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Types of Prenatal Diagnosis

Types of Prenatal Diagnosis

There are several types of prenatal diagnoses other than NIPT (new-type prenatal diagnosis) to check for congenital abnormalities in the fetus.
Among them, there are "nonconfirmatory tests" and "confirmatory tests," and we will introduce what each test is, what its characteristics are, and when it should be performed.

Nonconfirmatory and confirmatory inspections

As mentioned earlier, there are two types of prenatal diagnosis: non-confirmatory and confirmatory.
Simply expressed, as the name implies, a non-confirmatory test is only an indication of the condition of the fetus (although some tests are quite accurate), while a confirmatory test is a test that can diagnose 100% of the fetus' condition.
The specific types and details of the tests are explained below, so those interested in prenatal diagnosis should check them out.

inconclusive (verdict)

Nonconclusive tests do not increase the risk of miscarriage because they are performed using only ultrasound (echocardiography) and blood sampling.
Some types of tests can be performed as early as the first trimester of pregnancy.
Conventional nonconclusive tests, such as maternal serum markers and combined tests, are not very accurate, but the recently developed NIPT (new prenatal diagnostic test) is quite accurate with only blood sampling.

However, even if a positive result of "possible chromosomal abnormality" is obtained from a non-confirmatory test, the diagnosis is not confirmed, and the patient can undergo a confirmatory test such as an amniotic fluid test or chorionic villus test if desired.

Maternal serum markers (Quattro test)

In the maternal serum marker test, blood is drawn from the mother and analyzed for four proteins (four serum markers) of fetal origin.
This allows us to check for the possibility of Down syndrome (21 trisomy), Edwards syndrome (18 trisomy), and open spina bifida.

The values of these serum markers fluctuate as the gestational weeks progress, but are abnormal if the fetus is the disease being tested for.

The test results are determined by taking into account the maternal age-specific establishment, variation of the four markers with gestational week, maternal weight, family history, and the presence of type 1 diabetes.
The main testing period is 15-18 weeks, and results take approximately 2 weeks to be available.

combined inspection

The combined test uses a combination of ultrasound and blood sampling to diagnose the results.
Combining the two tests increases the accuracy of diagnosis of Down syndrome (21 trisomy) and Edwards syndrome (18 trisomy).

Ultrasonography measures the swelling of the nape of the fetal neck, called NT, and blood sampling measures the levels of two protein components (two serum markers) derived from the placenta.

The results of the combined test are diagnosed from items similar to the maternal serum marker test, such as maternal age-specific establishment, NT measurement and protein component values, number of weeks of pregnancy, maternal weight, family history, and presence of type 1 diabetes.
It is important to note that depending on the posture of the fetus on the day of the examination, ultrasound may not be possible.
The test period is 11-13 weeks, and it takes about 2 weeks to get the results.

NIPT (New Prenatal Diagnosis)

Fragments of DNA derived from the fetus are present in the mother's blood.
By diagnosing the DNA fragments, the test can measure three possibilities: Down syndrome (21 trisomies), Edwards syndrome (18 trisomies), and Patow syndrome (13 trisomies).

In NIPT (New-Information Prenatal Test), first, information on each DNA fragment is analyzed through blood sampling.
Next, by looking at the quantitative percentage of those DNA fragments that are derived from chromosome number, we can identify specific chromosomal changes and compare them to standard values to determine whether they are positive or negative.

For example, normally there are two chromosomes 21, but if the fetus has Down syndrome, there will be three.
The fetus will then contain 1.5 times the normal percentage of chromosome 21, resulting in a positive test result.

Although the accuracy of the NIPT (new prenatal diagnosis) test is quite high, it predicts probability and does not confirm the diagnosis.
Therefore, it is necessary to undergo an amniotic fluid and chorionic villus examination to confirm the diagnosis.

final inspection

It is only a guideline, and is a definitive test to confirm the diagnosis, as opposed to a nonconfirmatory test to check probability.
Although it can reliably determine whether chromosomal abnormalities have occurred in the fetus, there is a risk of miscarriage because a needle is inserted into the abdomen to remove amniotic fluid and chorionic villi. The probability is from chorionic villi (1/100) to amniotic fluid (1/300).

