test is to identify those pregnancies at "high risk" for certain problems who are candidates for further diagnostic testing. Over the last 10 years, new technology has improved the methods of detection of some fetal abnormalities, including Down’ syndrome. While there are invasive ways to diagnose Down’ syndrome by obtaining fetal tissue samples by amniocentesis or chorionic villus sampling, it is not appropriate to examine every pregnancy with invasive tests. These procedures are costly and carry a small risk to the fetus, and thus are used only in pregnancies that have been documented to be "at risk" due to certain situations.

Previously, health care providers have offered their pregnant patients a screening test called the Triple Screen which isolates three substances from a small sample of the mother’s blood, called alpha-fetoprotein (AFP), estriol (uE3), and human chorionic gonadotropin (hCG). These substances are normally made by the fetus as it develops and are passed into the amniotic fluid. The substances are then transported through the placenta into the mother’s blood where they can be measured. These levels are compared to amounts normally present during pregnancy. Although the levels change significantly during the course of a normal pregnancy, it is predictable; and the health care providers use these results as well as a woman’s age, age of the fetus, the woman’s weight and race to calculate the risk of having a baby with problems. Specific patterns and levels of these substances are recognized to be associated with various concerns in the pregnancy. Abnormal values do not diagnose a specific defect but may identify pregnancies at a higher risk for a fetus with a birth defect such as an open neural tube defect (spina bifida), an abdominal wall defect, or a chromosome problem such as Down’ syndrome. If this calculated risk is determined to be "significant", additional testing, including detailed ultrasound, amniocentesis, and genetic counseling may be indicated to provide additional information about the baby. In most cases, the screen will be negative and no other tests will be necessary. Although this is reassuring, it does not rule out all birth defects. The Triple Screen facilitated prenatal screening for fetal Down’ syndrome, resulting in the prenatal detection of approximately 70% of Down’ syndrome pregnancies in the under 35 maternal age group. Additionally, the "Triple Screen" detected certain other high-risk pregnancies.

On July 1, 2002, the Human Genetics Laboratory and Regional Pathology Services at University of Nebraska Medical Center added a fourth marker, dimeric inhibin A (DIA), to the Triple Screen. DIA, in conjunction with the three other analytes and maternal age, race, weight, and gestational age is referred to as the Quad Fetal Risk Assessment and allows prenatal care providers to screen for Down’ syndrome more accurately then ever before.

DIA is a glycoprotein of placental origin quite similar to hCG. Maternal serum levels of DIA are twice as high in pregnancies affected by Down’ syndrome as in unaffected pregnancies. In contrast to the other analytes, levels of DIA in maternal serum remain relatively constant through the 15th-18th weeks of pregnancy and thus are less dramatically changed by dates.

In the Quad Fetal Risk Assessment, DIA is used to decrease the screen-positive rate from 5% to 2.9% while maintaining the expected detection rate. It has been our experience that practitioners, as well as patients, have found the previous false-positive rate unacceptable. Consequently, they are choosing not to obtain screening. The use of the Quad Fetal Risk Assessment results in the necessity for fewer additional prenatal procedures. Specifically, because of the increased sensitivity and specificity of the Quad as compared to the Triple Screen, fewer amniocenteses are necessary, thus reducing the overall prenatal cost and parental anxiety, without jeopardizing detection rates. For most cases, additional information gathered by the prenatal care providers enable them to provide optimal care for their patients while reassuring them that the pregnancy is progressing as it should.

Use of the Quad Fetal Risk Assessment should not change how screening is offered to patients. Screening is still offered between 14 and 20 weeks after the first day of a woman’s last menstrual period. The incorporation of this analyte does not require additional conditions for blood draws or sample handling. The Quad Fetal Risk Assessment report is similar to the Triple Screen report, except that the DIA level and its MoM (Multiple of the Median) are included and are incorporated into the risk calculation for Down’ syndrome. Questions regarding the Quad Fetal Risk Assessment should be directed to Melonie Welsh at (402)559-8157.

Contributed by Melonie Welsh, M.S., UNMC Munroe Meyer Institute

Date last updated:  January 27, 2003