What’s missing from non-invasive prenatal testing for Down syndrome

AutonomyNIPTGiven all the attention the past few years on advances in prenatal testing, it should be relatively simple to decide what prenatal testing an expectant mother should have if she chooses to accept prenatal testing, right? Well, not exactly.

Prenatal testing began with the diagnostic tests amniocentesis and chorionic villus sampling (CVS). Indeed, these remain the tests to provide a diagnosis (and even then, false positives still may occur, however slight, particularly with CVS).

Then came ultrasound and, then, tests based on a mother’s blood sample, which provided a recalculation of a woman’s chance that she was carrying a child with Down syndrome. First it was alpha-fetoprotein (AFP), still a screening test for spina bifida and other neural tube defects. Then, the quad test. Both AFP and the Quad are offered in the second trimester.

In the late 1990′s, the National Institutes of Health granted millions of dollars for the First And Second Trimester Evaluation of Risk (FASTER) study, which validated the combined test as a first trimester screening test. Combining a test of the mother’s blood with an ultrasound measurement of the fetus’ neck (nuchal translucency), the combined test approached the same detection levels as the Quad test.

Then, practitioners started using various combinations of these tests to arrive at even higher detection levels: step-wise or contingent sequential testing, where second trimester screening tests are offered depending on whether first trimester screening tests suggested an elevated chance; integrated testing, where both first and second trimester are performed and then both results analyzed for an even higher detection rate; and, then other variations depending on ultrasound measurements.

But, then, non-invasive prenatal screening was introduced. It was hailed as the “holy grail” of prenatal testing: highest detection rates based off of a mother’s blood sample, offered at anytime in the pregnancy after 9 weeks. However, serious concerns were raised about its reported accuracy and few studies have showed the same detection rates in the general population. Further, NIPS  identifies only a select few chromosomal conditions, while the other screening tests could identify other conditions and possible health concerns for the mother.

So, what is an expectant mother to do when offered prenatal testing? Which option should she select?

After attending the Society for Maternal-Fetal Medicine annual conference, and based on research presented there, I don’t think the answer is any clearer.

In a statewide study of California’s screening program, researchers led by Mary Norton found that for women whose screen results showed an increased chance for having a child with Down syndrome or Trisomy 18, 80% of them would have been detected through NIPS. However, 17% of pregnancies with other chromosomal conditions would have been missed using NIPS only.

Further, two studies found that “NIPT was one of the least cost-effective methods for T21 screening.” As compared to other screening options, for each 10,000 patients NIPS cost $6 million more than integrated screening and about $10 million more than combined screening or quad screening. A study also found including nasal bone measurement along with combined screening was more cost effective for women 35-39 than solely using NIPS. Conversely, another study concluded that NIPS was more cost-effective than first and second trimester screening options, at a savings of about $8 million per 10,000 patients.

Another study compared the cost-effectiveness of NIPS as compared to amnio with microarray, finding NIPS would cost about twice as much, more than $100 million, due to NIPS only identifying a limited number of conditions as compared to microarray detecting far more. Similarly, a study found that 10% of pregnancies with an increased nuchal translucency measurement and normal karyotype still reported a significant finding with microarray testing.

Yet, another study suggested what else is missing if only NIPS were used. Women who had integrated screening results were

more likely to have a fetus with a chromosomal abnormality, neural tube defect (NTD) or abdominal wall defect…. In addition, screen positive women were more likely to have obstetric complications related to placenta function (preeclampsia, placenta pre via and abruption []), preterm delivery [], fetal/neonatal mortality [] or a fetus with a non-NTD structural birth defect (with highest risks observed for central nervous system, cardiac, circulatory, and respiratory structural birth defects ….

None of those conditions would have been identified relying on NIPS only. As another study that reported similar results concluded

The importance of serum analyses and their link to poor placental function and pregnancy outcomes … and preterm birth, should not be forgotten in the era of [NIPS].

So, while NIPS may have high detection rates for Down syndrome, women who rely solely on it will be unaware of a significant chance of other conditions if their NIPS result does not report an increased chance for Down syndrome. By forgoing traditional screening, they will be unaware of potential concerns with their pregnancy like preeclampsia. From a health planning perspective, a NIPS-only strategy could be unreasonably costly, and miss this same information as well.

What prenatal testing should a woman have? It is is far less than clear, and, as the reports and professional guidelines caution, expectant mothers should be counseled about the limitations of whatever testing option they choose.

Comments

  1. Nice article and thanks for writing this up though. I’ve one doubt and thought of asking you, sir.

    Is there a risk of miscarriage with array CGH testing?

  2. Thank you so much for the article.

    It was informative, yet wanted to ask if we combine NIPT with first trimister and second trimister ultrasound results – would it show correct results with better accuracy and lesser limitations.

    • The professional guidelines for ISPD, ACOG, and NSGC all only recommend offering NIPS after the mother is already deemed at an increased chance for having a child with Down syndrome (or the other tested-for conditions). This is because almost all of the studies were done on these “high risk” women, and other studies of low risk women show lower accuracy for the NIPS results. So, yes, first do traditional screening and if at a higher chance based on those, then NIPS has a higher accuracy as a second-tier screen.

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