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An Infant with Down Syndrome

The sole parameter that was used in the past for evaluating the risks of having an infant with a chromosome abnormality was the mothers age. Amniocentesis was recommended for women over the age of 35, but despite these efforts, no significant decrease in the incidence of Down syndrome was observed. The main reason was that most pregnancies are in young women, and 80% of all cases of Down syndrome in the population are born to young women. In the last ten years, there has been a revolution in medical science that has allowed accurate identification of young women in the high-risk group for having infants with chromosome abnormalities. The first of these new tests to be introduced was a maternal blood biochemical screening test that is conducted in the second trimester (alpha-fetoprotein test). The introduction of this test reduced the incidence of Down syndrome in Israel to a third of its former extent. Over the last few years, first trimester pregnancy tests have also been incorporated. These are the fetal nuchal translucency test and early biochemical screening. Using these tests, the rates of Down syndrome in pregnancy can be reduced even further.

Major tests that can be performed on pregnant women:

Nuchal translucency

What is the nuchal translucency test?
This is an ultrasound test in which the thickness of the fluid accumulated in the region of the base of the fetus-s head is measured. In order to obtain maximal accuracy, a vaginal electrode (inserted into the birth canal) should be used to perform the test.

Why is nuchal translucency testing performed?
During fetal development, between the 9th and the 14th week, fluid accumulates under the skin in the scalp and nape region.

In cases where there is excessive fluid (usually a fluid band of greater than 3 mm width) there is an increased risk of a fetus with both chromosomal defects (e.g. Down syndrome) and anatomical defects (such as severe heart defects).

This test can detect women who are at increased risk for having infants with chromosomal or structural disorders.
When is the test usually performed?
The test should be performed between 11th and 13th weeks of gestation. If it is carried out at other times, it is difficult to compare the results with those of the women who have normal fetuses.

What is the significance of the result?
There is a correlation between the thickness of the fluid in the region of the base of the fetus-s head and the risk of having an infant with chromosomal disorders. There are tables that convert the results of this test together with the age of the mother into the degree of risk for having an infant with such a disorder. As a rule, a nuchal translucency of 3 mm or above indicates that the risk of having an infant with a chromosomal disorder is increased more than tenfold for each age group. The degree of the ability of the test to identify affected fetuses varies from one medical center to another (at a rate of 30% to 90%), but it is estimated that this simple test can usually identify 50% of fetuses with Down syndrome. If the result of the nuchal translucency test is integrated with the calculation of the first trimester biochemical screening, more than 80% of fetuses with Down syndrome can be identified.

What are the advantages of nuchal translucency testing?
The measurement of nuchal translucency is a simple, non-invasive test that does not endanger the pregnancy (as opposed to amniocentesis or chorionic villus sampling). If you have not yet decided that you wish to undergo amniocentesis or chorionic villus sampling, this test may help you with your decision (for example, if a very high nuchal translucency result is obtained, you may well decide to undergo invasive testing because of the increased risk for Down syndrome). Because the test is performed at a relatively early stage of pregnancy (up to week 14), if an affected fetus is detected, the pregnancy may be terminated by curettage without having to perform a late abortion involving induced labor.

The test is important mainly in multiple gestations. In these cases, it is the only test that is reliable for determining the risk for chromosomal syndromes. However, in all cases in which a high value for nuchal translucency is obtained and the prenatal test (chorionic villus sampling or amniocentesis) indicates a normal chromosomal structure, further testing should be performed, including directed ultrasound testing and fetal echocardiography (heart ultrasound), in order to rule out congenital defects and/or genetic syndromes. Hence genetic counseling should be offered in all such cases.

What are the disadvantages of nuchal translucency testing?
Firstly, this test is usually not funded by the HMO, although it does not cost as much as the other tests. Also, its reliability is still at the research stage.

Nuchal translucency is a newly introduced ultrasound test that measures the thickness of the fluid accumulated in the region of the base of the fetus-s head. The most reliable results are obtained between the 11th and the 13th week of pregnancy. The normal value in these weeks is up to 3 mm, and values in excess of this indicate a risk of congenital defects (especially heart defects) and of chromosomal syndromes in general and Down syndrome in particular. After the 14th week, the upper limit of nuchal translucency is 4-5 mm.

Nuchal translucency varies with the weeks of pregnancy, so in order to quantify the risk, the week of pregnancy and the size of the fetus in millimeters (CRL - crown-rump length) are taken into account. These indices together allow for the calculation of the weighted risk for Down syndrome. In the case of high risk (greater than 1:386), the mother is invited to come for genetic counseling, and the need for performing invasive prenatal diagnosis is discussed with her (the meaning of the statistical risk is explained below).

In cases in which a high nuchal translucency value is obtained and the prenatal test (chorionic villus sampling or amniocentesis) shows that the chromosomes are normal, a thorough ultrasound examination should be performed, including fetal echocardiography, in order to rule out congenital defects and/or genetic syndromes, and possibly other tests should be performed as well. In these cases, it is essential to provide genetic counseling.