Because of the existence of the above risks, many medical institutions recommend a risk-free, nonconfirmatory test instead of a definitive test.
If you have a strong desire to confirm the diagnosis, you should consult with your doctor before undergoing any tests.

amniotic diagnosis

The amniotic fluid in the uterus contains cells derived from the fetus.
Amniotic fluid examination 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 through ultrasound images, and fetal-derived cells in the fluid are cultured to check for changes in the shape and number of chromosomes.

Amniotic fluid testing is available for all chromosomal disorders.
The test time is after 15-16 weeks, and it takes about 2 weeks from specimen collection to results.

As mentioned earlier, amniotic fluid testing involves many risks because a needle is inserted into the abdomen to collect amniotic fluid.
There is a risk of complications such as water breaking, bleeding, intrauterine infection, premature delivery, amniotic fluid embolism, and maternal damage (e.g., blood vessels and intestinal tract) due to puncture.
In addition, since there is a possibility of miscarriage or stillbirth in approximately 1 in 300 women, the examination should be taken with great care and consideration.

Furthermore, because of the limited number of items that can be tested for, even if the possibility of Down syndrome (21 trisomy), Edwards syndrome (18 trisomy), or Patow syndrome (13 trisomy) is undetected and diagnosed as normal, the child may be born with other diseases such as heart disease.

chorionic test

The "chorionic villi" in the chorionic villus test refers to the part that will become the placenta in the future.
In the chorionic villus examination, a needle is inserted into the abdomen to collect trophoblast cells while the mother's abdomen is observed via ultrasound to check for changes in the shape and number of chromosomes.

Like the amniotic fluid test, the chorionic villus test can be used to check for the presence of chromosomal disorders in general.

The testing period is 11-14 weeks, and most places take about 2 to 3 weeks to get the test results.

The risks are also similar to those of amniotic fluid testing.

Because the test is performed by inserting a needle into the abdomen, there is a risk of complications such as water breaking, bleeding, infection in the uterus, premature delivery, and maternal damage (blood vessels, intestinal tract, etc.) due to the puncture.

In addition, about 1 in 100 may result in stillbirth.
Few health care providers are willing to perform this test because of the higher risk of stillbirth than amniotic fluid testing.

Also here, as with the amniotic fluid test, there are limitations to the test.
The fetus may not reflect the normal state of the fetus, specifically a condition called placental localized mosaicism (the fetus is normal, but only the placenta contains a mixture of cells with chromosomal changes), which is present in about 1% of cases.
In this case, even if the test result is positive, the child born may not have a chromosomal disorder.
And because of the limited number of items that can be tested, a baby may be born with other diseases, such as heart disease, even if the test results are normal.

However, there is no "perfect" prenatal diagnosis that can eliminate all concerns, for example, the results of a risk-free test are only a rough guide, a definitive diagnosis of the presence or absence of a chromosomal disorder is possible but carries serious risks, or the test covers the diagnosis of a chromosomal disorder but has limitations in its scope.
Again, couples should discuss the prenatal diagnosis with each other, receive a detailed explanation from the doctor, and make the decision to undergo the test after careful consideration.

Target rate of NIPT (new prenatal diagnosis)

Let's focus on NIPT (new-type prenatal diagnosis), which more and more women are choosing as a prenatal diagnosis, and check the accuracy rate of the diagnosis results.
The greatest feature of NIPT (new prenatal diagnosis) is its accuracy.

Down syndrome (21 trisomy)

For example, the table below shows the negative and positive predictive values for Down syndrome (21 trisomy) when NIPT (sensitivity 99.1%) is performed at 12 weeks gestation.

