Types of Prenatal Diagnosis
There are several types of prenatal diagnosis to check for congenital abnormalities in the fetus, in addition to NIPT (New Prenatal Diagnosis).
Among them are "non-diagnostic tests" and "diagnostic tests." This article introduces what each test is, their characteristics, and when they are performed.
Table of Contents
Non-Diagnostic and Diagnostic Tests
As mentioned earlier, there are two types of prenatal diagnosis: non-diagnostic tests and diagnostic tests. Simply put, as the names suggest, non-diagnostic tests are tests that serve as a guide to the condition of the fetus (although some are quite accurate), while diagnostic tests are tests that can diagnose the condition of the fetus with 100% certainty. Below, we will explain the specific types and contents of these tests, so please check if you are interested in prenatal diagnosis.
Non-Diagnostic Tests
Non-diagnostic tests are conducted using only ultrasound (echo) or blood tests, which do not increase the risk of miscarriage. Depending on the type of test, it can be performed from early pregnancy. Traditional non-diagnostic tests, such as maternal serum markers and combined tests, were not very accurate, but the recently developed NIPT (New Prenatal Diagnosis) boasts high accuracy with just a blood test.
However, even if a non-diagnostic test results in a positive indication of a possible chromosomal abnormality, the diagnosis is not definitive. If desired, you can undergo definitive tests such as amniocentesis or chorionic villus sampling.
Maternal Serum Marker (Quad Test)
In the maternal serum marker test, blood is drawn from the mother, and four proteins derived from the fetus (four serum markers) are analyzed. This allows for the detection of the possibility of Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and open spina bifida.
The values of these serum markers fluctuate as the weeks of pregnancy progress, but if the fetus has the target disease of the test, abnormal values will be shown.
The test results are determined by considering factors such as the mother's age-specific probability, the fluctuations of the four markers according to the gestational week, the mother's weight, family history, and the presence of type 1 diabetes. The testing period is mainly between 15 to 18 weeks, and it takes about two weeks for the results to be obtained.
Combined Test
The combined test is a diagnostic test that uses a combination of ultrasound and blood tests. By combining these two tests, the diagnostic accuracy for Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18) is increased.
In the ultrasound test, the nuchal translucency (NT), which is the swelling at the back of the fetal neck, is measured. In the blood test, the values of two protein components derived from the placenta (two serum markers) are measured.
The results of the combined test are diagnosed based on factors similar to those of the maternal serum marker test, such as the mother's age-specific probability, NT measurement, protein component values, gestational week, mother's weight, family history, and the presence of type 1 diabetes. One point to note is that the ultrasound test may not be possible depending on the fetal position on the day of the test. The testing period is between 11 and 13 weeks, and it takes about two weeks to obtain the results.
NIPT (New Prenatal Diagnosis)
In the mother's blood, there are fragments of DNA derived from the fetus. This test measures the possibilities of Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13) by diagnosing these DNA fragments.
In NIPT (New Prenatal Diagnosis), the information of each DNA fragment is first analyzed through a blood test. Then, by examining the quantitative ratio of these DNA fragments derived from specific chromosomes, changes in specific chromosomes are identified, and compared with standard values to determine whether the result is positive or negative.
For example, normally there are two copies of chromosome 21, but if the fetus has Down syndrome, there will be three copies. As a result, the proportion of chromosome 21 in the fetus will be 1.5 times the normal amount, leading to a positive test result.
The accuracy of NIPT (New Prenatal Diagnosis) is quite high, but it is a predictive test and does not provide a definitive diagnosis. Therefore, to confirm the diagnosis, it is necessary to undergo amniocentesis or chorionic villus sampling.
Diagnostic Tests
Non-diagnostic tests are used to investigate probabilities and serve as a guide, while diagnostic tests provide a definitive diagnosis. Diagnostic tests can accurately determine if the fetus has chromosomal abnormalities, but they involve inserting a needle into the abdomen to collect amniotic fluid or chorionic villi, which carries a risk of miscarriage. The probability of this risk is about 1/100 for chorionic villus sampling and 1/300 for amniocentesis.
