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
Major tests that can be performed on pregnant women:
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
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
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
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
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
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
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.
Biochemical screening test in the first
trimester for identifying women at high 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
- 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.
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.