A blood test early in pregnancy to screen for foetal genetic abnormalities raises as many questions as it answers. By Megan Howe.

Non-invasive prenatal screening tests

Non-invasive prenatal blood tests are becoming a popular way of screening for genetic abnormalities in a foetus.

A glance at any of Australia’s popular pregnancy blog sites reveals much discussion about new tests that screen for genetic abnormalities in the foetus earlier and more accurately than conventional methods.

 “I had the Harmony test yesterday at 10 weeks on the dot,” reads one comment on Essential Baby. “It’s the earliest you can have it but we are heading overseas in three weeks so if any issues arise I really need to know before we leave. I’m not really high risk as I am 29 but
I just want to know for peace of mind…”

At 10 weeks, the foetus is the size of a small strawberry but, by then, fragments of its DNA have made their way from the placenta into the mother’s blood.

The discovery about 15 years ago of these tiny pieces of foetal DNA in maternal blood led to the development of a new, non-invasive way of screening for genetic problems in the foetus known as cell-free DNA (cfDNA) testing or non-invasive prenatal testing (NIPT).

The blood test to screen for Down syndrome (trisomy 21), Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) and sex-chromosome-related disorders can be done at 10 weeks. This means women can get earlier, more accurate results than through conventional screening using nuchal translucency ultrasound and biochemical testing.

And it means many women can avoid invasive screening by amniocentesis or chorionic villus sampling (CVS), both of which carry a risk of miscarriage.

When it first became available to Australian women via offshore laboratories in 2011, NIPT cost $2000. Today, at least three Australian providers are offering it for about $450.

But the growing popularity of NIPT has raised questions about whether women receive adequate counselling before testing, about whether Medicare should fund the test, and about the potential for women to be pressured to terminate pregnancies because of genetic abnormalities, or perhaps even the gender of the foetus.

Associate Professor Andrew McLennan, a member of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists prenatal diagnosis committee, says many women attending his obstetric practice now seek NIPT. But he stresses it is a screening test, not a diagnostic test.

Women who receive a result showing a likely genetic abnormality are advised to have either amniocentesis or CVS to confirm the result.

While it is by far the most accurate screening method for Down syndrome, boasting accuracy of more than 99 per cent, he says NIPT cannot replace traditional prenatal screening. At present, it only covers five of the 23 chromosomes, which account for about 80 per cent of chromosomal problems, he says. And chromosomal problems make up a relatively small proportion of “things that go wrong” with babies.

“People think it is a replacement for the nuchal translucency screen, but that test also gives information about placental function, major foetal structural abnormalities and growth issues” he says. “No one has really worked out the best screening model, but the ideal is still probably to have the traditional nuchal translucency test, then offer a cell-free DNA test if the result is equivocal.”

McLennan says there are still a small number of false negative results (where an abnormality is not detected) and false positive results (where a normal baby is incorrectly classified as abnormal).

 “I know of two babies born in Sydney this year with Down syndrome that were not picked up by NIPT screening,” he says. Other experts who spoke to The Saturday Paper are also aware of the two cases, although those involved with specific types of NIPT say the cases are not associated with tests used by their companies.

In McLennan’s opinion, “hypermarketing” of the tests has led to some women having tests without adequate counselling about what the test can and can’t do.

 “It is seen to be a simple process, but it is not,” he says. “It needs more detailed and up-to-the-minute pre-test counselling than nuchal translucency screening, which the community and GPs are now very familiar with.”

The first company to offer NIPT in Australia, Genea, has tested more than 5000 blood samples, using a test called GeneSyte, since it launched local services in March. It now receives more than 650 test referrals each month, according to scientific director Steven McArthur.

Genea is now rolling out genetic counselling services, both face to face and via phone or Skype, for women undergoing its testing, he says.

Sonic Healthcare previously sent blood samples offshore for testing but began testing in Australia in October. However, its director of genetics, Professor Graeme Suthers, doesn’t advocate testing for all pregnant women.

“This is not a test for the faint-hearted,” he says.

He explains that NIPT works by analysing the proportion of DNA fragments (from both mother and foetus) in the mother’s blood that are derived from each chromosome, to see if they fall within a narrow, normal range. If there is an unusually high or low proportion of one of the chromosomes, it can indicate an abnormality.

However, Suthers says the amount of foetal DNA in the blood varies among pregnant women, with recent research showing that obese women may have lower levels of foetal DNA in their blood. In effect, he says, the maternal DNA may “drown out the signal from the baby”.

Different tests on the market take different approaches to assessing the proportion of foetal DNA, he says.

Sonic Healthcare recently began using a test called Harmony, based on its ability to give an accurate measure of the proportion of foetal DNA, he says. “If less than 4 per cent comes from the foetus, it is too low to analyse reliably and the test says it can’t report on that basis.”

Suthers says women need to understand the limitations of whichever type of NIPT they are referred for, and to be prepared for the result.

“When the test comes back [with an abnormal result] and they feel the edges of their world beginning to melt, it is not the time for considered discussion about what they should do. It needs to be considered and planned beforehand.

“If that information is not useful to you – perhaps because you wouldn’t have a termination in the event of abnormal result – then it may not be the test for you.”

Professor Caroline de Costa, an obstetrician and gynaecologist at the James Cook University School of Medicine in Cairns, believes NIPT should not be limited to those women who can afford it. “It’s unfair really at the moment that these women can access this information and other women can’t,” she says.

In an editorial de Costa co-authored in the Medical Journal of Australia, she wrote: “There are strong arguments, both ethical and financial, for making NIPT available through the public health system in the near future, at least for major chromosomal anomalies. The inequity of access to NIPT and its current lack of regulation is a concern to many healthcare professionals.”

De Costa says having information about the foetus’s genetics at an earlier stage of pregnancy opens a Pandora’s box of issues that need further consideration.

 “If the diagnosis is made earlier, and termination methods that are less stressful and safer for the woman and more acceptable to medical staff are available, there could be greater pressure to undergo testing (and termination, when abnormalities are detected) than is currently the case,” she wrote. “What message does this then send to people with trisomy 21 in our community and their families?”

She tells The Saturday Paper: “I am extremely pro-choice but I think we need to think about the implications of this technology.”

With scientific advances, there’s a good chance NIPT will become possible even earlier in pregnancy, and will eventually give more genetic information about the foetus.

However, if NIPT was done before nine weeks, McLennan says it would be likely to detect abnormalities that would naturally result in miscarriage.

“You are turning a possible miscarriage into a decision about termination of pregnancy. You haven’t let the pregnancy go long enough,” he says.

In the MJA article, de Costa points out the final goal of NIPT – while it may be some time off – will be sequencing the entire foetal genome.

“Before this happens,” she says, “it is important that we have widespread community understanding of all the questions involved, so that wise decisions can be made about how this testing should be made available to Australian women.”

This article was first published in the print edition of The Saturday Paper on Dec 12, 2015 as "Behind the screens".

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Megan Howe is a Sydney-based medical writer.