The most common chromosomal disease is Down syndrome (trisomy 21). A person with Down syndrome can live a long life but needs constant assistance. The next frequent chromosomal diseases are trisomies 13 and 18, and Turner syndrome.

The main cause for changes in the number and structure of chromosomes is an error in parental germ cells. That means that the sperm or egg does not contain the right number of chromosomes. Errors of this kind can arise due to the elevated age of the mother as well as many environmental factors (e.g., X-ray radiation, medications, household chemistry, alcohol). Also, random errors occur in nature and not all germ cells are always of high quality.

The risk

The risk of having a baby with a chromosomal disease increases with maternal age. For a 20-year-old woman, the risk of having a baby with Down syndrome is 1:2500, but for a 37-year-old it is already 1:100 (1%). For a 40-year-old woman, the risk is already 2% and for a 45-year-old 5% and more.

Nevertheless, most babies with Down syndrome are born to young mothers because the screening tests have not detected the disease. Also, some expecting mothers decide not to take part in screening tests. The argument “all my three children are well” may not hold for the fourth one, because maternal age is higher and the risks have gone up.

The risk of having a baby with Down syndrome depending on maternal age.

Estonian practice

In Estonia, a combined screening is used to detect the risk of chromosomal diseases prenatally. The screening helps find foetuses with an elevated risk from thousands of pregnant women and then suggests additional genetic analyses. These analyses are reimbursed by the Estonian Health Fund. In the combined screening, the level of certain biomarkers in maternal blood serum is determined, the foetus is examined by ultrasound and pregnancy related risk factors are taken into account. That is all done without interfering with the foetal environment. For this reason, the combined screening is known as non-invasive and it is safe for the foetus.

The screening determines pregnant women with an elevated risk of having a baby with chromosomal disease. In case of high risk, the women are advised to confirm the diagnosis via an invasive analysis (diagnostic foetal chromosomal analysis). This is the most precise analysis that involves an invasive procedure (amniocentesis, chorion villus biopsy or cordocentesis) to get a sample of foetal DNA. In an invasive test, the foetal DNA is taken from either amniotic fluid or placenta. However, invasive procedures may cause miscarriage in 1% of cases.

Annual testing

Invasive procedures pose a small but definite risk of miscarriage (up to 1%). More than 600 invasive procedures are done in Estonia annually. Currently, the used screening tests help find 80-96% of foetuses with chromosomal diseases. The false-positive rate (the screening detects elevated risk, but the foetus is well) is 2-10%. These women go though invasive procedures to confirm that the foetus does not have a chromosomal disease. More than 90% of women that go through invasive procedures receive the answer that the foetus is well. That means that the stress, spent time and money have been in vain.

12-23% of the screening results are false-negative. This means that a foetus with chromosomal disease is not found during pregnancy. Non-detection of chromosomal disease during screening is one of the main reasons why a woman becomes aware of a child’s illness at only the third trimester.

Despite the fact that pre-natal screening has been organised in Estonia in the best possible way, current methods are not able to ensure the flawless testing of foetuses. A major drawback is the lack of precision of the screening methods in use. Therefore, it is important to apply a modern and significantly more advanced NIPT method that detects the possible additional chromosome of the foetus directly from the mother’s blood sample.

NIPTIFY is the most up-to-date screening method for chromosomal diseases

Advantages of NIPTIFY

NIPTIFY has been developed in Estonia in collaboration with KU Leuven in Belgium. Belgium and the Netherlands were the first countries in the world to offer state compensated NIPT to all pregnant women in 2017. The tests are performed in university laboratories. NIPTIFY laboratory analysis is based on well-performing standards, and data analysis uses NIPTmer software, which was developed by scientists from the Competence Centre on Health Technologies and University of Tartu.

In Estonia, NIPT tests are offered by several companies that send samples to foreign laboratories for testing. Thus, blood samples and most of the questionable amount for the test move to foreign biotechnology companies. However, Tervise-TAK offers research-based molecular diagnostics in its laboratory in Estonia. This allows you to maintain and develop the expertise of precision medicine and to provide quality medical services in our own laboratory. The benefits of testing will be directed towards further research and development and the creation of new genetic tests. Thus, every person who has made a NIPTIFY test is able to make a conscious contribution to the development of Estonian science and biotechnology.

NIPT limitations

Although NIPT is highly accurate non-invasive prenatal genetic test, it is screening test and need diagnostic confirmation in following reasons:

Studied foetal cell-free DNA has placenta origin. The NIPT results show the risk of chromosomal disease in placental tissue. There is slight theoretical and practical probability that placenta tissue has chromosomal disease but foetus inside it is still healthy.

Foetal cell-free DNA is mixed with maternal DNA. Foetal risk of chromosomal disease is calculated in distant, through maternal DNA sample. Although NIPT methods detect 4-15% foetal origin DNA in mother blood sample, and that is sufficient for reliable analysis, it may theoretically affect the outcome. Therefore the results of NIPT should be confirmed by direct, invasive diagnostic method.

NIPT methods in general may give false-positive or false-negative results in case of mosaicism. Mosaicism may occur in foetus or mother.In general, mosaicism denotes the presence of two or more populations of cells with different number of chromosomes or part of chromosomes in one individual who has developed from a single fertilized egg. In other words, mosaicism may be normal variability in smaller or larger scale if it is not fatal.

NIPTIFY test is not developed to detect sex chromosome anomalies (except Turner syndrome, X0). The test does not detect partial chromosomal copy-number variances, chromosomal microdeletions or microduplications.  NIPTIFY is valid only for single pregnancies.

Why NIPT and NIPTIFY are still screening tests?

Like other NIPT tests, NIPTIFY is a high-sensitivity prenatal testing method that evaluates the risk of certain chromosomal diseases occurring in the fetus. However, NIPTIFY is not a diagnostic test as it analyzes fetal health through a pregnant blood sample. The mother and fetal DNA are mixed in the blood sample. However, false-negative or false-positive results are still possible. The test may give false results for a variety of clinical reasons (such as placental mosaic, maternal chromosomal abnormalities, or tumors), or for technical reasons that are not dependent on the pregnant woman.

A low chromosomal risk test does not rule out other developmental abnormalities. NIPTIFY does not provide information on fetal developmental issues (such as brain or heart developmental disorders, spinal developmental disorders, fetal growth disorders, etc.). An ultrasound examination of the fetus is performed to detect such side effects.

Only a NIPTIFY result should not lead to a decision to discontinue pregnancy. In the case of a high chromosomal risk, the result is also confirmed by an invasive method (amniocentesis or chorionic biopsy). Gynecologists emphasize that despite the results of NIPT, national screening, including ultrasound, should be continued.