A blood test that can be done during pregnancy, to detect genetic disorders in the fetus.
This article is pending medical review.
Written by Sophie Oppelt and Julian Zeegers
Reviewed by Alizeh Ahsan and Darina Obuhova
Edited by Juliëtte Gossens
There are a lot of traceable components in your bloodstream (meaning they can be detected via, for example, a blood test), including genetic information from different tissues of the human body. This is because, as your cells die off and grow new cells, a bit of DNA is released into the surrounding tissue and eventually into the blood. This is called cell-free DNA (cfDNA). When you’re pregnant, about 10% of cell-free DNA in your blood actually comes from your baby’s placenta, which is usually identical to your baby’s DNA. This is called cell-free fetal DNA (cffDNA – two f’s!). Based on this concept, non-invasive prenatal testing (NIPT) was developed. This method can be to investigate any genetic abnormalities of the fetus non-invasively while it’s still inside your uterus.
What we're covering
To carry out NIPT, your doctor only needs to draw blood from you, the pregnant person. Then, lab technicians perform a technique called whole genome sequencing, which essentially allows them to read the entire genome (the genetic code) of your fetus. Cell-free fetal DNA length is shorter than that of your own cell-free DNA, whereby they can be distinguished from one another. Theoretically, NIPT allows scientists to look at all genetic errors present in the genome, but in practice the test is mainly used for the screening of the common trisomies 13, 18 and 21. These conditions are typically characterized by the presence of an extra chromosome in each cell of the body. You can read more about these common trisomies here.
NIPT can also be used to detect other types of aneuploidies or big copy number changes (for example, part of the genome being present twice in each cell). These include several sex chromosome aneuploidies (such as Turner syndrome or Klinefelter syndrome), variations in the structure of chromosomes, some monogenic diseases (which involve an error in a single gene, such as in cystic fibrosis), and trisomies that are not the trisomy 13, 18, or 21 that we mentioned earlier (1-4).
It is important to keep in mind that NIPT is a screening method and not a diagnostic tool – it can only raise the suspicion that something’s going on. This means that a positive NIPT result (which would indicate an error in the genome of your fetus was found) always requires invasive testing for confirmation. You can read more about invasive testing here.
Advantages of NIPT
The major advantage of NIPT is that less invasive testing is needed, like amniocentesis or chorionic villus sampling (more about this here). This is because without NIPT, the only way to test the fetus’ genetic material is through this invasive testing. Since invasive testing carries a small (but significant) risk of complications such as miscarriage, using NIPT can reduce the risks pregnant people have to undergo: if the result is negative, invasive testing is usually not needed. For example, the TRIDENT-1 study implemented NIPT for pregnancies in the Netherlands with high risk for genetic abnormalities. This led to a reduction of 62% in using invasive testing methods (2).
NIPT has also been proven to be an accurate and cost-effective method for assessing genetic abnormalities in a fetus. The test has been shown to have very high sensitivity and specificity. Especially for the three common trisomies 13, 18, and 21, sensitivities of more than 94% were reported (5, 6). This means that out of 100 pregnancies with one of those trisomies, about 94 of them were detected using NIPT, missing only 6.
Limitations of NIPT
Even though NIPT is a painless, non-invasive method, it also has several limitations (7, 8).
For NIPT to work most effectively, the fetal fraction (which is the proportion of cffDNA [explained above] compared to all of the cell-free DNA in your blood) should be at least 4%. NIPT most often fails because this fetal fraction is too low. This happens more frequently in pregnant people with a high body mass index (BMI) (9), but it’s unknown why.
Some samples can’t be interpreted with certainty due to other biological reasons, for example if you have genetic abnormalities yourself, if you have cancer, or if your pregnancy was a case of non-identical vanishing twins (7, 8). This is a twin fetus that is not viable (meaning it didn’t survive) and is often not recognized. Tissue from its placenta can remain detectable in a pregnant person for quite a while. Non-identical twins come from different eggs, meaning their genetic information is different. A vanishing twin can therefore potentially lead to an incorrect NIPT result (8).
It is also possible that the genetic information of your fetus is different from that in the placenta, which is also called fetoplacental mosaicism (7, 8). Mosaicism is the condition in which genetic errors are only present in certain tissues or cells and absent in others. In case of fetoplacental mosaicism, it means that cells with errors are only present in the placenta but not in the baby itself. As explained above, the cffDNA assessed by NIPT originates from the placenta, meaning that NIPT results can, in some cases, differ from findings in cells from the baby. In the most extreme case, a cell line with errors may be restricted to the placenta entirely with really no traces in other tissues, known as confined placental mosaicism (CPM) (8, 10). CPM occurs in about 1% of clinically recognized pregnancies (11). This may lead to false positive results in NIPT – meaning NIPT says there’s a genetic error present in the fetus, but in reality, it’s only present in the placenta.
Costs of NIPT
NIPT costs depend on the country and can range between $795 to $2900 according to literature (12). Likewise, the coverage of costs by your health care system varies between countries (13).
Through the TRIDENT-2 project (2), NIPT became available to all prospective parents in the Netherlands. To make the test accessible to most people, NIPT tests are available for €175, which is the same as the costs for first trimester combined testing (which consists of a special ultrasound examination and two blood tests). The remaining costs for NIPT are covered by subsidies from the Dutch government.
