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New Down’s syndrome blood test 'more reliable'

“A new test can reliably tell if an unborn baby has Down’s syndrome without putting it at risk,” Metro reports.

Screening for Down’s syndrome is currently offered to all pregnant women.

However, the current screening test has a false positive rate (that is, the results suggest a problem when the foetus is in fact healthy) of around 3-4%.
This means many women have needless invasive testing, using chorionic villus sampling (CVS) or amniocentesis. Both of these procedures carry around a one in 100 risk of causing a miscarriage.

If the false positive rate of the screening test could be reduced this would reduce the number of women who need invasive testing, resulting in fewer miscarriages.

This new screening technique involves analysing the small amounts of foetal DNA found in the mother’s blood stream.

After testing 1,005 women, researchers found the new technique had a much lower false positive rate (around 0.1%). This means many fewer normal pregnancies had an unnecessary invasive diagnostic test with the new test. However, in about 2% of women the new test did not produce a result, meaning that the conventional screening technique had to be used.

These results are promising, but until the findings are replicated in larger studies, it is unlikely the current national screening procedures will be changed.

Where did the story come from?

This research was carried out at King’s College Hospital and University College Hospital in London.

It was published in the peer-reviewed journal, Ultrasound in Obstetrics and Gynecology.

It was funded by The Fetal Medicine Foundation: a research, education and training charity. The Foundation is funded by an associated private clinic, which carries out ultrasound scans for pregnant women and donates all profits to the Foundation, and by private donations.

The research was covered by many news sources and generally, the findings were reported reasonably. However, there are a few inaccuracies.

Many of the news sources suggest the new test can pick up more foetuses with the conditions (is more sensitive) than the existing test. While previous studies have suggested that this might be the case, this was not the case in the current study. Both tests picked up the same number of cases where the screening tests were performed successfully.

However, the new test did not work on the blood sample for one pregnancy that turned out to be affected by Down’s syndrome, which was picked up by the existing screening test. Larger studies may provide a better estimate of how sensitive the new test is.

Some reports, including the BBC and Daily Mail correctly state that the current screening programme includes both an ultrasound scan and a blood test, but, The Daily Telegraph only states that ultrasound is used.

What kind of research was this?

This was a study looking at a new screening test for detecting three specific chromosomal abnormalities called ‘trisomies’ early in pregnancy. It compared this new test against an existing screening test. Both tests require women with at risk pregnancies to have an invasive diagnostic test to confirm the results.

Initial studies have suggested that the new screening test could reduce the number of women who needed to have the invasive diagnostic test, but still identify most of the affected foetuses.

In trisomies, foetuses carry all or part of an extra chromosome 21 (called trisomy 21 or Down’s syndrome), or chromosome 18 (called trisomy 18 or Edwards’ syndrome), or chromosome 13 (called trisomy 13 or Patau syndrome). These conditions are rare but Down’s syndrome is the most common. All three conditions have a large impact on the health and development of the foetus, with the effects of Down’s syndrome generally less severe than the other two syndromes. Many babies with Edwards’ or Patau syndrome will miscarry or be still born, and those that survive to birth rarely live for longer than a year.

Currently, women are offered screening for Down’s syndrome in the first trimester of pregnancy. This screening involves what is called the “combined test” which includes an ultrasound scan to measure the thickness of the soft tissue at the back of the foetus’ neck and taking a blood sample to measure certain proteins in the mother’s blood. The results of this test and the mother’s age are used to calculate the risk of the foetus being affected by Down’s syndrome. The combined screening test picks up about 90% of foetuses with Down’s syndrome. This test also sometimes identifies foetuses with trisomy 13 or 18.

Women whose screening test results show that they are at higher risk of having an affected foetus are offered a diagnostic test to check whether the fetus does have Down’s syndrome. However, this confirmation involves an invasive procedure, either chorionic villus sampling or amniocentesis to collect cells from the foetus that are found in the placenta or in the fluid surrounding the foetus. The combined screening test picks up about 90% of foetuses with Down’s syndrome. This test also sometimes identifies foetuses with trisomy 13 or 18. The problem with both of these invasive procedures is that they is that they carry around a one in a 100 chance of causing a miscarriage.

Not all foetuses the combined test identifies as having an increased risk of Down’s syndrome have the condition. About 5% of pregnancies which are not affected by Down’s syndrome will have a combined test result suggesting they are at risk, they are called false positives.

Researchers would like to have a test returning fewer false positives, to reduce the number of women who have invasive testing unnecessarily.

The new screening test assessed in this study is based on testing the small amounts of foetal genetic material (DNA) found in the mother’s blood stream. This is now possible due to advances in DNA technology.

What did the research involve?

The researchers enrolled 1,005 pregnant women attending their clinic in London who were not having twins and were at the right time in their pregnancy to offer the screening tests.

Women in the study were between 20 and 49 years old. Most had conceived naturally (85.7%), with 11.6% having conceived by IVF and 2.7% having conceived after taking drugs to promote ovulation.

They took blood samples from the women at 10 weeks into their pregnancy to perform the new DNA-based screening test and part of the existing screening test (called the combined test), and at 12 weeks they performed the ultrasound needed as part of the combined test.

The analysis of the blood samples for the new DNA-based screening test was done in the US. The parents had counselling before the tests to explain what they were and what the implications of the findings might be. Both the existing and new screening tests evaluate how much risk a woman has of having a foetus affected by one of the three conditions.

