Triple and Quad Marker Blood Screening for Down Syndrome

Women Less Than 35 Years of Age

 Maternal serum screening involves obtaining a small amount of blood from the pregnant woman's arm. Prior to the mid 1980's no screening tests were available to identify fetuses with Down syndrome in women less than 35 years of age. However, with the introduction of maternal serum alpha-fetoprotein screening, initially used to identify fetuses at risk for spinal cord defects, approximately 20% of fetuses with Down syndrome were identified in women in this age group. Subsequent studies in the late 1980's reported that the measurement of human chorionic gonadotropin and unconjugated estriol increased the identification of Down syndrome from 20% to 49%. These substances are made by the mother's placenta and the fetus.

 Triple Test

At each week of pregnancy there are different amounts of these substances in the mother's blood. In 1994, the American College of Obstetricians and Gynecologists recommended that every pregnant woman less than 35 years of age be offered this test during the second trimester of pregnancy (Down Syndrome Screening. ACOG Committee Opinion. 141, August, 1994).The Genetics Disease Branch of the state of California has implemented a statewide program in which Triple Marker Screening is offered to all pregnant women less than 35 years of age. Click here for information on the California Expanded AFP Screening Program for women under 35 years of age.

QUAD Test

In the early 1990's researchers reported that the addition of a fourth hormone produced by the placenta, inhibin-A, increased the detection of Down syndrome from 49% to 69%. For this reason, many clinicians have offered the QUAD test (alpha-fetoprotein, unconjugated estriol, human chorionic gonadotrophin, and inhibin-A) instead of the triple-marker test. Although the QUAD test is a better screening test for women in this age group, the California Expanded AFP Screening program still only offers the Triple Marker Test. However, if each patient were offered GENETIC ULTRASOUND as performed by Dr. DeVore, then the detection of fetuses with Down syndrome increases to from 69% to over 95%.

This compares the detection rate of Down syndrome using the Triple and Quad Marker maternal serum screening test. Notice that the QUAD tests increases the detection rate for Down syndrome from 49% to 69% in women less than 35 years of age. In women 35 years of age and older, there is only a minimal increase from 88% to 91%.

Women 35 Years of Age and Older

The current detection rate of 49% to 69% for Down syndrome is acceptable for women less than 35 years of age since the detection rate prior to maternal blood screening was close to 0%. However, a 69% detection rate is not acceptable for women 35 years of age and older when the alternative is amniocentesis, which has a detection rate approaching 100%. The following discussion applies, in principle, to both the TRIPLE and QUAD marker screening tests for women 35 and older, since both have similar detection rates for fetuses with Down Syndrome (see above graphic).

 Historical Background

In a research study reported in the New England Journal of Medicine in 1987, the authors suggested that the Triple Marker Screening blood test could be used to adjust the risk for Trisomy 21 in patients of advanced maternal-age (35 years of age and older). They compared their findings with universal amniocentesis, in which 100% of patients undergo this invasive procedure. The study found that after first using Triple Marker Screening, 89% of fetuses with Down syndrome were identified. To identify 89% of fetuses with Down syndrome would only require 25% of the screened patients to undergo amniocentesis. This approach was attractive since it would reduce by 75% the number of normal fetuses lost from complications following amniocentesis. However, unlike universal amniocentesis, which identifies almost 100% of all chromosomal abnormalities, Triple Marker Screening only identified 65% of all chromosomal defects. To counter this argument, however, the authors stated that the other chromosomal abnormalities were either lethal (Trisomy 13 and Trisomy 18), or were so infrequent (unbalanced translocations) that the benefit of saving normal fetuses from loss following an amniocentesis far outweighed the identification of rare chromosomal defects.

Following the above study, the state of California implemented the Expanded Alpha-Fetoprotein Screening Program. In this program women over the age of 35 are given a brochure to read entitled, "Prenatal Testing Choices For Women 35 Years and Older," in which the options of the Triple Marker Screening blood test, chorionic villus biopsy, and genetic amniocentesis are explained.

The most important concept to recognize, which is explained in the brochure, is that the detection rate for Down syndrome using Triple Marker screening varies as a function of maternal age. In the New England Journal of Medicine article the overall detection rate for Down syndrome was reported to be 89%, as previously mentioned. This, however, was the average for all women 35 years of age and older. In reality, the detection rate for Down syndrome is less than 89% for women between the ages of 35 and 39. THIS IS AN IMPORTANT CONCEPT WHICH MAY NOT BE CLEARLY UNDERSTOOD BY MANY PATIENTS AND PHYSICIANS, even though the above brochure clearly explains this. The following graph illustrates this principle.

 

The detection rate for Down syndrome increases from 71% at age 35 to 99% at age 44 by increasing the positive screen rate. The positive screen rate is equivalent to the THE NUMBER OF WOMEN WHO ARE INFORMED THAT THERE TEST IS POSITIVE FOR DOWN SYNDROME, THEREFORE REQUIRING AN AMNIOCENTESIS.

Using Triple Marker screening, 13% of women 35 years of age will have an abnormal Triple Marker Blood test indicating an increased risk for Trisomy 21, thus requiring an amniocentesis. However, only 71% of fetuses with Trisomy 21 will be identified from this group. Thus, for every 10 fetuses with Down syndrome, only 7 will be detected. From this graph you can see that the detection rate for Down syndrome is lower than that reported in the New England Journal of Medicine (89%) for women between 35 and 39 years of age. For women between 35 and 39 years of age the detection rate for Down syndrome can be increased to over 99% if GENETIC ULTRASOUND is performed in conjunction with maternal serum screening. The combined use of Triple Marker screening and Genetic Ultrasound to increase the detection rate for Down syndrome in this group of women was reported in a study from the Perinatology Research Branch of the National Institutes of Health, authored by Dr. Greggory DeVore and Dr. Roberto Romero.

Advantages of Triple Marker OR QUAD Screening For Women 35 Years of Age and Older

The advantage of the Triple Marker or QUAD Screening Program for women 35 years of age and older is that it adjusts the risk for Trisomy 21 for women who might not choose to undergo universal amniocentesis based only upon their age-related risk. If their risk following the Triple Marker or QUAD test is lower than their initial age-related risk, then the test result is reassuring. If the Triple Marker or QUAD test is followed by a negative Genetic Ultrasound, then their risk can be reduced as much as 99%.

Limitations of Triple Marker Screening For Patients 35 Years of Age and Older

Although the Triple Marker Screening test is useful for identifying Down syndrome, these tests have the following limitations:

*     Identifies between 71% and 87% of fetuses with Down syndrome in women between 35 and 39 years of age. This age groups contains the largest number of women seeking genetic amniocentesis because of advanced maternal age. However, the detection rate for Down syndrome can be increased if coupled with a GENETIC ULTRASOUND.

*      Identifies less than 50% of fetuses with Trisomy 18 and rarely identifies a fetus with Trisomy 13. Although the majority of fetuses with these chromosomal abnormalities will die within the first year of life, these conditions are still quite serious.

*      Identifies less than 65% of all chromosomal abnormalities. However, if the patient undergoes GENETIC ULTRASOUND, the detection rate for all chromosomal defects increases from 65% to 81%, as reported in a recent study by Dr. DeVore.

*      If the test is negative, some patients may not be offered an ultrasound examination because their screening test for Down syndrome was normal. This is a mistake because the advantage of an ultrasound is that it may identify birth defects which are not associated with abnormal chromosomes, as well as increase the detection rate for Down syndrome if a GENETIC ULTRASOUND is performed.