Understanding YOUR NIPT results

I counseled a patient this week on a lesser-known genetic condition that can be detected on non-invasive prenatal testing (NIPT). Our conversation inspired me to build off my last post of basic yet essential points to consider prior to pursuing NIPT, as many of the concepts below were discussed in our session and seem important for other pregnant people to know.

As a reminder, NIPT is a screening test. The results you get are not able to tell you with 100% certainty that your pregnancy has or does not have what is being screened for.

Now, I am not an enormous fan of "The Maths", as my daughter likes to call them. Though before I get too far into this blog, I feel I need to explain three foundational concepts - in simpler "Not A Math Fan" terms, of course. I will use Down syndrome in my examples, but know that most labs that perform NIPT offer a basic panel that includes Down syndrome, trisomy 18, trisomy 13, and conditions associated with X and Y aneuploidy (i.e., the presence of an abnormal number of chromosomes in a cell.)

What makes these terms important is knowing what GROUP of people they are referring to.

• Sensitivity – the proportion of people who ARE affected with a condition who get a POSITIVE result, i.e. in NIPT, its ability to identify a pregnancy that has Down syndrome.

• Specificity – the proportion of people who ARE NOT affected with a condition who get a NEGATIVE result, i.e. in NIPT, its ability to identify a pregnancy that does not have Down syndrome.

• Positive predictive (PPV) - the proportion of people with a positive result who truly have the specific condition screened for, i.e. in NIPT, the probability that a patient with a positive result has a pregnancy with Down syndrome.

NIPT shows high sensitivity and specificity for detecting Down syndrome, trisomy 18, and trisomy 13 in pregnant people with different clinical indications (i.e., whatever the reason is they had the screen). In other words, most people who have a pregnancy with Down syndrome get a positive result and most people who do not have a pregnancy with Down syndrome get a negative result.

However, PPV really depends on the clinical indication. Consider these scenarios:

Scenario	Background Risk at 12 weeks gestation	PPV (i.e., in light of the positive result, the chance the pregnancy is truly affected)	What is affecting the PPV
A 20-year-old has an NIPT result that is positive for Down syndrome.	1/1068	48%	Down syndrome is relatively common when compared to other conditions.
A 20-year-old has an NIPT that is positive for trisomy 13.	1/7826	6%	Trisomy 13 is relatively rare when compared to other conditions.
A 42-year-old has an NIPT result that is positive for Down syndrome.	1/38	96%	The risk for Down syndrome increases with advancing maternal age.
A 42-year-old has an NIPT result that is positive for Down syndrome after the finding of an increased nuchal translucency	>1/38	>96%	There is an association between increased NT measurement and risk for Down syndrome

If I’ve lost you on the difference between sensitivity, specificity, and PPV, stop here. This is important to understand, so before continuing:

• Reread it.

• Give yourself a few minutes to process it.

• Ask a friend, email me (storkgenetics@gmail.com), or google them.

• Eat a cookie. I find this helps not only with “The Maths” but with life problems in general.

Patients ask me about Down syndrome all the time; not so much about trisomies 18 or 13, and almost never about sex chromosome aneuploidies like Turner syndrome (45, XO), Klinefelter syndrome (47, XXY), or Jacobs syndrome (47, XYY), unless they have a family history of the condition or a positive prenatal screen like NIPT.

But these lesser asked about conditions are important because they are VASTLY different clinically. While Down syndrome, trisomy 18 and trisomy 13 are associated with varying degrees of intellectual disabilities, birth defects, and life expectancies, on the spectrum of clinical presentations, sex chromosome aneuploidies tend to be much less severe.

Hence the question from my last post, "What you would do with the information you receive from NIPT?"

Say you are a 28-year-old with an NIPT result that is positive for Jacobs syndrome. The PPV is 25%. Clinically what you would expect in a person affected with Jacob syndrome is the following:

• The incidence of intellectual disabilities and multiple birth defects is not increased. Patient presentations vary with many patients having relatively few, if any, features. Of note, researchers believe that at least 85% of patients with XYY syndrome are undiagnosed. Some boys may be taller or have a larger head circumference, have issues with fine motor skills and/or coordination, mild tremors, or low muscle tone, or have involuntary movements, seizures, and asthma. There is a small but statistically significant lowering of IQ, with a mean of 10-15 points below siblings, however still within the normal range. More than 50% have special educational needs, the most common areas being speech, language, reading, and English. There is a higher incidence of behavioral issues, with ~ 20% having autism spectrum disorder and a 76% risk of ADHD. Secondary sexual development is normal though possibly delayed by ~6 months. Most men are fertile with chromosomally normal sperm. Most patients go on to live long and fulfilling lives and treatment is generally supportive.

For some patients, having a pregnancy that potentially has Jacob syndrome is very different than having a pregnancy that potentially has trisomy 13. For some, having a PPV of 25% is very different than having a PPV of 90%. For others, there is no difference. The choices they would make moving forward would remain the same.

My point in writing this, heck the point of my entire profession, is to educate patients, guiding and supporting them in whatever reproductive choice they make. And while I think it is really hard to make a decision for a given situation without being IN it, I encourage everyone to at least consider what you might do to avoid the chance of being in a given difficult position because you didn’t have all the information, whether it was knowing what was screened for, more about those screened-for conditions, or exactly what that screen can tell you.