For trisomy 18 and 21, the doctors relied on the results of the new DNA-based screening test to counsel the parents about their risk of having an affected baby and what their options were if they were at high risk. For example, if the DNA-based test suggested the women had low risk of these conditions, the women were reassured that their risk was low regardless of the result of the combined test.

For trisomy 13, because affected foetuses often have many abnormalities detected by ultrasound, which is part of the existing screening test but not the new screening test, the doctors used the results of both tests.

If the DNA-based screening test found that the foetus was at low risk, but the combined test suggested they were at very high risk, the parents were still advised to consider having invasive diagnostic testing. If the DNA-based test did not give a result then the result for the combined test was used.

Women who were not identified as being at high risk, or not found to have a trisomy on diagnostic testing, went on to have the usual second trimester ultrasound scan that looks for problems in the developing foetus.

What were the basic results?

The DNA-based test gave a result in about 95% of women (957 women), and failed on the first attempt in about 5%. The failed tests were repeated on a second blood sample for most of the women (40 out of 48 women) – they worked in this second sample for 27 of these 40 women.

The new screening test suggested that among the 984 women:

  • 967 had very low risk (<0.01%) for all three trisomies
  • 11 were at high risk (>99%) for trisomy 21 only
  • five were at high risk (>99%) for trisomy 18 only
  • one had an increased risk (34% risk) for trisomy 13 only

One woman whose pregnancy was at high risk for trisomy 21 had a miscarriage before her planned diagnostic test. The remaining 16 women whose pregnancies were identified as being at increased risk for trisomy all had CVS for diagnostic testing. Fifteen were confirmed as having the trisomy they had been predicted as being at high risk for.

One pregnancy predicted as being at high risk of trisomy 18 was not found to have a trisomy on diagnostic testing. This foetus was 20 weeks old at the time the paper was written and appeared to be normal in the second trimester ultrasound.

Assuming this foetus did not have trisomy 18, this would mean that the new test had a false positive rate of 0.1% – so one in 1,000 women without a trisomy pregnancy would be offered invasive testing.

One foetus did not have results for the DNA-based test but was found to be at high risk of trisomy 21 from the combined test and so had CVS and was found to have trisomy 21.

Overall, the combined screening test identified 5% of women (49 women) to be at increased risk of trisomy 21 (over 1% risk). Sixteen of these women were found to have a trisomy pregnancy on diagnostic testing.

This meant the test had a false positive rate of 3.4%, meaning that 34 in 1,000 women with a normal pregnancy would be offered invasive testing.

All of the cases of trisomy 13, 18, and 21 identified as being at increased risk by the DNA-based test were also identified as being at increased risk by the combined test.

The one pregnancy incorrectly identified as being at high risk of trisomy 18 by the new DNA-based test was not identified as being at increased risk on the combined test.

As well as the 16 women who had invasive diagnostic testing due to a high-risk result in the new screening test, invasive diagnostic testing was also carried out on four who had no result on the new test but were at high risk on the combined test, and 12 who had a low risk on both tests.

Most of the pregnancies without high risk on the screening tests or diagnostic testing (968 women) had not reached term at the time the paper was published. So it is not clear if any trisomies were missed in these pregnancies.

How did the researchers interpret the results?

The researchers concluded that routine use of the new screening test for trisomies 21, 18 and 13 at 10 weeks into pregnancy is feasible, and gives fewer false positive results than the existing screening test for trisomy 21. The results of the screening test still needed to be confirmed by invasive diagnostic testing.

Conclusion

The current study suggests that screening for trisomies 13, 18, and 21 using a DNA based maternal blood test may identify similar numbers of affected foetuses to the current screening test. However, the new screening test appears to be better at ruling out the condition in women with normal pregnancies, this means that fewer women would be offered unnecessary invasive diagnostic testing.

There are a few important points to note:

  • Not all women in this study had given birth when the study was published, and these babies will need to be assessed to make sure that no cases of trisomy were missed.
  • If this test does become more widely used, it is unlikely to be used on its own to screen for these trisomies. It is more likely to be used as part of an overall screening strategy for these conditions. For example, combined testing could be used in cases where the new test did not provide a result, and ultrasound is likely to continue to be used to identify those foetuses with abnormalities. It will be important to assess the overall potential effect of whatever screening strategy is proposed.
  • The current test only looked at women at 10 weeks into their pregnancy, other studies would be needed to determine whether the test performed similarly at other stages in pregnancy.
  • These three conditions are relatively rare, and therefore only a few women in this study had them. Larger studies are needed to confirm these findings, and the newspapers suggest that such studies are ongoing. These studies will also need to confirm what level of risk on this new test should be considered high, and prompt an offer of diagnostic testing.
  • Invasive diagnostic testing is still needed to confirm the results, as although the false positive rate is much lower with the new test, it does still have some false positives – where a foetus is predicted as being at high risk but found to be unaffected.

The cost of the test (currently not conducted by labs in the UK) is quoted at £400 in the papers. This is likely to be too high a cost for all 700,000 pregnancies per year in the UK.

The researchers mention the possibility of only using the test in women who tested positive on the current screening test but before the invasive diagnostic test. This could cut down on the number of the new tests needed, and also reduce the need for invasive testing for some of the women who test positive on the combined test.

Alternatively, the news reports suggest the researchers hope the cost of the new test may fall.

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