Check Programme

Case one

Julie is 34 years old and is planning a pregnancy. Julie is anxious that she might have a baby with Down syndrome and asks what tests are available in her pregnancy to determine if her baby will be healthy.

HK Pract 2001;23:461-465

Question 1
What can you tell Julie about her risk of having a baby with Down syndrome?

Answer 1
Tables based on empiric data assist counselling couples about their risk of having a baby with Down syndrome (refer to Table 1). For Julie, if she is 35 at the time of delivery, her risk of having a liveborn child with trisomy 21 is 1/355. There is an increased risk of spontaneous loss of chromosomally abnormal foetuses, therefore the risk of identifying a foetus with a chromosome anomaly is greater with earlier gestation. Eg. if Julie chooses to have prenatal chromosomal analysis by CVS at 11 weeks gestation, the chance of finding Down syndrome is 1/250. Again tables of empiric data exist to assist with counselling. Although amniocentesis and Chorionic Villus Sampling (CVS) are available in Australia to pregnant women of any age through the private health system, the availability of testing in the public health system is usually limited to women over 35 or 37 years, although the specific age cut-off varies from state to state.

Feedback

One is 700 liveborn children in Australia has Down syndrome (trisomy 21). Increased life expectancy due to improved management of associated congenital anomalies and the trend towards integration of intellectually disabled individuals into the community has heightened public awareness of the condition. Concern about the risk of having a child with Down syndrome is common among pregnant women and highlighted by the availability of prenatal tests aimed at detection of affected foetuses. Women of any age can have a baby with Down syndrome. The risk of having a child with a chromosomal anomaly, in particular trisomy 21, increases with increasing maternal age (refer to Table 1). This fact has taken on new relevance as an increasing proportion of women choose to delay childbearing until their thirties and forties (over 2% of children are now born to women over 40 years of age, compared to 0.9% ten years ago).

Question 2
Julie tells you her sister recently had a son with Down syndrome. Does this information alter your advice about Julie's risk of having a baby with Down syndrome?

Answer 2
Yes. There are two different genetic mechanisms whereby trisomy 21 can occur, and they have different implications for other family members. The majority of individuals with Down syndrome (>97%) have an addition of one whole chromosome 21, so called 'classical trisomy 21'. This is a sporadic event and does not carry an increased risk to other family members. The remaining cases result from an unbalanced translocation. This translocation may be present in a balanced form in one of the child's parents (and potentially in other family members). For family members who carry the translocation the risk of having a child with Down syndrome can be up to 10%.

Question 3
How can Julie determine if her nephew has Down syndrome due to classical trisomy 21 or a translocation?

Answer 3
If a child has classical trisomy 21 it is not necessary to do chromosome tests on the parents or on any other family members. If a child has Down syndrome due to a translocation however, it is appropriate to test other family members to determine if they carry the translocation in a balanced form. In the first instance this involves a chromosome analysis on the parents of the affected child. If one of them carries the translocation, their own parents and brothers and sisters could also be offered testing.

Question 4
What other aspects of the family history should be explored when a couple is planning a pregnancy?

Answer 4

1. Family history of genetic conditions, birth defects, multiple miscarriages or intellectual disability
   
   Any of these features may provide a clue as to the existence of a genetic condition in a particular family. If a diagnosis can be made in a family member, a couple can be counselled about the risk their child will also have the condition, and in many cases prenatal diagnosis can be offered. The possibility of an x-linked condition (affecting males and carried by females) should always be considered.

2. Ethnic background
   
   Some autosomal recessive genetic conditions have higher frequencies within particular ethnic groups. Often at-risk couples have no personal family history of a disorder which is none the less common in their ethnic group. For some examples refer to Table 2. Assumptions should not be made on the basis of physical appearance or about the origin of the surname.

3. Consanguinity
   
   Consanguinity is common in some cultures. This may result in an increased risk of congenital anomalies in offspring secondary to an increased risk of autosomal recessive conditions. Genetic counselling services are available in each state to discuss the possible implications of consanguinity with couples at risk.

Question 5
There do not appear to be any other concerns within Julie's family history and it has been confirmed that her niece has a sporadic form of trisomy 21. Julie is relieved, but is still concerned about her risk of having a baby with Down syndrome, and asks about the tests available to her. What are the two major categories of tests available in a pregnancy to detect Down syndrome?

Answer 5
The tests developed can be divided into two types:

1. Screening tests (maternal serum screening, Ultrasound).
2. Diagnostic tests (chorionic villus sampling, amniocentesis).

