Screening differs from diagnosis

Antenatal screening is the process of identifying those at high risk of a disorder. Prenatal diagnosis establishes whether or not the disorder is definitely present. Screening is used to select a high risk group so that they can be offered prenatal diagnosis. Selection is needed, since for most disorders diagnosis is only possible by an invasive procedure and this carries a slight risk of miscarriage. The main procedures are amniocentesis and chorionic villus sampling (CVS). Screening does not replace diagnosis; it aims to provide information which can help decision making.

Decision making

Those considering screening need to make a number of decisions. Initially there are three: whether to be screened at all, for which specific disorders, and which test. For those screened and identified as high risk, there is the decision whether to undergo prenatal diagnosis. Following this, if the pregnancy is found to be affected a further decision will need to be made: whether to have a termination of pregnancy.

Disorders

Tests are designed principally to screen for Down's syndrome and Cystic Fibrosis. In addition the Down's syndrome screening tests can also detect other disorders. These are Edwards' syndrome, and if testing is after 15 weeks gestation, Neural Tube Defects (NTDs) and Abdominal Wall Defects (AWDs). The table shows that most of the additional disorders are either rare, incompatible with survival, or surgically correctable:

† in the 1970's: current rates unknown but thought to be lower because of dietary changes.

Some Terminology

The results of a screening test are either 'screen positive' or 'screen negative'. A screen positive result means that the risk is high enough to consider having prenatal diagnosis. It does not mean that the baby is definitely affected. Most of those with screen positive results go on to have normal babies. Similarly, a screen negative result means that there is not a high risk. It does not mean that an affected pregnancy has been completely excluded.

The quality of a screening test is determined by the 'detection rate' and the 'false-positive rate'. The detection rate is the percentage of affected pregnancies identified as high risk, and the false-positive rate is the percentage of unaffected pregnancies identified as high risk.

Timescale

Certain time constraints influence the decision about which test to choose. They are summarised here for ease of reference.

Diagnosis

Amniocentesis and CVS are the main diagnostic procedures for Down's syndrome, Edwards' syndrome and Cystic Fibrosis. Fetal cells are obtained and analysed for chromosome number and CFTR mutations. Amniocentesis can also be used for biochemical diagnosis of NTDs and AWDs although an ultrasound 'anomaly' scan at 18-20 weeks gestation can also be definitive. This scan can also be used to modify the risk of Down's syndrome and Edwards' syndrome but it cannot be used to exclude these disorders.

Amniocentesis involves inserting a fine needle through the woman's abdomen into the womb. A sample of the fluid surrounding the baby (amniotic fluid) is taken and from this fetal cells are extracted. CVS can be done either by the insertion of a fine needle through the abdomen or through the vagina. A sample is taken of the placenta which comprises fetal cells only.

Both procedures take about 10 minutes and are performed on an out-patient basis. Some women may experience slight discomfort. The advantage of CVS is that it can be done earlier in pregnancy, from about 10 weeks; amniocentesis is usually performed around 16 weeks, although practice varies. Both procedures carry an element of risk and about one woman in every 100-200 may miscarry, over and above those who would have miscarried anyway. In some cases other mild complications occur such as bleeding or leakage of amniotic fluid.

For chromosomal anomalies, results are usually available within 2-3 weeks. With CVS, a provisional result may be given within 1-2 days; however, it may take 2-3 weeks to confirm. Occasionally, a conclusive result is not obtained and the procedure needs to be repeated. For cystic fibrosis, results are available within days.

Down's Syndrome

This is the most common cause of intellectual disability. All children with Down's syndrome have a degree of intellectual disability and although they have special educational needs, many attend mainstream schools. The ability of adults with Down's syndrome varies considerably. This is reflected in the degree of independence and level of employment.

Certain medical conditions are more common in people with Down's syndrome; these include dry skin, slow feeding, poor tongue control and a tendency to develop chest and sinus infections. Some 40% of affected babies have a heart defect, ranging from a slight murmur to a severe abnormality requiring surgery. Hearing, vision and thyroid problems may also occur. However, many people with Down's syndrome enjoy a healthy life, and a life span of 40-60+ years is not uncommon.

The Cause

Down's syndrome is the result of a chromosomal anomaly. It can be inherited, though this rarely happens, and most cases occur in couples with no family history. Every human cell contains chromosomes, which incorporate the genes that influence our individual characteristics. In a normal human cell there are 46 chromosomes. In individuals with Down's syndrome there are 47 chromosomes. The extra one is a copy of chromosome number 21, hence the disorder is sometimes called 'trisomy 21'. Most cases are known to result from an error in cell division during the early stages of egg production.

