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Non-invasive Prenatal Screening: How it Works and Why it Matters

I figure if I’m going to offer up some sciencey stuff related to parenting, the best place to start is part of my professional background: prenatal genetics. I will caution that if you are going to have ANY genetic testing performed (NIPS, carrier screening, karyotype, etc.) you should consult a genetic counselor. They are awesome explainers.

If you are currently pregnant, or have been recently, you have probably heard about non-invasive prenatal screening (NIPS). Sometimes it’s referred to as NIPT (non-invasive prenatal test) but since it is not DIAGNOSTIC on its own, I think it is more commonly referred to as a screen. It’s a pretty amazing test that has been developed extensively over the last decade or so. While it used to be marketed extensively to high-risk mothers, it’s becoming increasingly standard for all pregnant women.

What is NIPS?

NIPS is a blood test, using maternal (mom’s) blood, that can detect chromosomal abnormalities in a developing fetus. A pregnant woman can have blood drawn as soon as 9 weeks or much later into their second trimester. Typically the test is validated for a relatively wide range of time but is offered around 11-18 week gestation.

What is NIPS looking for?

NIPS is looking for aneuploidy, which is an incorrect number of chromosomes. Normally, humans have 2 copies of chromosomes 1-22, in addition to 2 sex chromosomes. It is possible to check for all 23 pairs of chromosomes but typically a company will offer a standard panel of chromosomes:

21 (Downs syndrome), 18 (Edwards syndrome), 13 (Patau syndrome), X & Y

The X and Y analysis can detect sex chromosome imbalances like Turner’s syndrome (XO) and Klienfelter’s Syndrome (XXY), in addition to identifying if the fetus is female (XX) or male (XY).

Some NIPS test panels delve further into the fetus’s genome, looking for small segments of missing chromosomes called microdeletions. While there are good indications that these can be useful, many doctors aren’t particularly impressed by their validation (yet), since it is difficult to find numerous patients with these rarer conditions.

How does it work?

Fetal DNA is in Mom’s blood.

You may be asking, “How does the baby’s DNA get into the mom’s blood?” The answer is the placenta. Small fragments of DNA are sloughed off the placenta and into mom’s bloodstream. THIS is what the NIPS is measuring. It is called ccffDNA which stands for circulating cell-free fetal DNA. It’s small and fragmented but it’s enough to detect and use.

From here the testing options include:

Comparative model: Is there more material present or absent than all other chromosome material? For example, there is an extra amount of chromosome 21 material, which would mean a higher risk that the fetus has Downs Syndrome.

Sequencing model: The DNA is sequenced (i.e. read) along the base pairs. Using the same example, all base pairs are read and there is a considerably higher number of chromosome 21 reads. This method is considered more accurate.

DNA condensation and wrappingWhy is NIPS a Big Deal?

For quite some time there was a different set of parameters to assess risks of chromosomal abnormalities: Sequential Screening and a Nuchal Translucency Ultrasound

I won’t get into the specifics here, but it is basically 2 blood draws measuring specific hormones, coupled with an ultrasound measuring the back of the fetus’s neck. The values (along with other demographic information) were run through an algorithm that estimated the odds of the fetus having Downs Syndrome, Edwards Syndrome, or an Open Tube Neural Defect (issues with the brain or spinal cord). While these were (and still are) valuable tools at flagging fetuses with those potential issues, there were a large number of False Positives (test results indicating increased risk when the fetus did not have the condition.)

Many of these women would go on to have amniocentesis testing. While an amnio is a very valuable and relatively safe test, it isn’t a particularly pleasant process for the mother. A large needle is used to remove some of the amniotic fluid. The cells in the fluid are then grown in an incubator, treated, and the chromosomes analyzed. The hardest part of an amnio (I think) is the wait. It takes at least a week, but usually about 10 or more days, for enough cells to grow to analyze by visually looking at the chromosomes of the fetus.

Once NIPS was developed, it allowed for testing that was more accurate than the sequential screen + NT test. This yields far less false positives, meaning there are less unnecessary invasive procedures.

Things of Note with NIPS

Is NIPS perfect? No. But it is pretty accurate overall. This is also why it is not considered a DIAGNOSTIC test. That would be the amniocentesis.

One of the biggest issues with NIPS, are samples that are unable to yield a result. Typically there is a redraw and another attempt at analysis (in case the fetal fraction was too low) but sometimes it just doesn’t work. This is the minority of cases but it does happen. Sometimes this is due to an issue with the fetus but sometimes it is an unknown issue as to why it would not work.

Another issue is Confined Placental Mosaicism (CPM). This is where the aneuploidy is confined to the placenta and not the fetus. Since the ccffDNA is from the placenta, it would yield a positive result even if the fetus did not have a chromosomal imbalance. These results can still be valuable though since CPM can affect the efficacy of the placenta later in pregnancy.

Additionally, NIPS has the ability to (unintentionally) detect certain cancers in the pregnant mother. This can be the case if multiple aneuploids are detected or there are “chaotic” findings.

 

Do you have any experience with NIPS? Comment below with your story.

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