Feedback

Screening tests are aimed at identifying foetuses with an increased risk of an anomaly. In general, screening tests categorise pregnancies into high and low risk categories based on an arbitrary cut off risk for the anomaly in question (often 1 in 250 or 1 in 300).

The advantages of screening tests are that they pose no risk to the foetus are available to most women. The disadvantages of screening tests are that they will not detect all cases of Down syndrome, and as most women who have an abnormal result will not have a baby with Down syndrome, they may be falsely alarmed. Conversely, diagnostic (invasive) tests offer a greater accuracy, but also carry a risk of miscarriage, and in many centres are only available to women over the age of 37 years.

Question 6
What is the risk of miscarriage for amniocentesis and chorionic villus sampling (CVS)?

Answer 6
The risk of these tests depends largely on the skill and experience of the person performing the tests. The usually quoted risk of miscarriage is about 1 in 200 for amniocentesis and 1 in 100 for CVS.

Question 7
Julie and her partner decide they would prefer to avoid an invasive test during the pregnancy but would like to find out more about screening tests. What proportion of cases of Down syndrome are detected by second trimester maternal serum screening (triple or quadruple) tests?

Answer 7
There is some variability in detection rates according to the mother's age and the laboratory methods used. Current evidence suggests that about 70% of cases of Down syndrome will be detected by second trimester maternal serum screening. Most cases of trisomy 18 and neural tube defects are also detected. A similar proportion of cases of Down syndrome can be detected by ultrasound measurement of the nuchal translucency in the 1st trimester (see Table 3).

 

Table 3: Screening for Down syndrome by nuchal translucency measurement

Until recently, screening of pregnancies for trisomy 21 by amniocentesis or chorionic villus sampling (CVS) was offered to pregnant women on the basis of maternal age alone. A criticism of this approach was that the majority of babies with trisomy 21 are born to younger women. Screening tests were developed in an attempt to identify women of all ages who were at increased risk of having a baby with trisomy 21. The first such test to be developed was the maternal serum screening test (triple or quadruple test), utilising the variation in hormone levels that is often present in the pregnant woman's blood when the baby has trisomy 21. The nuchal translucency measurement has also been devised to detect pregnancies at increased risk of trisomy 21. The term nuchal translucency refers to the gestation dependent physiological accumulation of fluid in the skin at the back of the neck of all foetuses. A reproducible measurement of this fluid filled space is possible by ultrasound at 11-14 weeks gestation (see Figure 1). Usually the measurement is performed via a trans-abdominal scan, however a transvaginal scan is sometimes required. Foetuses with trisomy 21 have, on average, an increased nuchal translucency at this gestation, which often resolves by the second trimester. A specific risk figure for trisomy 21 is then calculated, based on the combination of maternal age and the nuchal translucency measurement. The accuracy of this risk is critically dependent on the skill of the sonographer. The availability of the test in Australia is variable, with most women only having access through private providers. Similar to other screening tests, the detection rate is not 100% and most pregnancies with an increased nuchal fold will not be found to have trisomy 21. Large studies of nuchal translucency measurement show that for a false positive rate of 5%, the detection rate for trisomy 21 is around 70-80%. Women whose calculated risk is greater than a set cut-off (often 1/300) are usually offered CVS rather than amniocentesis, because of the early gestation. The combination of nuchal translucency screening and first trimester serum markers (PAPPA and inhibin) is currently being trialled by some services to improve detection rates.

Figure 1: Screening for Down syndrome by nuchal translucency measurement

Question 8
Julie's partner asks, "is there anything else we can do to reduce the risk of having a baby with a congenital anomaly?"

Answer 8
A number of simple measures can reduce the risk of having a baby with a congenital abnormality.

Folate

All woman planning a pregnancy should take 0.5mg of oral folate daily in addition to a folate rich diet for at least one month prior to conception and for the first three months of pregnancy. This has been shown to result in a significant reduction in the risk of neural tube defects (spina bifida and anencephaly). Women with a family history of neural tube defect should increase their dose to 5mg daily.

Avoid known infectious teratogenic agents

All women should have a rubella titre prior to planning a pregnancy and be immunised if not immune. The avoidance of other infectious agents including Listeria, toxoplasmosis and parvovirus should also be discussed.

Avoid teratogenic drugs and social drugs if possible

Review of medications in particular anti-epileptic medications and counselling regarding the reduction of smoking and alcohol intake can assist in a healthy pregnancy.

Test mother for thalassaemia carrier status.

Royal Australian College of General Practitioners