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Screening for Down's syndrome from maternal blood sample and by ultrasound

What is Down's syndrome?

Down's syndrome (trisomy 21) is caused by the presence of an extra chromosome number 21 (three instead of two) in the cells. In the absence of antenatal screening, about 1 in 700 babies born would be affected. Since Down's syndrome is not inherited, a baby can be affected even if there is no history of Down's syndrome in the family. The risk of having a term pregnancy with Down's syndrome increases with maternal age. In Hungary, expectant mothers over the age of 35 are offered a foetal chromosome test, but this intervention increases the risk of miscarriage by 1%. Since this test is not done routinely among pregnant women under 35, most Down's syndrome babies are born to younger mothers.

The majority of severe mental disabilities are caused by Down's syndrome, which is manifested, apart from learning difficulties, in other physical problems (heart diseases, sight and hearing abnormalities, etc.).

Risk of Down's syndrome by maternal age (international data)

What are open neural tube defects?

Neural tube defects are among the most common serious congenital malformations. In the absence of antenatal screening, about 1 in every 400 babies born would be affected, but the risk can be reduced considerably by taking prenatal vitamin supplements. An opening in the bones of the spine can result in spinal cord damage, which can lead to paralysis or damage the nerves controlling the lower part of the body. These babies can have an abnormal build-up of cerebro-spinal fluid, called hydrocephaly, which can be treated surgically, but often results in cognitive impairments. In every fifth foetus with a neural tube defect, the spinal cord is covered by a thickened layer of tissue. This condition is called a closed neural tube defect, which cannot be detected from the maternal blood test, but can be screened with considerable accuracy by genetic ultrasound testing at week 18-20.

Available lab tests:

The Combined test is carried out at week 12-14, by the combination of ultrasound examination and blood tests. By measuring the crown-rump length (CRL) with ultrasound, the exact gestational age is determined, then the nuchal translucency thickness is measured and the nasal bone is checked. We calculate the concentration of two foetal markers (PAPP-A and free- ß-hCG) from the maternal blood sample. The entire test takes around 1-1.5 hours, so expectant mothers can receive the results straight away at their consultation. Negative test results are followed by the AFP test at week 15-18 and a genetic ultrasound examination at week 18-20. Some labs do the AFP at week 16, but in our laboratory it can be arranged through appointments any time between week 15-20 and the results are available within 1 hour.

The risk of Down's syndrome cannot be determined from the AFP test alone!

The Quadruple test (Sequence screening) is available if the Combined test has an intermediate risk value (1:150 - 1:1000), or the mother wishes to have this test.

The Integrated test involves two blood tests and an ultrasound screening; the latter can be done by the mother's own physician. The first blood test is in the 1^st trimester (first three months of the pregnancy), at week 12-13, when the level of the PAPP-A marker (pregnancy associated plasma protein) is determined. The second blood test is carried out in the 2^nd trimester (second three months of the pregnancy), at week 15-18, when the AFP, free-ß-hCG, uE3 and Inhibin-A markers are measured. Results are available after the second blood test.

The Quadruple test is recommended after the 14th week of pregnancy. This test is identical to the second part of the Integrated test.

The exact timing for these tests is crucial, therefore test appointments will be given by our staff.

Reliability of tests for the detection of Down's syndrome (international data):

* False positive rate: percentage of non Down's syndrome pregnancies with screen-positive results.

** Sensitivity: probability of a screen-positive result, where the foetus is affected with Down's syndrome.

Data considered during the risk analysis:

• Maternal age

  The risk of having a term pregnancy with Down's syndrome increases with maternal age, so this must be considered during testing. It also means that an older woman is more likely to have a screen-positive result, but the sensitivity of our tests also increases. The reason for this is that we aim to detect more chromosome-defects, but use less amniocentesis tests. Based on this reasoning, in certain countries (USA, Canada) maternal age limits for tests were scrapped from 2007 and amniocentesis is only offered based on the results of the risk analysis methods.

• Serum markers from maternal blood

  In the 1980's AFP (alpha fetoprotein) was the first protein, whose concentration in maternal blood was linked to the probability of certain defects. In the case of open neural tube defects, the AFP concentration often rises significantly, while with Down's syndrome it usually drops by 20-30%, so, maternal age risk, coupled with the AFP results, has increased the chance of detecting Down's syndrome to 30%. The problem was that, with a low AFP level, the foetus was completely healthy in the majority of cases and detectability remained relatively low. This, however, could start the process of building more and more serum markers into the screening systems, thus enhancing their reliability. The most commonly used current blood serum markers are PAPP-A (pregnancy associated plasma protein) and free-ß-hCG (free beta human chorionic gonadotrophin) in the first trimester (first three months of the pregnancy) and AFP (alpha-fetoprotein), uE3 (unconjugated oestriol), free-ß-hCG and Inhibin-A in the second trimester (second three months of the pregnancy).

