# Calculating the risks of Down's syndrome

## What is meant by ‘risk’?

A risk is the chance of an event occurring. For example, a risk of Down's syndrome of 1 in 100 means that if 100 women have this test result, we would expect that 1 of these women would have a baby with Down's syndrome and that 99 would not. This is the same as a 1% chance that the baby has Down's syndrome and a 99% chance that the baby does not.

When calculating the risk of Down’s syndrome, one should take the following into consideration:

## Maternal age

The risk of having a term pregnancy with Down's syndrome increases with maternal age as shown in the table below. It is known as the maternal age-specific risk and is the background risk of Down's syndrome used when interpreting a screening result.

 Maternal age at term Risk of Down’s syndrome Maternal age at term Risk of Down’s syndrome Maternal age at term Risk of Down’s syndrome 20 1:1450 30 1:940 40 1:85 21 1:1450 31 1:820 41 1:70 22 1:1450 32 1:700 42 1:55 23 1:1400 33 1:570 43 1:45 24 1:1400 34 1:460 44 1:40 25 1:1350 35 1:350 45 1:35 26 1:1300 36 1:270 46 1:30 27 1:1200 37 1:200 47 1:30 28 1:1150 38 1:150 48 1:30 29 1:1050 39 1:110 49 1:25
Morris et al (2003)

## Effect of maternal age on screening performance

An older woman is more likely to have a screen-positive result than a younger woman as she starts with a higher age-specific risk of Down's syndrome. For this reason, the test is more likely to detect a Down's syndrome pregnancy in an older woman than in a younger woman. Whatever the woman's age, the best estimate of her risk is obtained using her age in conjunction with her marker values.

Compare the age specific performance of the three screening tests:

## Markers

There are several different markers that are used in screening for Down’s syndrome, some are useful only in the first trimester of pregnancy (10-13 weeks) and some are useful only in the second trimester of pregnancy (14-22 weeks). The five screening tests use different combinations of these markers.

### First trimester markers

• Pregnancy Associated Plasma Protein-A (PAPP-A)
• free ß-human chorionic gonadotrophin ( free ß-hCG)
• Nuchal translucency (NT)

### Second trimester markers

• Alpha-fetoprotein (AFP)
• unconjugated oestriol (uE3
• total human chorionic gonadotrophin (hCG)
• Inhibin-A (inhibin)

In the first trimester of pregnancy the PAPP-A level is, on average, low in Down's syndrome pregnancies (about half that of unaffected pregnancies), and the nuchal translucency measurement and free ß-hCG levels are, on average, high (about double that of unaffected pregnancies).

In the second trimester AFP and uE3 levels are, on average, low (about three-quarters that of unaffected pregnancies) and inhibin and hCG levels are, on average, high (about double that of unaffected pregnancies).

The concentrations of the markers vary with gestational age. In the first trimester PAPP-A and NT increase, while free ß-hCG decreases. In the second trimester AFP and uE3 increase, hCG decreases, and inhibin decreases before 17 weeks and increases after 17 weeks. Also, the measurement of serum markers may vary between laboratories. In order to take account of this variation, the concentration of each marker is expressed as a multiple of the median for unaffected pregnancies of the same gestational age (MoM).

In the diagram below the median marker level is 2.5 iu/mL at 10 weeks, 5.0 iu/mL at 12 weeks and 10.0 iu/mL at 14 weeks. If a woman is found to have 5.0 iu/mL at 10 weeks her level is twice the median (5.0/2.5) or 2.0 MoM. Similarly if the level is 5.0 iu/mL at 14 weeks this is half the median (5.0/10.0) or 0.5 MoM.

### Risk of Down's syndrome in relation to marker levels

The graphs below show the overlapping relative frequency distributions of the markers in Down's pregnancies. The points of intersection are the value at which the risk of Down’s syndrome is the same as the background risk in the population. From these graphs, it can be seen that AFP, uE3 and PAPP-A values below 0.86 MoM, 0.83 MoM and 0.64 MoM respectively and NT, inhibin-A and free ß-hCG values above 1.46 MoM, 1.54 MoM and 1.67 MoM respectively will tend to increase the risk of Down’s syndrome above the background risk while values in the opposite directions will tend to decrease the risk below the background risk.

For a 75K PDF showing all six curves more clearly, please click any graph above.

## Factors affecting the screening test

### Maternal weight, ethnic group , In Vitro Fertilisation (IVF), Insulin Dependent Diabetes Mellitus (IDDM) and smoking

• Serum marker levels tend to be decreased in heavier women, and increased in lighter women.
• AFP levels tend to be about 20% higher, free ß-hCG and hCG levels about 10% higher and PAPP-A levels about 60% higher in Afro-Caribbean women than in Caucasian women.
• Free ß-hCG and hCG levels tend to be about 10% higher and uE3 and PAPP-A levels about 10% lower in women who have become pregnant as a result of IVF compared with non-IVF pregnancies
• AFP and uE3 levels tend to be low (about 8% and 6% respectively) in women with insulin dependent diabetes mellitus.
• PAPP-A, free ß-hCG and hCG levels tend to be about 20% lower and inhibin levels about 60% higher in women who smoke.

### Twins

The serum marker levels are raised in twin pregnancies. Adjustments are made to take account of this.

Screening in twin pregnancies poses a difficulty because of the possibility that one fetus may be affected and the other may not. Because of the presence of two fetuses the amniocentesis is a slightly more complex procedure in a twin pregnancy. If one twin is found to be affected and the other unaffected, selective feticide can be offered. This procedure poses a substantial risk to the unaffected twin. The presence of a twin pregnancy may therefore be seen by some women as a reason to avoid screening.

### Previous affected pregnancies

If a previous pregnancy with Down’s syndrome or  is reported, the result will be classified as ‘screen-positive’ regardless of the level of the screening markers so that further testing can be discussed with the woman. A risk is calculated which takes account of a woman’s previous pregnancy with Down’s syndrome. The woman's age at the time of her previous pregnancy with Down's syndrome affects the recurrence risk and this is taken into account in the risk calculation.

### Taking account of screening in a previous pregnancy

If a woman has been screened for Down’s syndrome or open neural tube defects in a previous pregnancy the levels of the screening markers in that pregnancy can be used to adjust the marker levels in the current pregnancy. This is useful because markers used in screening tend to 'track' between pregnancy (e.g. a free ß-hCG level that is high in one pregnancy tends to be high in a subsequent pregnancy). So a woman with a false positive result in one pregnancy is likely to have a false positive result again in a subsequent pregnancy. Adjusting marker levels for those in a previous pregnancy can help avoid this problem of false-positives recurring in different pregnancies.

### Vaginal bleeding

Vaginal bleeding immediately before taking the second blood sample can affect the screening result by increasing the maternal serum AFP level and so, in these circumstances, it may be advisable to delay collecting blood for the screening test until a week after bleeding has stopped.

### Testing after amniocentesis

If an amniocentesis has been attempted in the pregnancy prior to taking the second blood sample, the result cannot be interpreted. This is due to the possibility of feto-maternal transfusion which can increase the maternal serum AFP level.