Extremely high nuchal translucency is called cystic hygroma. This defect indicates the possibility of syndromes other than those described, requiring detailed counseling. Some of these syndromes cannot be tested for during pregnancy.

Biochemical screening for Down syndrome - what is it?

These tests are aimed at identifying, within the population of pregnant women, those who are at high risk of having an infant with Down syndrome and other congenital defects. They are screening rather than diagnostic tests. The difference between them is that the screening tests identify those women who should undergo further tests such as amniocentesis, chorionic villus sampling or special ultrasonography, which are diagnostic tests. These give an accurate evaluation about the condition of the fetus. They are usually invasive tests that carry a certain risk for the pregnancy, so that the purpose of the filtering (screening) tests is to identify those women who need to undergo an invasive test.

In general, the goals of the screening tests are to identify the 5% of pregnant women for whom amniocentesis is recommended. These women are often apprehensive about the test results, but in fact, the result is normal in approximately 98% of subjects.

What biochemical tests are available?
There are two biochemical tests that are used to evaluate the risk for Down syndrome. One is performed in the first trimester of pregnancy and the other in the second. These tests measure the levels of a number of substances secreted either by the fetus or the placenta, whose levels are significantly correlated with Down syndrome in certain weeks of pregnancy, as different quantities are secreted at different ages of gestation.

What may affect the results?
It is very important for the age of the pregnancy (gestational age) to be determined precisely. The results are calculated according to the gestational age as determined by the ultrasound examination and according to the date of the mother-s last period. Also taken into account are such factors as the mother's weight, whether she suffers from any chronic illnesses such as diabetes mellitus, and whether the pregnancy is spontaneous or following fertility intervention. Sometimes abnormal values do not result from a true pathological condition, but from imprecise assessment of the gestational age, or because the pregnancy started as a twin pregnancy where one of the fetuses later stopped developing.

Is the test reliable in a multiple gestation?
It is important to note that the tests, especially for evaluation of the risk for Down syndrome, are reliable and accurate for pregnancies involving a single fetus, but their predictive power in multiple gestations is much lower. Why? The test is performed using the mother's blood, meaning that even if one of the fetuses is abnormal, the test results may still be normal because of the results of the other fetus or fetuses. Therefore in the case of multiple gestations, it is not advisable to rely on these results, and nuchal translucency ultrasound tests should be performed at the correct time. This test examines each fetus individually, so that it can predict more accurately the risk of Down syndrome.

What is the significance of the test result?
The result of the screening tests is obtained as a weighted risk. One out of a number of women with an identical result will have a child with Down syndrome. Hence a woman receiving a result indicating a 1 in 100 risk will be at greater risk than a woman who has received a 1:500 result. In the former case, out of 100 women with identical results, 99 will have normal infants and one will have an affected one. In the latter case, 499 women with identical values will have normal children and one will have an affected one. A risk in excess of 1:386 is considered high (a result defined as "abnormal"). Women with a high weighted risk are invited to come for genetic counseling, where the results are explained to them and they are advised to undergo invasive diagnostic testing (amniocentesis or chorionic villus sampling, depending on the week of gestation). The result of the invasive test will give an exact, final answer as to whether the fetus has Down syndrome, another chromosomal disorder, or normal chromosomes.

Considering a risk of 1:386 as the borderline between high risk and lower risk means that the predictive power of the screening test is not 100% absolute, and there is a possibility that children with Down syndrome will be born to a certain percentage of women despite the result of the screening test having been regarded as "normal". On the other hand, there is a more common situation in which a woman receives an "abnormal" result in a screening test, only for the fetus to be found to be normal in prenatal testing (chorionic villus sampling or amniocentesis) performed subsequently. Essentially, approximately 98% of women who receive an abnormal result in the screening test have healthy fetuses. Despite these limitations, a risk group can be reliably defined using this test. Performing amniocentesis on women in the high-risk group has often prevented the birth of infants with chromosomal defects.

It should be noted that the biochemical screening tests can also indicate conditions apart from Down syndrome - for instance other chromosomal problems, defects of the closure of the spinal column, kidney defects, etc.

Biochemical screening test performed in the second trimester of pregnancy (the alpha-fetoprotein test)
This test is well known to most of the population and is routinely performed in all women between the 16th and the 18th weeks of pregnancy. It involves the testing of three markers: AFP, hCG and UE3. The levels obtained for the three markers, in conjunction with the mother's age, predict the risk for Down syndrome in 65% of cases. In addition, this test provides a weighted risk for trisomy 18 (the implication of the statistical risk obtained was described in the previous paragraph). Another advantage of this test is that an abnormal result for any of the individual markers is clinically significant irrespective of the weighted risk for Down syndrome.