• Ultrasound

  At week 12-13 nuchal translucency (NT) is measured, which is suitable for the screening of chromosome defects and some congenital heart diseases. The nasal bone (NB) can also be scanned, the presence of which significantly reduces the risk of Down's syndrome.

  At the 18-20 week ultrasound check-up, when the AFP result is already available, we scan for open neural tube defects, and examine the bones, internal organs and the heart.

  The ultrasound scan and the blood serum markers enable us to modify the maternal age risk and determine a new, revised risk value for the pregnancy. For example, in the case of an expectant mother aged 40, where maternal age risk for Down's syndrome is 1% (1:100) and the screening reduces this risk twenty times, the calculated risk for Down's syndrome is modified to 0.5 ‰ (1:2000). This risk value is identical with the maternal age risk of a 20 year old expectant mother, so the test concludes that the 40 year-old's chance for a Down's syndrome baby is the same as a 20 year old's who did not have these tests.

  These new, improved tests enable us to have a 95% detection rate for common developmental and chromosome abnormalities, so many expectant mothers can avoid the unnecessary amniocentesis.

• MoM

  The concentration of foetal proteins in the maternal blood changes with the gestational age, and this concentration can be significantly affected by certain factors, such as maternal weight, in-vitro fertilisation (IVF), insulin dependency and twin pregnancy. These problems can be eliminated by using the so-called MoM (multiples of median) values. This value indicates the deviation from the concentration for unaffected pregnancies of the same gestational age, also taking into account the above-mentioned modifying factors. The average is 1.0 MoM, but considerable deviations may occur.

The evaluation of results:

Risk calculation from the maternal blood serum is not a diagnostic procedure. It is a screening test; therefore it does not detect all foetuses with Down's syndrome or open neural tube defects and may produce false negative or false positive results.

A screen-positive result or high risk is when the risk of having a term pregnancy affected with a chromosome defect is higher than 1 in 150. A screen-positive result does not mean that the foetus definitely has the defect, therefore a foetal chromosome test is required to confirm the presence of the defect (e.g. with a 1:100-risk, only every hundredth amniocentesis has a true positive result).

With a high risk for open neural tube defect (AFP over 2.5 MoM), a detailed ultrasound scan is necessary at week 18-20. Almost all cases of anencephaly and 95% of open neural tube defects can be detected with this method. The efficiency of the ultrasound scan depends on the sophistication of the equipment and the experience of the sonographer.

If you have a screen-positive result, please visit the experts recommended by the Genetic Diagnostic Centre as soon as possible.

Screen-negative result: when the risk is lower than 1:150. A screen-negative result does not rule out the possibility of a pregnancy with abnormalities, it only refers to a low probability.

Invasive procedures:

If the expectant mother is over the age of 35 and the ultrasound scan, the blood test or their combination had screen-positive results, the doctor can recommend a foetal chromosome test.

Amniocentesis (taking a sample of the amniotic fluid): The amniocentesis is carried out at week 15-19. Under the guidance of an ultrasound a needle is inserted (through the abdominal wall) to take some amniotic fluid. Foetal cells from this sample are then used for the chromosome test.

Chorionic villus sampling (CVS): the procedure involves taking a sample of placental tissue, again by inserting a needle through the abdominal wall. This is carried out from week 10-12. Its advantage is that it provides an early diagnosis.

Recommended for:

Since expectant mothers under the age of 35 are not routinely offered the foetal chromosome tests, they can only rely on risk analysis systems. However, their risks can also be reduced significantly with the currently used, most efficient screening methods.

Risk analysis systems can also be recommended for those pregnant women over the age of 35, who would like to avoid amniocentesis. With this option, however, they choose a less reliable screening method instead of a diagnostic method with an almost 100% result.

Not recommended for:

Prenatal risk assessment from maternal blood sample is only recommended for those who are willing to have amniocentesis in the case of a screen-positive result or willing to consider an abortion in the case of a positive amniocentesis result.

It is not recommended for expectant mothers who decide to have a foetal chromosome test irrespective of the screening results.

In the case of insulin-dependent diabetes and twin pregnancies, only the Combined test provides an accurate risk value, so this is the best option. In such cases the Quadruple and Integrated tests are only marked as POSITIVE or NEGATIVE, so their results have a limited value!