In Scandinavian countries, the costs for NIPT are also partially or fully covered by health insurance. However, patients in central Europe such as Germany, Austria, Poland, and several other countries, have to carry the whole cost for NIPT analysis themselves (13).
NIPT Around the World
NIPT in Europe
Throughout the last decade, NIPT has been implemented as a screening procedure for trisomy 13, 18, and 21, along with sex chromosome aneuploidies, in five nations. More extensive NIPT for genome-wide testing is currently available in Belgium, the Netherlands, Lithuania, Greece, Cyprus and Italy (13).
Only Belgium and the Netherlands have made NIPT available to all pregnant parents. Most other European countries only offer this examination for high-risk pregnancies (meaning there have been other signs or factors that increase the likelihood that there are genetic abnormalities in the fetus). As a result, more than 75% of parents in Belgium choose to have NIPT performed. In the Netherlands, Austria, Italy and Spain, 25%-50% of prospective parents use the test. In most other European countries where NIPT is available, the percentage ranges between 5-25% (13).
NIPT in the United States of America
In the USA, there are no nationwide laws governing or restricting NIPT. As a result, it is commonly used and coverage depends on your health insurance. Only few US insurance providers pay for NIPT. Throughout the states of America, between 25% to 50% of all pregnant parents obtain NIPT. (13)
NIPT in China
NIPT was initially made available in 2011 in Hong Kong and the Chinese mainland, but the costs are not covered. Since mainland China and Hong Kong have different healthcare administrations, NIPT is applied differently in each location.
The recent NIPT price ranges from RMB 860 to 2,600 (USD $130 to $380), and there are regional differences in funding coverage. (14)
If you're interested in having NIPT done during your pregnancy, ask your doctor or midwife what your options are and whether NIPT is right for you!
Meck J, Kramer Dugan E, Matyakhina L, Aviram A, Trunca C, Pineda-Alvarez D, et al. Non-Invasive Prenatal Screening for Aneuploidy: Positive Predictive Values Based on Cytogenetic Findings. American journal of obstetrics and gynecology. 2015;213(2):214.e1-5. DOI: 10.1016/j.ajog.2015.04.001
Van der Meij KRM, Sistermans EA, Macville MVE, Stevens SJC, Bax CJ, Bekker MN, et al. TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands. Am J Hum Genet. 2019;105(6):1091-1101.DOI: 10.1016/j.ajhg.2019.10.005
Petersen AK, Cheung SW, Smith JL, Bi W, Ward PA, Peacock S, et al. Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory. Am J Obstet Gynecol. 2017;217(6):691.e1-e6. DOI: 10.1016/j.ajog.2017.10.005
Zheng J, Lu H, Li M, Guan Y, Yang F, Xu M, et al. The Clinical Utility of Non-invasive Prenatal Testing for Pregnant Women With Different Diagnostic Indications. Front Genet. 2020;11:624. DOI: 10.3389/fgene.2020.00624
Stokowski R, Wang E, White K, Batey A, Jacobsson B, Brar H, et al. Clinical performance of non-invasive prenatal testing (NIPT) using targeted cell-free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies. Prenat Diagn. 2015;35(12):1243-1246. DOI: 10.1002/pd.4686
Taylor-Phillips S, Freeman K, Geppert J, Agbebiyi A, Uthman OA, Madan J, et al. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open. 2016;6(1):e010002. DOI: 10.1136/bmjopen-2015-010002
Health Quality Ontario. Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions: A Health Technology Assessment. Ont Health Technol Assess Ser. 2019;19(4):1-166.
Benn P. Non-Invasive Prenatal Testing Using Cell Free DNA in Maternal Plasma: Recent Developments and Future Prospects. J Clin Med. 2014;3(2):537-565. DOI: 10.3390/jcm3020537
Harraway J. Non-invasive prenatal testing. Australian Family Physician. 2017;46(10):735-739
Mardy A, Wapner RJ. Confined placental mosaicism and its impact on confirmation of NIPT results. Am J Med Genet C Semin Med Genet. 2016;172(2):118-122. DOI: 10.1002/ajmg.c.31505
Kalousek DK, Dill FJ. Chromosomal mosaicism confined to the placenta in human conceptions. Science. 1983;221(4611):665-667. DOI: 10.1126/science.6867735
So Yeon Kim, Seung Mi Lee, Jong Kwan Jun, You Jung Han, Min Hyoung Kim, Jae-Yoon Shim, et al. Prospective observations study protocol to investigate cost-effectiveness of various prenatal test strategies after the introduction of noninvasive prenatal testing. BMC Pregnancy and Childbirth. 2018;18(1):307. DOI: 10.1186/s12884-018-1930-y
Gadsbøll K, Petersen OB, Gatinois V, Strange H, Jacobsson B, Wapner R, et al. Current use of noninvasive prenatal testing in Europe, Australia and the USA: A graphical presentation. Acta Obstet Gynecol Scand. 2020;99(6):722-730. DOI: 10.1111/aogs.13841
Ravitsky V, Roy M, Haidar H, Henneman L, Marshall J, Newson AJ, et al. The Emergence and Global Spread of Noninvasive Prenatal Testing. Annual Review of Genomics and Human Genetics. 2021;22(1):309-338. DOI: 10.1146/annurev-genom-083118-015053
Please note: the information we provide to you here is for educational purposes only. If you’re experiencing any discomfort or have any complaints or questions about your health, please contact your doctor or other relevant health professional. We don’t provide medical advice.