This year marks the 30th anniversary of the use of laboratory tests to screen pregnancies for Down syndrome. The tests have evolved over the last three decades and as have their ability to detect affected fetuses. Currently there are several different lab tests available to screen for Down syndrome during pregnancy, including the recently developed cell-free DNA tests (commonly referred to as non-invasive prenatal testing, or NIPT).
How has the landscape of Down syndrome screening evolved over the last few decades? That was the question considered by investigators of a recent report that sought to determine the number of women screened for Down syndrome in the United States in 2011 and 2012, along with the type of test they received.
The results of this report were based on surveys completed by 168 laboratories that offered Down syndrome screening tests in 2011 and/or 2012 and are rather interesting:
- Of the 4.13 million pregnancies that occur each year in the United States, approximately 72% are screened for Down syndrome.
- The most common screening test is the quadruple test (50%) followed by the first-trimester combined test (18%), and the sequential test (14%). The other types of tests (e.g. triple test, full integrated test, and serum integrated test) were less commonly performed.
- The 6 largest laboratories (those that screened more than 100,000 pregnancies each year) performed 61% of all screening tests.
- The 32 smallest laboratories (those that screened fewer than 1,500 pregnancies each year) performed only 1% of all screening tests.
- Between 2011 and 2012, the use of the first trimester and integrated testing increased by 27% and 6% and the use of the quad test decreased by 1.2%.
- As shown in the figure below, there was an inverse relationship between the percent of laboratories that offered testing only in the second trimester (e.g. triple or quadruple tests) and the number of pregnancies screened each year.
That last bullet point is an important one because nearly 70% of women have their first prenatal visit in the first trimester and it is recommended that integrated screening be offered at this visit. However, because the number of laboratories offering only second trimester testing is much greater than the number of labs that offer all types of screening tests, this recommendation may not be easily adopted.
In a previous post I described the clinical performance of DNA-based screening tests for fetal aneuploidies like Down syndrome. Overall, these tests have excellent detection rates (~99%) with very low false-positive rates (~0.2%). In other words, these tests are about 99.0% sensitive and 99.8% specific.
With performance like that one might expect these to be considered diagnostic tests. They are not! Although quite good, test results must not be interpreted as definitive evidence that a fetus does or does not have an aneuploidy. Recent recommendations from the American College of Obstetricians and Gynecologists (ACOG) are quite clear on that issue.
In those same recommendations, ACOG also states that DNA-based screening tests may be performed only on women who are at increased risk of having a fetus with aneuloidy. Among the indications listed for women considered to be at increase risk are:
- Maternal age 35 years or older at delivery
- Fetal ultrasound findings suggesting aneuploidy
- A previous aneuploid pregnancy
- Abnormal biochemical screening test results
The ACOG is right to avoid recommending that DNA-based screening tests are acceptable to use regardless of risk factors. Unfortunately, many women who are not at increased risk are using these new tests as a primary screening test and that's not a good idea.
To understand why, considered a population of 100,000 pregnant women from the general population and assume that the prevalence of Down syndrome is 1 in 500 pregnancies. That means that there would be 99,800 unaffected pregnancies and 200 pregnancies with Down syndrome. The table below compares the results of the most commonly used biochemical screening test (the Quad test) to a DNA-based screening test.
Clearly, the DNA-based test has several advantages over the Quad test. Its positive predictive value is nearly 17 times greater than the Quad's and a positive DNA-based test result substantially increases the odds of having an affected fetus. So why not use the DNA-based test as a primary screening test? For the following reasons:
- No studies have been published that have evaluated the performance of DNA-based tests in women who are not at increased risk of having a fetus with an aneuploidy
- DNA-based tests are not widely available
- The time it takes to report results of DNA-based testing is about 3 times greater than it is with biochemical testing
- DNA-based tests are considerably more expensive than biochemical tests
- Relative lack of insurance coverage for DNA-based tests
Until these these limitations can be resolved, it makes more sense to use DNA-based testing as a secondary screening test. In other words, it is only done after one of the risk factors described by ACOG (above) are met. Doing so greatly improves the performance of both tests (see figure below). A limitation of this approach is that the detection rate is that of the biochemical test which is not as high as it is with the DNA-based test. Still, given the current limitations of DNA-based testing, this 2-step testing approach makes the most sense.