Due to the above risks, many medical institutions recommend non-diagnostic tests, which do not have these risks, instead of diagnostic tests. If you have a strong desire to confirm the diagnosis, be sure to consult with your doctor thoroughly before undergoing the test.
Amniocentesis
In the amniotic fluid within the uterus, there are cells derived from the fetus. Amniocentesis is a test in which a needle is inserted into the mother's abdomen to collect amniotic fluid while observing the inside of the abdomen with an ultrasound image. The fetal cells in the amniotic fluid are then cultured to check for changes in the shape and number of chromosomes.
Amniocentesis covers a wide range of chromosomal disorders. The testing period is after 15-16 weeks of pregnancy, and it takes about 2 weeks to get the results from the time of specimen collection.
As previously mentioned, amniocentesis involves inserting a needle into the abdomen to collect amniotic fluid, which carries many risks. There is a danger of complications such as rupture of membranes, bleeding, intrauterine infection, premature birth, amniotic fluid embolism, and maternal injury (to blood vessels or intestines) due to puncture. Additionally, there is a possibility of miscarriage or stillbirth in about 1 in 300 cases, so careful consideration and caution are necessary when undergoing the test.
Furthermore, the items that can be tested are limited. Even if the test does not detect the possibilities of Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), or Patau syndrome (trisomy 13) and a normal diagnosis is given, it is still possible for the baby to be born with other conditions, such as heart disease.
Chorionic Villus
The "chorionic villi" in chorionic villus sampling refer to the part that will become the placenta in the future. Chorionic villus sampling involves inserting a needle into the mother's abdomen to collect chorionic cells while observing the inside of the abdomen with an ultrasound scan, and checking for changes in the shape and number of chromosomes.
Like amniocentesis, chorionic villus sampling can detect the presence of a wide range of chromosomal disorders.
The testing period is between 11 and 14 weeks, and it usually takes about 2 to 3 weeks to get the test results.
The risks are similar to those of amniocentesis.
Since it is a test that involves inserting a needle into the abdomen, there are risks of complications such as rupture of membranes, bleeding, intrauterine infection, premature birth, and maternal injury (to blood vessels or intestines) due to puncture.
Moreover, there is a possibility of stillbirth in about 1 in 100 cases. Because the risk of stillbirth is higher than with amniocentesis, fewer medical institutions are willing to perform this test.
Like amniocentesis, this test also has its limitations. It may not accurately reflect the condition of the fetus. Specifically, about 1% of cases involve a condition called confined placental mosaicism (where the placenta has chromosomal changes while the fetus is normal). In this case, even if the test result is positive, the child may be born without chromosomal disorders. Additionally, since the testable items are limited, the child may be born with other conditions such as heart disease even if the test results are normal.
As we have explained various prenatal diagnoses so far, it is important to note that there is no "perfect" prenatal diagnosis that can eliminate all concerns. Non-diagnostic tests provide only a guideline and cannot definitively diagnose the presence of chromosomal disorders, while diagnostic tests can definitively diagnose but come with significant risks and limited scope.
It is important to discuss thoroughly with your partner, receive detailed explanations from your doctor, and make a well-considered decision when opting for prenatal diagnosis.
Accuracy of NIPT (New Prenatal Diagnosis)
Let's focus on NIPT (New Prenatal Diagnosis), which has become a popular choice for many women as a prenatal diagnosis, and examine the accuracy of its diagnostic results. It is no exaggeration to say that the greatest feature of NIPT (New Prenatal Diagnosis) is its high accuracy.
Down Syndrome (Trisomy 21)
For example, the table below shows the negative predictive value and positive predictive value of Down syndrome (trisomy 21) when NIPT (with a sensitivity of 99.1%) is performed at 12 weeks of pregnancy.
| Mother's Age | Frequency of Disease | Positive Predictive Value | Negative Predictive Value |
|---|---|---|---|
| 30 years old | 1/626 (0.16%) | 61.3% | 99.99% |
| 35 years old | 1/249 (0.40%) | 80.0% | 99.99% |
| 40 years old | 1/68 (1.47%) | 93.7% | 99.99% |
| 45 years old | 1/16 (6.25%) | 98.5% | 99.99% |
The disease frequency mentioned here refers to the probability that a mother at 12 weeks of pregnancy is carrying a child with Down syndrome (trisomy 21). The positive predictive value refers to the probability that a child will actually have Down syndrome (trisomy 21) when the NIPT (New Prenatal Diagnosis) result is positive. The negative predictive value is the opposite.