Mother's age Disease Frequency Positive neutrality rate Negative neutrality
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 here is the probability that a mother at 12 weeks gestation is pregnant with a child with Down syndrome (21 trisomy).
Positive predictive value refers to the probability that the result of NIPT (new prenatal diagnosis) is positive and that the child to be born really has Down syndrome (21 trisomy).
The negative target rate is the opposite.

It can be seen that the older the mother is, the higher both the disease frequency and the positive predictive value.

The positive predictive value, for example, is 61.3% for a disease frequency of 0.16% at age 30, and the negative predictive value is 99.99%.
You can see that NIPT (new prenatal diagnosis) is quite accurate.

Edwards syndrome (18 trisomy)

Next, let's check the target rate of Edwards syndrome (18 trisomy).
Edwards syndrome (18 trisomy) is a more severe condition than Down syndrome.
Therefore, both the probability of the fetus being affected during pregnancy and the frequency of birth is lower than that of Down syndrome (21 trisomy).

The sensitivity of NIPT (new prenatal diagnosis) for Edwards syndrome (18 trisomy) is 99.9%,
It is.
The table below shows the negative and positive predictive values for Edwards syndrome (18 trisomy) at 16 weeks gestation.

Mother's age Disease Frequency Positive neutrality rate Negative neutrality
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 (21 trisomy), both disease frequency and positive predictive value increase with increasing maternal age.
However, it boasts a negative target rate of 99.99%.

Patou syndrome (13 trisomy)

Finally, let's look at the target rate of Patou syndrome (13 trisomy).
Patou syndrome (13 trisomy) is an even more severe condition than Down syndrome (21 trisomy) or Edwards syndrome (18 trisomy).
Therefore, both the probability of the fetus being affected during pregnancy and the frequency of birth is lower than that of Down syndrome (21 trisomy) and Edwards syndrome (18 trisomy).

The sensitivity of NIPT (new prenatal diagnosis) for Pato syndrome (13 trisomy) is 91.7%,.

Mother's age Disease Frequency Positive neutrality rate Negative neutrality
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%

Because of the low disease frequency of Patow syndrome (13 trisomy), the positive predictive value is even lower than for Down syndrome (21 trisomy) or Edwards syndrome (18 trisomy).

However, the frequency of disease and positive predictive value for maternal age tend to increase, as do Down syndrome (21 trisomies) and Edwards syndrome (18 trisomies).

For those undergoing NIPT (new prenatal diagnosis), the accuracy of the target is very important.

In particular, NIPT (new-type prenatal diagnosis) has a negative predictive value of 99.99% for both Down syndrome (21 trisomies) and Edwards syndrome (18 trisomies) and Patou syndrome (13 trisomies).

Therefore, a negative result almost always indicates the absence of chromosomal abnormalities.

The number of women undergoing NIPT (new-type prenatal diagnosis) is increasing worldwide because it requires only a blood draw, has no risk of miscarriage or stillbirth, and has a high accuracy rate.

However, as you can see, the accuracy rate is not "100%". The results of the diagnosis are not "certain".
This classifies NIPT (new prenatal diagnosis) as a nonconclusive test.

Even with the high accuracy of NIPT (new prenatal diagnosis), there are still rare cases of false positive results.
There are false positives and false negatives, in which a patient is found to be positive even though no chromosomal abnormality has occurred, or conversely, a patient is found to be negative even though a chromosomal abnormality has occurred.

The new and highly accurate NIPT (new-type prenatal diagnosis) is already in general use overseas and has become a popular test among pregnant women.
More and more women in Japan are considering this test, but it is not good for the body during pregnancy to be overconfident or sad about the results just because they are highly accurate.

In some cases, the impact of test results and subsequent decisions can be a heavy decision.

In Japan, it is somewhat discouraged to take prenatal testing as a "risk hedge," but a serious disease in one's own child can have a significant impact on both the couple's future and the child's future.

If you are considering taking the test, discuss it with your spouse often, get a detailed explanation from the specialist, and make sure you understand the advantages and disadvantages of the test before taking it.