Screening for Down's Syndrome

In the past, advanced maternal age or a previous Down's syndrome pregnancy were the only ways of identifying a high risk group. The risk of having a baby with Down's syndrome increases with the mother's age. For example the risk is about 1 in 910 at age 30, and 1 in 28 at age 45. A previous affected pregnancy increases the risk further, to about 1 in 200 at age 30 and 1 in 25 at age 45.

However, with this approach a large number of normal pregnancies and relatively few affected pregnancies were identified as high risk. Most babies with Down's syndrome are born to young women - about half are born to women under 30 - since most pregnancies are in this age group. A very small proportion of affected births occur in couples with a family history.

Now, a simple blood test or a special ultrasound examination can be used to screen more effectively. This involves measuring 'markers' which are either chemicals in the mother's blood or structures seen on ultrasound.

Markers

The level of each marker is typically either increased or reduced on average in a Down's syndrome pregnancy. The table shows a typical profile for the most important markers found so far:

† the number of + and - signs gives the increase or decrease in a typical affected pregnancy.

All are blood markers except for nuchal translucency, which is a temporary swelling of the fetal neck measurable by ultrasound.

The average levels for each of the markers change with gestational age. To quantify the extent of increase or decrease in marker level they are expressed as multiples of the normal median (MoMs) for the gestation. For example, 2.0 MoM means that the level is double that expected for the gestational age of the pregnancy.

Interpretation

Although, on average, a Down's syndrome pregnancy follows a typical profile there is a lot of variability and many are atypical. Equally, some unaffected pregnancies have a profile similar to Down's syndrome. When someone is screened we use a computer program to calculate how close their profile is to that of an affected pregnancy.

Taking the maternal age, family history and profile together our program calculates the risk of the pregnancy ending in the birth of a baby with Down's syndrome. If the risk exceeds 1 in 250 the result is regarded as screen positive, otherwise it is screen negative. We also report the actual risk which could be as low as 1 in 50,000 or as high as 1 in 10.

Choice of tests

Various combinations of markers can be used in a screening test. We offer a number of tests, using combinations with the highest detection rates. These are the Primark, Biomark and Beta triple tests. When choosing which test to have the most important factors to consider are the gestational range over which it is effective, whether additional disorders can be detected, and if there are twins.

In general we recommend that a test is performed as early in pregnancy as possible, to allow plenty of time for further decision making. If screening is required for NTDs and AWDs, testing should be delayed until 15 weeks' gestation. However, a separate AFP test may be routinely offered at the local hospital. Additionally a detailed ultrasound 'anomaly' scan may be offered at 18-20 weeks gestation and this detects most NTDs and AWDs.

In twins, tests involving NT are more accurate than those based on blood markers alone. This is because the NT treats each fetus separately whereas maternal blood marker levels are influenced by both an affected twin and its normal co-twin.

Additional Disorders

Edwards' syndrome, like Down's syndrome, is caused by an extra chromosome, in this case number 18, hence it is also known as 'trisomy 18'. Although most infants die in the first weeks of life there are long-term survivors with profound physical and intellectual disability. The typical profile for some of the markers is different from Down's syndrome. Results are interpreted by calculating the risk of an affected birth. If this exceeds 1 in 50 it will be interpreted as screen positive. The estimated detection rate is high and the false-positive rate is very low.

NTDs and AWDs These are caused by failures in the early development of the embryo. With NTDs the neural tube has failed to close fully, leaving a hole. If this results in absence of the brain it is anencephaly, if it leads to damage in the spinal chord it is spina bifida. Anencephaly is incompatible with life and only about half of those with spina bifida survive infancy. The extent of handicap due to spina bifida varies considerably but many have paralysis of the lower limbs and incontinence. Generally, there is no intellectual disability. With AWDs it is the abdominal wall that has failed to close fully . As a result some of the abdominal organs, although still attached, are displaced outside the body.

AFP is produced in the feœtal liver, and during normal pregnancy a very small amount reaches the maternal blood. In NTDs and AWDs this level is increased as more AFP leaks from the fetus through the open lesion. After 15 weeks' gestation the level is sufficient for AFP to be a strong marker. If the AFP level exceeds 2.5 MoM the result will be interpreted as screen positive. More than three-quarters of NTDs and two-thirds of AWDs have raised AFP levels. The false-positive rate is 2-3%.

There are some other disorders for which we do not specifically screen but are detected as a result of our tests. Rarer chromosomal anomalies (eg Turner's syndrome, triploidy) rather than Down's or Edwards' syndrome may be found following invasive prenatal diagnosis. Structural abnormalities (eg heart defects) may be found when measuring NT.

This article was first published on the site in 2002.

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