The new era of Down syndrome prenatal testing

The newest prenatal testing recommendation now adds microarray testing to the options available for expectant moms. But how does this apply specifically to prenatal testing for Down syndrome?

Fig. 1: Prenatal testing for Down syndrome

Fig. 1: Prenatal testing for Down syndrome

Microarray testing can identify thousands of genetic variations. Unlike a karyotype, the traditional diagnostic test up until now, microarray is not looking at the chromosomes, but the genes on the chromosomes. While microarray reports much more genetic information, it has its limitations.

Namely, for purposes of prenatal testing for Down syndrome, the ACOG/SMFM committee opinion notes:

Unlike conventional karyotyping, chromosomal microarray analysis cannot detect balanced inversions, balanced translocations, or all cases of tissue mosaicism.

This is significant because there are three types of Down syndrome: Trisomy 21, the most common where a 3d copy of Chromosome 21 is present in every cell; translocation, where the extra 21st Chromosome is translocated onto another chromosome; and mosaicism, where the extra copy is only in a certain percentage of the cells. In the case of translocation, this means Down syndrome may be passed on from the parent with the translocated 21st Chromosome, making it an inheritable condition.

To complicate matters, while microarray cannot detect translocations, it would still detect the extra dosage of the third 21st Chromosome. So, a fetus with translocated Down syndrome would still report “Down syndrome” from a microarray test, but not “translocated Down syndrome.” Because karyotyping views the actual chromosomes, it is the diagnostic test for determining translocation. This means that whenever a mother receives a microarray diagnosis of “Down syndrome,” the only way for her to know for certain whether it is translocation Down syndrome–and therefore has a significant increase for the chance of having another child with Down syndrome in a subsequent pregnancy–a karyotype would still need to be done.

But, the ACOG/SMFM committee opinion does not address this need for karyotyping for a finding of trisomy. Instead, it still recommends that microarray be offered as an option for any women undergoing invasive prenatal testing, and as a replacement test for karyotyping when there is an ultrasound finding of a major structural abnormality.

The ACOG/SMFM committee opinion introduces confusion into how prenatal testing for Down syndrome is to be administered. Incorporating the new committee opinion into existing prenatal recommendations results in the following checklist. Fig. 1 attempts to demonstrate this in a flow-chart fashion, but it should be viewed as informed by the fuller description below:

  1. All pregnant women are to be offered invasive diagnostic testing based on ACOG and ACMG recommendations.
  2. If the patient initially declines invasive testing, then she is to be offered screening tests.
  3. If in the first trimester, she is to be offered nuchal translucency combined testing.
  4. If she accepts and the test reports an increased chance for Down syndrome, then she is to be offered non-invasive prenatal screening (which patients are to be offered initially if they are over the age of 35, have had a prior pregnancy with a trisomy, or have been diagnosed with a translocation).
  5. The patient is also to be offered invasive testing following a screen test with an increased-chance result.
  6. If they decline NIPS, the NIPS comes back negative, or they decline invasive testing, the patient still may have an ultrasound finding in the second trimester of a major structural abnormality.
  7. If the patient accepted the offer of invasive testing at any point along this continuum where a structural abnormality was identified by ultrasound, then the new ACOG/SMFM committee opinion instructs that microarray testing is to be offered, and that microarray replaces karyotyping.
  8. If the patient accepted the offer of invasive testing at any point along this continuum with a structurally normal fetus, she is to be offered either microarray or karyotype testing.

And that’s it, as far as the type of testing to be offered pursuant to current prenatal recommendations. I have added to this list two additional steps:

  • While no professional statement explicitly says this, it is simply better practice to offer NIPS prior to the offer of invasive prenatal testing.
    • Whereas guidelines recommend offering invasive testing initially, or, with the new opinion, after an ultrasound finding, the relatively high accuracy rates of NIPS for ruling pregnancies out for having Down syndrome should be offered prior to invasive testing.
    • The NIPS testing companies have presented research which is corroborated by anecdotal evidence from both practitioners and expectant mothers that patients are choosing to stop when they receive a negative NIPS result in most cases. Patients are relying on the low false negatives and avoiding the risk of miscarriage from invasive testing.
    • Hence the boxes offering NIPS prior to the offer of invasive testing.
  • The other critical addition to the flow chart is the additional step of “Karyotype” testing after “Microarray” testing. This is because if the microarray test finds Down syndrome, the only way to know whether that is a case of translocation is through a karyotype.

There are a few other key points about the flow chart and about the administration of prenatal testing:

  • The flow chart does not show the multitude of other screening strategies involving first and second trimester screening tests. These are covered in the ISPD updated guidelines and in ACOG Practice Bulletin No. 77, such as sequential, contingent sequential, and what ACOG describes as the testing to be offered “ideally,” integrated testing.
  • There are also two alphas-and-omegas to the administration of prenatal testing:
    1. Note that each step for testing mentions “offered“–this is because prenatal testing is not to be routine, but the result of informed consent, at each step of the way, which includes the option of declining testing at any point–hence the lines leading to “decline” as an option for both screening and invasive testing.
    2. The statements on non-invasive prenatal screening and the ACOG/SMFM microarray opinion both emphasize the need for pre- and post-test genetic counseling:

Comprehensive patient pretest and posttest genetic counseling from qualified personnel such as a genetic counselor or geneticist regarding the benefits, limitations, and results of chromosomal microarray analysis is essential.

If the array of arrows, lines, and boxes in Fig. 1 are confusing, hopefully that confusion actually makes the following point clear: that genetic counseling is essential in this new age of Down syndrome prenatal testing to understand what tests are available, what they test for, and to make an informed decision about whether to accept or decline testing at each step.

The new ACOG/SMFM committee opinion adds yet another testing option, microarray, to the mix of prenatal testing available for expectant mothers. But to know for certain what kind of Down syndrome is diagnosed, a karyotype is still needed.

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