Noninvasive prenatal testing (NIPT) is a method used to determine the risk for the fetus being born with certain

chromosomal abnormalities A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where ther ...

, such as

trisomy 21 A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...

trisomy 18 A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...

and

trisomy 13 A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...

. This testing analyzes small DNA fragments that circulate in the blood of a pregnant woman. 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 The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...

provides the opportunity for early detection of certain chromosomal abnormalities without harming the fetus.

Background

The use of

ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...

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%. If these tests indicate an increased risk of aneuploidy, then invasive diagnostic testing is used, such as

amniocentesis Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is ne ...

chorionic villus sampling Chorionic villus sampling (CVS), sometimes called "chorionic ''villous'' sampling" (as "villous" is the adjectival form of the word "villus"), is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It ent ...

. Many women, however, feel uncomfortable with the invasive testing, because of the risk associated with miscarriage, which is around 0.5%. 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. Circulating cffDNA can be detected in maternal blood between the 5th and the 7th week of

gestational age In obstetrics, gestational age is a measure of the age of a pregnancy which is taken from the beginning of the woman's last menstrual period (LMP), or the corresponding age of the gestation as estimated by a more accurate method if available. Suc ...

, however more fetal DNA is available for analysis usually after 10 weeks, because the amount of fetal DNA increases over time. 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 Massive parallel sequencing or massively parallel sequencing is any of several high-throughput approaches to DNA sequencing using the concept of massively parallel processing; it is also called next-generation sequencing (NGS) or second-generation s ...

(MPS) and

digital polymerase chain reaction Digital polymerase chain reaction (digital PCR, DigitalPCR, dPCR, or dePCR) is a biotechnological refinement of conventional polymerase chain reaction methods that can be used to directly quantify and clonally amplify nucleic acids strands includi ...

(PCR), are currently under exploration for the detection of chromosomal aneuploidies via NIPT/NIPS. Since 2014, noninvasive testing has identified aneuploidies in chromosomes 13, 16, 18, 21, 22, X and Y, including

Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...

(caused by trisomy 21),

Edwards syndrome Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features in ...

(caused by trisomy 18),

Patau syndrome Patau syndrome is a syndrome caused by a chromosome, chromosomal abnormality, in which some or all of the Cell (biology), cells of the body contain Trisomy, extra genetic material from chromosome 13 (human), chromosome 13. The extra genetic mater ...

(caused by trisomy 13), as well as sex chromosomes aneuploidies, such as Turner syndrome (45, X) and Klinefelter syndrome (47, XXY). 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. 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. NIPT can determine paternity and fetal sex earlier in gestation than previous tests (including possibly ultrasound). It is also used to determine fetal Rhesus D, which can prevent mothers who are Rhesus D negative from undergoing unnecessary prophylactic treatment. Finally, it is used to detect

genetic mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mit ...

, 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. 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. 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.https://www.natera.com/womens-health/panorama-nipt-prenatal-screening Non-Invasive Prenatal Testing – A Potential Screening tool for early Detection of Chromosomal Abnormalities and Genetic Disorders, '
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References

Obstetrics Gynaecology Medical diagnosis