  • The AFP marker. The normal range is 0.5-2.49 MoM (multiples of the mean). High levels of AFP (alpha-fetoprotein) indicate an increased risk of open defects of the central nervous system and the abdomen. Other problems, such as kidney diseases, defects of the integrity of the skin, defects in the closure of the abdominal wall, and placental defects, may also be indicated. When raised levels of this marker are found, the mother is advised to undergo a directed ultrasound test, and in certain cases amniocentesis too. In all these cases, the mother is invited to come for genetic counseling.

  • The hCG marker. The normal range is 0.2-3 MoM (multiples of the mean). High levels indicate a significantly raised risk for Down syndrome. Apart from this, high levels of hCG have no correlation with specific genetic problems. However, high hCG values can predict that the woman is at risk for developing pregnancy complications such as toxemia and placental problems. Usually, however, high values do not indicate a significant gynecological problem. On average, out of 100 women with high hCG values, only 10 will have obstetric complications, compared to 5 out of every 100 women with a normal hCG. It is important for the case physician to know these values when monitoring the fetus growth and the mothers blood pressure.

  • The UE3 marker. The normal value is above 0.15 MoM (multiples of the mean). Extremely low levels (close to 0) indicate an increased risk for two genetic syndromes. One is a skin disease affecting males and causing fishlike scaly skin (ichthyosis), and the other is a syndrome causing many defects and mental retardation (SLO syndrome). There may also be other defects, so if low UE3 values are found, the mother is invited to come for genetic counseling and to undergo further tests.

Biochemical screening test in the first trimester for identifying women at high risk for Down syndrome
This is a newly introduced test, usually performed between the 9th and the 14th week of gestation, but preferably not later than the 12th week. In this test, the levels of two substances are measured - these are PAPA-A and hCG. The weighted results of these two markers in conjunction with the mother's age can predict the risk for having an infant with Down syndrome in 63% of cases. It is advisable to perform the test in conjunction with the fetal nuchal translucency ultrasound scan.

What screening tests should be performed in order to identify women at high risk for having infants with Down syndrome?

A mother undergoing the nuchal translucency test is advised to undergo the first trimester biochemical screening test during the same timeframe using maternal blood. The results of both the blood test and the nuchal translucency test can be weighted by the genetic institute performing the blood test, providing much greater predictive power for Down syndrome (80% compared to 66% in the case of the second trimester biochemical screening test).

The main advantage of the first trimester screening test is that it has a high predictive power for evaluating the risk of Down syndrome. In cases where the test is performed early and an increased risk is indicated, an early prenatal testing (chorionic villus sampling) may be performed rather than waiting for amniocentesis, which can only be performed later in pregnancy.

Integrated risk calculation

The latest advance integrates all the information obtained. Recently, researchers have shown that combining the results of all the tests - i.e. nuchal translucency (in weeks 11-14) + first trimester biochemistry (PAPA-A and hCG in weeks 10-13) + second trimester biochemistry (blood alpha-fetoprotein, UE3 and hCG in weeks 16-18) - significantly contributes to detecting Down syndrome at a rate of 95% or more. In other words, the integrated risk calculation is more accurate than a calculation made based on a single test.

The future of screening tests for detecting Down syndrome

Today it is possible to calculate the weighted risk taking into account all the tests that the mother undergoes. Recent studies have shown that the statistical data evaluating the risk for Down syndrome can be weighted to obtain a single combined risk. This combined risk has been found to be more reliable than a risk that is calculated based on a single test. Whereas a single screening test such as measurement of alpha-fetoprotein performed in the second trimester can identify 66% of cases of Down syndrome in the country, and amniocentesis is performed only on those women in the risk group (who have a risk greater than 1:386), the combined risk assessment can result in the detection of over 95% of all cases of Down syndrome without increasing the number of women for whom amniocentesis is recommended. It must be emphasized that the combined risk assessment method is still undergoing evaluation.

In the not so distant future, it should be possible to perform chromosome testing of the fetus by examining the pregnant woman's blood. Between the 5th and the 8th week of pregnancy a blood sample will be taken from the mother. At that stage of gestation the mother's blood contains cells from the fetus that have passed through the placenta into the maternal bloodstream. We already have today systems that can "enhance" (increase the relative concentration of) the percentage of fetal cells in the mother-s bloodstream for the purpose of identifying fetal chromosomal problems. The intention is that this test will join the current screening tests both in order to reduce further the number of invasive interventions in pregnancy, and also to identify a greater percentage of problems.

It is anticipated that by the end of the decade the test tube pregnancy (in vitro fertilization) rate will have increased significantly. Then each fertilized embryo will be examined before being returned to the uterus in order to ensure that the embryos that are returned are chromosomally normal. Today at least two in vitro fertilization centers in the USA are carrying out trials in which only embryos that have undergone chromosomal testing are returned to the uterus. The risk of chromosomal disorders in embryos returned to the uterus using this method is less than 1:50,000. The purpose of the trials is to see whether the success rate of in vitro fertilization treatments can be increased. As mentioned, these tests are currently expensive and on an experimental basis only.

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