It can be seen that the higher the mother's age, the higher both the disease frequency and the positive predictive value.
For example, at the age of 30, the disease frequency is 0.16%, and the positive predictive value is quite high at 61.3%, while the negative predictive value is 99.99%. This demonstrates the high accuracy of NIPT (New Prenatal Diagnosis).
Edwards Syndrome (Trisomy 18)
Next, let's examine the accuracy of Edwards syndrome (trisomy 18). Edwards syndrome (trisomy 18) is a more severe condition than Down syndrome. Therefore, both the probability of a fetus having it during pregnancy and the birth frequency are lower than for Down syndrome (trisomy 21).
The sensitivity of NIPT (New Prenatal Diagnosis) for Edwards syndrome (trisomy 18) is 99.9%. The table below shows the negative predictive value and positive predictive value of Edwards syndrome (trisomy 18) at 16 weeks of pregnancy.
| Mother's Age | Frequency of Disease | Positive Predictive Value | Negative Predictive Value |
|---|---|---|---|
| 30 years old | 1/2100 (0.05%) | 10.6% | 99.99% |
| 35 years old | 1/840 (0.12%) | 22.9% | 99.99% |
| 40 years old | 1/230 (0.43%) | 52.2% | 99.99% |
As with Down syndrome (trisomy 21), the disease frequency and positive predictive value increase with the mother's age. However, the negative predictive value boasts 99.99%.
Patau Syndrome (Trisomy 13)
Finally, let's look at the accuracy of Patau syndrome (trisomy 13). Patau syndrome (trisomy 13) is a condition with even more severe symptoms than Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18). Therefore, both the probability of a fetus having it during pregnancy and the birth frequency are lower than those of Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18).
The sensitivity of NIPT (New Prenatal Diagnosis) for Patau syndrome (trisomy 13) is 91.7%.
| Mother's Age | Frequency of Disease | Positive Predictive Value | Negative Predictive Value |
|---|---|---|---|
| 30 years old | 1/626 (0.16%) | 61.3% | 99.99% |
| 35 years old | 1/249 (0.40%) | 80.0% | 99.99% |
| 40 years old | 1/68 (1.47%) | 93.7% | 99.99% |
Since the frequency of Patau syndrome (trisomy 13) is low, the positive predictive value is lower compared to Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18).
However, the disease frequency and positive predictive value also tend to increase with the mother's age, similar to Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18).
For those undergoing NIPT (New Prenatal Diagnosis), accuracy is extremely important.
Especially with NIPT (New Prenatal Diagnosis), the negative predictive value for Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13) is 99.99%.
Therefore, if the result is negative, it can be determined with almost certainty that there are no chromosomal abnormalities.
The fact that it only requires a blood test and poses no risk of miscarriage or stillbirth, coupled with its high accuracy, has led to an increase in the number of women worldwide undergoing NIPT (New Prenatal Diagnosis).
However, as can be seen, the accuracy is not "100%". This means that the diagnostic results are not "definite." This is why NIPT (New Prenatal Diagnosis) is classified as a non-diagnostic test.
Moreover, even with such a highly accurate NIPT (New Prenatal Diagnosis), there are rare cases of misdiagnosis. There are instances of false positives, where a positive result is given despite no chromosomal abnormalities, and false negatives, where a negative result is given despite the presence of chromosomal abnormalities.
The new and highly accurate NIPT (New Prenatal Diagnosis) has already become widely used overseas and is a popular test among pregnant women. In Japan, more women are also considering this test, but it is not good for the body during pregnancy to become overly optimistic or pessimistic about the results because of the high accuracy.
The impact of test results and subsequent decisions can sometimes lead to heavy decisions.
In Japan, there is a somewhat negative attitude toward easily undergoing prenatal testing as a "risk hedge," but serious diseases in one's child will inevitably affect the future of both the couple and the child.
If you are considering undergoing the test, make sure to have thorough discussions with your partner, receive detailed explanations from specialists, and understand the benefits and drawbacks before taking the test.