NIPS: More Than Just a Sex Reveal
By Kelly Landucci

Each and every pregnancy is different, and advances in medical technology are allowing us to discover more helpful information that may affect the outcome. Medical professionals can now predict the sex as early as 10 weeks with fairly good accuracy, which is a lot of fun for many expecting parents. But did you know that this screening provides clues into the chromosomal makeup of the fetus as well? This information has the potential to empower women to make more informed decisions about their pregnancy—as lfong as they understand the testing that is being ordered for them and what it can and cannot tell them.

What is NIPS?

Non-invasive prenatal screening (NIPS) starts with a simple blood draw from a pregnant woman with a gestational age of at least 10 weeks. Small DNA fragments from the placenta naturally circulate in maternal blood. NIPS involves analysis of this blood sample to screen for common trisomies and other aneuploidies (whole extra or missing chromosomes), specifically focusing on chromosomes 21, 18, 13, X and Y. Relative amounts of placental and maternal DNA are analyzed. If the ratio is off, this may indicate a chromosomal imbalance in the pregnancy. Screening for aneuploidy and Trisomy 21 (Down syndrome) in particular has been available for many years, but NIPS is a much more accurate screening test for aneuploidy than older, more traditional screening tests, such as FTS (First Trimester Screening) or the Quad Screen. With normal screening results, more women may decline invasive diagnostic testing methods, such as CVS or amniocentesis. Commercial genetic testing laboratories including Invitae, Myriad Women’s Health, Natera, Sequenom and Progenity provide their own variations of NIPS (sometimes referred to as non-invasive prenatal testing, or NIPT) for pregnant patients; results are typically available in 5-10 days.

The results

While there are a few different approaches to NIPS screening, they all provide a result that is probabilistic—not diagnostic. The most common fetal aneuploidies in the second trimester of pregnancy and at birth are:

• Trisomy 21: an extra copy of chromosome #21, resulting in Down syndrome (~1/800 liveborns)
• Trisomy 18: an extra copy of chromosome #18, resulting in Edwards syndrome (~1/5,000 liveborns)
• Trisomy 13: an extra copy of chromosome #13, resulting in Patau syndrome (~1/16,000 liveborns)
• Monosomy X: only one X chromosome, resulting in Turner syndrome (~1/2,500 liveborns)
• Trisomy X: a third copy of the chromosome, result in Triple X syndrome (~1/1,000 liveborns)
• An extra X chromosome in a male, result in Klinefelter syndrome (~1/650 liveborn males)
• An extra Y chromosome in a male, resulting in 47,XYY syndrome (~1/1,000 liveborn males)

Each NIPS result includes not only whether or not an increased risk for a chromosomal aneuploidy was identified but also the fetal fraction quotient and, in most cases, reports now include the positive predictive value (PPV)––the probability that this positive screening result actually reflects fetal DNA. PPV is heavily influenced by a woman’s prior risk for aneuploidy (ex. maternal age) and by how common a given condition is. As you can see above, some aneuploidies are much more common than others! A study done in 2017 showed a PPV of over 90% for both Trisomy 21 and 18, and a PPV of around 70% for Trisomy 13.

What does a positive result mean?

A woman whose NIPS results are positive only indicates a high risk of aneuploidy, as this is a screening test––not a diagnostic test. A diagnostic procedure such as chorionic villus sampling (CVS) or amniocentesis will be recommended as a next-step option, and is the only way to get definitive results during pregnancy.

What about a negative result?

A negative NIPS result means that it is very unlikely that the pregnancy is affected by aneuploidy but does not rule it out completely.

What about no result at all?

There are also several reasons that the laboratory may not report out a result at all. Gestational age of less than 10 weeks and high BMI for the mother are two reasons this can happen. Re-testing is not generally recommended in the context of a screening test, so the next step for women in this situation is generally diagnostic testing.

Is NIPS right for me?

NIPS is a great low-risk option for women who are content with a very good screening option and prefer not to incur the discomfort and very small risks that go along with diagnostic testing such as CVS and amniocentesis. Until recent years, pregnant women only pursued NIPS if they were considered ‘high risk’ for aneuploidy based on maternal age (over 35yo at the time of delivery).  NIPS has now also been validated in low risk women, and many women are routinely offered this testing. NIPS may be a great option for some, but many patients do not want their pregnancy medicalized––and that is OK!

There are many reasons that expecting parents may want NIPS done during pregnancy. Many parents prefer to have as much information as possible about their pregnancy as possible at each step. Whether a NIPS result is positive or negative, the patient and her partner should be aware of the range of possible results as well as options and resources for the next steps. Attending pre-test genetic counseling is a great way to better understand risks and options and to be prepared for either result.

It is important to note that a positive NIPS result doesn’t mean termination of the pregnancy is the best option, or that is has to be an option at all. The main purpose of NIPS is to provide the pregnant woman with helpful information to give her the power to choose what is best in her individual situation! Many parents who would not choose termination may still prefer to have NIPS and/or prenatal diagnosis done during pregnancy to better prepare for the birth of their child. In some cases, different arrangements may be made, such as delivery at a hospital where appropriate specialists would be available for immediate intervention. In other cases, it can help parents to have the time to prepare themselves (and family and friends) for a raising a child that differs from what they were expecting! The essay “Welcome to Holland” is a beautiful take on this by a parent of a child with Down syndrome.

Want to find out more?

Check out our Patient Stories podcast with prenatal genetic counselor Janine Mash discussing NIPS and other options for pregnant patients.

Takeaway for Patients:

• It can be fun to learn the fetal sex early in pregnancy. But NIPS is actually a medical screening test and will give you other information that you may or may not want to know!
• NIPS is a very good screening test for Trisomy 21. But it is not diagnostic and also does not rule out a number of other possible genetic issues.
• Want to speak with someone to see if NIPS is right for you? Book an appointment with a genetic counselor who has expertise in prenatal genetics.

Takeaway for Healthcare Providers:

• Looking for more support for your practice to keep up with all of the rapid changes in genetics? Check out the new Grey Genetics support packages to find the option that works best for your practice.

References & Further Reading:

• Harraway, J. “Non-Invasive Prenatal Testing.” Aust Family Physician. 46(10):735-739. Oct 2017.
• Kingsley, E. “Welcome to Holland.” A Parent’s Perspective. 1987.
• Leach, M. “On parenting a child with Down syndrome.” Down Syndrome Prenatal Testing. 30 Oct. 2013.
• Dupras, C., Birko, S., Affdal, A., Haidar, H., Lemoine, M., Ravitsky, V. “Benefits, challenges, and ethical principles associated with implementing noninvasive prenatal testing: a Delphi study.” CMAJ Open. 6(4): E513-E519. Oct-Dec 2018.