A brief history of non-invasive prenatal screening (NIPS)

Non-invasive prenatal screening (NIPS), also known as cell-free fetal DNA screening, is now available to pregnant women across the U.S. It first became available in 2011, and in 2012, ACOG (the American College of Obstetricians and Gynecologists) approved its use as an alternative option for screening in pregnant women in certain increased risk categories.¹ At that time, there was insufficient data to say that it should be an option for all pregnancies. In 2016, ACOG published an updated Practice Bulletin discussing the pros and cons of all prenatal screening, including NIPS, and recommended that women be educated about, and make an informed decision regarding, the screening method that best meets their needs.² SMFM (the Society for Maternal-Fetal Medicine) reported a similar conclusion in their 2015 statement.³ In 2016, ACMG (the American College of Medical Genetics and Genomics) published a statement recommending that all pregnant women be informed about NIPS, along with the appropriate counseling and education about the possibility of negative, positive or no call results, and any follow up diagnostic testing that may be available.⁴

NIPS screening is done on a sample of maternal blood drawn at any time after 10 weeks gestation. A pregnant woman’s blood always contains a bit of DNA from her pregnancy, and laboratories use different methods to capture, test and interpret that DNA to report back a lower or higher risk for specific chromosomal conditions. The three that are commonly reported in a NIPS study are trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome). Some laboratories will also report an increased suspicion of microdeletions (small missing pieces of chromosomes) that are related to known syndromes, and an increased risk of sex chromosome abnormalities.

How is NIPS different from maternal serum screening?

Screening for risk of conditions such as open neural tube defects and some fetal chromosome abnormalities (trisomy 21, trisomy 18) through the mother’s blood has been available since the late 1980’s. The maternal serum alpha fetoprotein screen (MSAFP) was first developed to detect the higher levels of this protein often found in maternal blood in pregnancies affected with an open neural tube defect (such as spina bifida or anencephaly). Soon after, it was noted that some women carrying a baby with Down syndrome had lower levels of this same protein in their blood. Throughout the years, more markers have been added to the maternal serum screens (the triple screen, quad screen, first trimester screen) to increase the detection of trisomy 21, and in some screens, trisomy 18, but all of these screens carry a high false positive rate. This means that the use of maternal serum screening has led many women to receive a positive screening blood test, make a decision about invasive confirmatory testing such as amniocentesis, and then find out that their baby did not have a chromosome abnormality. In other words, they received a false positive result. In the 1990s and early 2000s, this type of blood screening test was further improved, but it has always carried a high false positive rate, meaning that many women and couples may experience a high level of anxiety during their pregnancy for no reason due to this screen.

What is special about NIPS?

NIPS examines DNA from the pregnancy. We use the word pregnancy, because much of the fetal DNA found in the mother’s blood comes from the placenta, not the baby itself.⁵ The placenta and baby come from the same fertilized egg, however, sometimes changes can happen in the placenta, only, that do not affect the baby’s development. For this reason, a positive NIPS result can still possibly be a false positive. This is one reason why the name was changed from NIPT (non-invasive prenatal testing), to NIPS (non-invasive prenatal screening). When a positive or high-risk NIPS result is received, diagnostic testing is still recommended to confirm the results.

Some specific differences between NIPS and maternal serum screens:

1) NIPS can be performed any time in the pregnancy after 10 weeks. This is to ensure that there is an adequate amount of cell free fetal DNA in the maternal blood. MSAFP and other maternal serum screens can only be done within a very specific time range of pregnancy, and the patient’s gestational age is required to interpret the results.

2) NIPS does NOT test for open neural tube defects. It is recommended that pregnancies screened by NIPS undergo either ultrasound assessment, an MSAFP test (measuring only AFP), or both, to screen for these at the appropriate gestational age.²

3) NIPS will screen for trisomy 21, trisomy 13 and trisomy 18. While the positive predictive value (PPV) for trisomy 21 is very high, the PPVs for trisomy 13 and 18 are generally less, due to some biological factors. Maternal serum screens will often screen only for trisomy 21, while a few will provide an increased risk result for trisomy 18.

4) NIPS is reliant on enough cell free fetal DNA to be present to provide an interpretation. If there is not enough cell free fetal DNA present in the mother’s blood, the testing will not yield a result.

5) NIPS may occasionally yield confusing and uninterpretable results that may require a repeat NIPS, a diagnostic test such as CVS (chorionic villus sampling) or amniocentesis, or other testing to clarify results. There are some NIPS cases that cannot be explained or clarified until after birth, or possibly not at all. Maternal serum screen positive results are usually clarified by ultrasound or a diagnostic CVS or amniocentesis test.

6) NIPS is usually able to determine the chromosomal sex of the baby, as well as risk for some sex chromosome abnormalities. Maternal serum screening cannot provide this information.

Please return to Metis on the Move in the future to read the next installment of our blog series on how NIPS has changed the world of prenatal screening. Our next blog will discuss different NIPS methodologies currently in use, and the unanticipated results that can possibly come from NIPS.

References

1. Committee Opinion: Noninvasive Prenatal Testing for fetal Aneuploidy. ACOG. No 545: December 2012

2. Practice Bulletin No 163 Summary: Screening for Fetal Aneuploidy. Obstet Gynecol 2016 May;127(5):979-981.

3. Society for Maternal-Fetal Medicine Statement: clarification of recommendations regarding cell-free DNA aneuploidy screening. Am J Obstet Gynecol,2015,213(6):753-754.

4.  ACMG Statement: Noninvasive prenatal screening for fetal aneuploidy,2016 update: a position statement of the American College of Medical Genetics and Genomics. Anthony R. Gregg, et al. Genet in Med,2016,18(10):1056-1065.

5. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks’ gestation: relation to maternal and fetal characteristics. G. Ashoor et al.Ultrasound Obstet Gynecol,2013,41/26-32.

Joy Redman, MS, CGC, MBA

Joy is a Trusted Advisor for Metis Genetics.  She is a board-certified genetic counselor with a long time interest in the translation of genetic information between the laboratory and healthcare providers. She has practiced clinically in both the prenatal and ophthalmology settings; educating patients about the risks and benefits of genetic testing to help them make decisions regarding their own healthcare. She has worked in a variety of laboratory settings; each one focusing on education about genetic test offerings as the field has evolved so that clinicians are able to provide the best testing options to each patient.