Triple Marker Study:
Women Less Than 35 Years Of Age
Until recently, 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, followed by the addition of other blood markers, women less than 35 years of age can be screened for Down syndrome.
Maternal serum screening involves obtaining a small amount of blood from the pregnant woman's arm. Her blood is tested for the amount of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. These substances are made by the mother's placenta and the fetus. At each week of pregnancy there are different amounts of these substances in the mother's blood. Using isolated or combinations of these blood tests, between 20% and 60% of fetuses with Down syndrome can be identified.
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.
Women 35 Years of Age and Older
The current detection rate of 40% to 60% 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 60% detection rate is not acceptable for women at 35 years and greater when the alternative is diagnostic testing using amniocentesis, which has a detection rate of 99%. However, by adjusting the number of patients undergoing amniocentesis, the rate of detection of Down syndrome can be increased.
This concept was recently reported in a study published in The New England Journal of Medicine by researchers who 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 genetic amniocentesis, which identifies 99% of Down syndrome fetuses. The study reported identifying 89% of fetuses with Down syndrome, which would only require 25% of the high-risk patients to undergo amniocentesis. However, unlike universal amniocentesis, which identifies 99% of all chromosomal abnormalities, Triple Marker Screening only identified 65% of all chromosomal abnormalities.
To counter this argument, however, the authors stated that the other chromosomal defects were either lethal (trisomy 13 and 18), or were so infrequent (unbalanced translocations) that the benefit of saving normal fetuses from loss far outweighed the identification of rare chromosomal abnormalities.
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 at 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 varies as a function of maternal age. In The New England Journal of Medicine article it was reported to be 89%. This, however, was the average for all women of 35 years of age and older. In reality, the detection rate of 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.
Thirteen percent (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 21will be identified. Thus, for every 10 fetuses with Down syndrome, only 7 will be detected. From this graph you can see that the detection rate of Down syndrome is lower than that reported in The New England Journal of Medicine (89%) for women between 35 and 39 years of age.
Advantages of Triple Marker Screening For Women at 35 Years of Age and Older
The advantage of the Triple Marker 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. For many of these women this is a better alternative than no test at all!
- In addition, if the Triple Marker Screening Test is negative, the risk for having a fetus with Down syndrome is less than the risk of miscarriage if they were then to have an amniocentesis. For example, if a 35-year-old patient had a normal Triple Marker Screening test and then elected to have an amniocentesis, the risk of miscarriage would be 6 times greater than having a child with Down syndrome.
Limitations of Triple Marker Screening For Patients at 35 Years of Age and Older
Although the Triple Marker Screening test is useful for identifying Down syndrome, it has the following limitations:
- Identifies between 71% and 87% of fetuses with Down syndrome in women between 35 and 39 years of age. These age groups contain the largest number of women seeking genetic amniocentesis because of advanced maternal age.
- 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.
- If the test is negative, patients may not be offered an ultrasound examination, which is routinely performed prior to amniocentesis. The advantage of an ultrasound is that it may identify birth defects, which are not associated with abnormal chromosomes.
The blood test is not valid if performed before 15 weeks or after 20 weeks of pregnancy.
