The nonmaleficent role of NIPT

ACMG 2013 Poster Presentation

ACMG 2013 Poster Presentation

At last week’s ACMG Annual Clinical Meeting, I presented a poster titled “The Ethics of Non-Invasive Prenatal Testing.” It turns out that the logic of my argument could very well be reflected in practice guidelines that are soon-to-be-released. I doubt the force of my abstract submitted last winter is to account for the change. But, it is a bit ironic that because NIPT will cause a test with risk to potentially have greater risk, NIPT has justified itself being inserted as a step before the test with risk. Read on, as I assure you, this will make sense. 

I regularly write about how the rules of the game of prenatal testing changed in 2007. Up until that time, only women over the age of 35 were recommended to be offered prenatal testing for Down syndrome. One of the stated rationales for that age as the cut-off was that the chance of having a child with Down syndrome and the chance of having a miscarriage were about even; therefore, the logic went, that age was justified since a few studies had found women who said they would be willing to risk a miscarriage in order to find out if their child had Down syndrome.

Fig. 1 Inverse relationship

Fig. 1 Inverse relationship

The age limit was lifted with the recommendations issued in 2007. The new guidelines recommended that all expectant mothers be offered both prenatal screening and diagnostic testing. The justification for the offer of screening testing was due to the accuracy of the then-new first trimester combined test–where the measurement of the fetus’s nuchal fold is combined with measurements taken from a maternal blood sample–equaled the accuracy of the second-trimester quad test (a test based just on a maternal blood sample). The recommendations for offering diagnostic testing to all women were based on then-current studies that found where invasive tests were performed at experienced facilities by experienced professionals, the risk of miscarriage was much lower than the percentage typically quoted of 1% for amniocentesis and 2% for CVS. This dynamic is depicted in Fig. 1.

So, that is the current standard of care: all expectant mothers are to be offered prenatal screening and diagnostic testing. The ACMG guidelines made it even clearer: expectant mothers are to first be offered diagnostic testing, and, if they refuse, then offer screening testing. The introduction of NIPT, however, upends the justification for the universal offering of prenatal diagnostic testing.

At the time I had submitted my abstract, it was largely just a matter of logic that increased uptake of NIPT would result in fewer invasive procedures. Indeed, NIPT labs and the media were reporting how NIPT could spare hundreds of thousands of women from having an invasive test, and risk a miscarriage. Instead, they could have NIPT and choose to rely on the high accuracy rate of that test; in most cases, relying on a negative result as an accurate-enough assessment without risking a miscarriage to receive confirmation through invasive testing. And, as it turns out, actual experience bears this logic out.

No less than four other poster presentations reported that with the increased uptake of NIPT, the number of invasive tests had decreased–plummeting in one instance by 40%. But, what was not reported–besides by my poster–was the other consequence of invasive procedures diminishing in number.

Fig. 2 NIPT & Inverse relationship

Fig. 2 NIPT & Inverse relationship

The 2007 guidelines were based on studies that found an inverse relationship with invasive testing: as experience went up, risk of miscarriage from a procedure went down. This stands to reason: as a professional becomes more experienced performing invasive testing, the risk of miscarriage from that procedure would diminish. But, this inverse relationship would hold true if the arrows pointed the other way. As shown in Fig. 2, then, as more expectant mothers accept NIPT, they opt to avoid invasive testing, causing the number of those procedures to go down, and, as a result, then the risk of miscarriage increases.

Hence the irony: one of the main selling points of NIPT is to reduce the number of invasive procedures, thereby sparing mothers from being exposed to a procedure-related miscarriage. As this becomes reality, then, the risk of miscarriage actually increases from the diminishing number of invasive procedures. And, therefore, NIPT can be justified as an intermediary step prior to offering diagnostic testing.

Fig. 3 Revised prenatal testing protocol

Fig. 3 Revised prenatal testing protocol

It can be argued, then that the bioethical principle of nonmaleficence justifies revising the current standard of care. Nonmaleficence is the bioethical principle that almost everyone is familiar with. It is encapsulated in the well-known edict of the Hippocratic Oath: “first, do no harm.” As the alpha and omega guiding principle of medical care, nonmaleficence can then justify inserting NIPT as an intermediary step prior to offering diagnostic testing. Fig. 3 illustrates this step-wise offering of prenatal testing:

  1. Offer expectant mothers prenatal screening testing;
  2. If the screening test indicates a higher likelihood of having a child with Down syndrome, or there exist other recognized factors to consider the mother “high risk,” e.g. advanced maternal age, prior Down syndrome pregnancy, then offer NIPT;
  3. If the NIPT result is positive, then offer diagnostic testing.

Through this step-wise offering of screening testing of increasing accuracy, it truly serves a screening process: screening out all but those women who may be carrying a child with Down syndrome who may then be subjected to the possible risk of miscarriage from undergoing invasive diagnostic testing.

On the basis of “do no harm,” this revised, step-wise process can be ethically justified. There remain other factors that impose tension into this protocol, namely issues of time and the bioethical principle of autonomy. I plan on writing on those in the posts for the beginning of next week. But, as I said, there are imminent revisions which are to be published that may adopt this process. I will report on those revised guidelines when they are available.

What do you think? Should expectant mothers first be offered screening testing or NIPT prior to being offered invasive diagnostic testing? Why or why not?


  1. It should just be standard, right off the bat. NIPT run instead of screening, then offer amnio as a confirmation. At which point the choice for a confirmed positive should be either abortion or a loss of coverage for the remainder of the pregnancy. Society should not be forced to bear these costs.

  2. Julia B says:

    If you look at the numbers, the “problem” with an increase in miscarriage rate due to fewer invasive procedures being performed is more than compensated for by a reduction in the number of invasive procedures that have to be performed due to fewer false positives after the NIPT. Assuming a false positive rate of 5% for the combination test, if you test 100,000 women, there will be 5,000 false positives, then using s miscarriage rate of 1% there are 50 miscarriages, or 0.5% there are 25 miscarriages. For the NIPT, the rate of false positives is only 0.3%, therefore in 100,000 women this means only 300 women have unnecessary invasive testing, with 3 miscarriages assuming a high miscarriage rate, and virtually none if doctors are skilled in performing the invasive tests without causing accidental miscarriage. Offering the NIPT first will decrease the number of invasive procedures and also the number of miscarriages when compared to the combination test, even if doctors’ skills in the invasive procedures decreases due to fewer invasive procedures being performed.

    • A fair point and I appreciate you making it. However, studies have yet to show that NIPS has the advertised accuracy rates in low-risk populations–instead, the studies show that NIPS only has its stated accuracy rate as a second-tier screen.


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