Down syndrome is an important medical condition that creates ongoing medical and societal
challenges for families with affected members. It is the most common of the major chromosome
disorders that are compatible with life, having a prevalence of about 1:650 livebirths.
Karyotyping the cells of affected individuals is a highly reliable diagnostic method, including
cells obtained during pregnancy from chorion villi or amniotic fluid. Identifying Down syndrome
prenatally has proven helpful to many families in decision-making about pregnancy management.
Because diagnostic procedures for obtaining fetal cells carry some risk for pregnancy
complications (e.g. fetal loss in I in 200 procedures), various screening tests have been
developed to minimize risk. The first of these, maternal age screening, was introduced in the
1980’s and continues in use, today. It takes advantage of the well-documented rise in risk for
Down syndrome in women age 35 and older. In the mid- 1980’s, a maternal serum screening test,
alpha-fetoprotein (AFP), was discovered, making it possible to offer screening to pregnant women
younger than age 35. This test, offered in the second trimester, was relatively inefficient,
however (detection rate 20 to 25%), and additional maternal serum markers were subsequently
discovered in the late 1980’s which improved detection to 60%, without increasing the number of
women requiring diagnostic procedures. Approximately 2.4 million pregnant women are now provided
with prenatal screening for Down syndrome annually. However, pregnant women who are found to
have positive screening test results (most of which are false positives) experience considerable
anxiety and usually require invasive studies to identify whether or not Down syndrome is present
in the fetus. It is important to minimize screen positive test results to avoid raising anxiety
and keep procedure related fetal losses to a minimum. One of the Priority Research Issues of the
Maternal and Child Health Bureau for FY 2000-2003 is “III. Development, Testing, and Validation
of Screening And Diagnostic Instruments Including Generic Methodologies To Conduct Needs
Assessments And Evaluate Performance in States”. This proposal is a demonstration project to
develop, test, and validate a new approach to serum based prenatal screening for fetal Down
syndrome that will dramatically reduce the false positive rate as compared to the current
standard of care, the triple test. This practical approach to Integrated Risk Evaluation for
Down syndrome (or PAIRED) serum test combines both first and second trimester maternal serum
biochemical measurements with maternal age to assign each pregnancy a Down syndrome risk. Those
risks are then used identify women at sufficient risk to warrant offering second trimester
amniocentesis and fetal karyotyping. Compared to the current standard of care (the triple test),
the PAIRED serum test will maintain high Down syndrome detection (75%) but will reduce the false
positive (and amniocentesis) rate by more than two-thirds (from 6.9 to 2.1%). Stated another way,
for every 1000 women screened, the number identified as potential candidates for amniocentesis
will be reduced from 69 to 21, a reduction of 70%. Thus, 48 fewer women will experience anxiety
and require diagnostic procedures, but the same number of cases of Down syndrome will be detected.
The medical and financial costs of diagnostic testing will also be reduced proportionally.
This innovative PAIRED serum approach to Down syndrome screening combines the best first and
second trimester serum screening markers to provide optimum screening performance. Use of easily
collected serum will allow the PAIRED serum test to be routinely offered to all of the general
pregnancy population no matter where they are located in the United States.