Noninvasive prenatal testing (NIPT) is a method used to determine the risk for the fetus being born with certain
chromosomal abnormalities, such as
trisomy 21,
trisomy 18 and
trisomy 13.[1][2][3] This testing analyzes small DNA fragments that circulate in the blood of a pregnant woman.[4] Unlike most DNA found in the nucleus of a cell, these fragments are not found within the cells, instead they are free-floating, and so are called
cell free fetal DNA (cffDNA). These fragments usually contain less than 200 DNA building blocks (base pairs) and arise when cells die, and their contents, including DNA, are released into the bloodstream. cffDNA derives from placental cells and is usually identical to fetal DNA. Analysis of cffDNA from
placenta provides the opportunity for early detection of certain chromosomal abnormalities without harming the fetus.[5]
Background
The use of
ultrasound and biochemical markers to detect aneuploidies is usually done in the first and / or second trimester of pregnancy. However, both of these approaches have a high rate of false positive results of 2–7%.[6] If these tests indicate an increased risk of aneuploidy, then invasive diagnostic testing is used, such as
amniocentesis or
chorionic villus sampling. Many women, however, feel uncomfortable with the invasive testing, because of the risk associated with miscarriage, which is around 0.5%.[7] Noninvasive prenatal testing is an intermediate step between prenatal screening and invasive diagnostic testing. The only physical risk associated with the procedure is the blood draw and there is no risk of miscarriage.[8]
Circulating cffDNA can be detected in maternal blood between the 5th and the 7th week of
gestational age,[9] however more fetal DNA is available for analysis usually after 10 weeks, because the amount of fetal DNA increases over time.[10] cffDNA, RNA and intact fetal cells can all be used to assess the genetic status of the fetus non-invasively. Recent advances in DNA sequencing, such as
massive parallel sequencing (MPS) and
digital polymerase chain reaction (PCR), are currently under exploration for the detection of chromosomal aneuploidies via NIPT/NIPS.[11][12][13][14]
Since 2014, noninvasive testing has identified aneuploidies in chromosomes 13, 16, 18, 21, 22, X and Y, including
Down syndrome (caused by trisomy 21),
Edwards syndrome (caused by trisomy 18),
Patau syndrome (caused by trisomy 13), as well as sex chromosome aneuploidies, such as Turner syndrome (45, X) and Klinefelter syndrome (47, XXY).[15][16][17] These methods of cffDNA sequencing have sensitivity and specificity rates greater than 99% in identifying Trisomy 21. Sensitivity and specificity rates are lower for other aneuploidies, such as trisomy 18 (97–99% and > 99%, respectively), trisomy 13 (87–99% and > 99%, respectively), and 45, X (92–95% and 99%, respectively). The low false positive rate (1–3%) is one of the advantages of NIPT which allows pregnant women to avoid invasive procedures.[18] In the UK the Advertising Standards Authority has stated that one should not quote “Detection Rate” figures unless the figures are accompanied by (i.e. alongside)a robust "Positive Predictive Value" figure; and a clear explanations about what both figures mean.[19]
NIPT can determine paternity and fetal sex earlier in gestation than previous tests (including possibly ultrasound).[20] It is also used to determine fetal Rhesus D, which can prevent mothers who are Rhesus D negative from undergoing unnecessary prophylactic treatment.[21][22] Finally, it is used to detect
genetic mutations, such as
duplications or
microdeletions, including 1p, 5p, 15q, 22q, 11q, 8q, and 4p. The sensitivity and specificity of these tests, however, for most have not yet been validated.[8]
The
Natera SMART study however has shown that most cases of 22q11.2 deletion can be detected using SNP based NIPT/NIPS (Panorama) including smaller nested deletions whilst still maintaining a low false positive rate.[23] Single nucleotide polymorphism (SNP) NIPT can also detect Triploidy and can differentiate between maternal and "fetal" DNA which reduces the redraw rate and allows determination of gender for each fetus in twin pregnancies and can be done from 9 weeks of pregnancy.[24][25]