Non-Invasive Prenatal Testing is 99 per cent accurate when screening for Down's syndrome
Test carries no risk of causing miscarriage unlike amniocentesis or CVS
When Doris Chan's prenatal test results showed that her 12-week-old fetus had a one in 125 chance of having Down's syndrome, she was in shock. At 35 years old, Chan (whose name has been changed for reasons of patient confidentiality) was stressed by her biological clock and had previously suffered two miscarriages.
"We started to ask ourselves hard questions, like 'Do we keep the baby?' and 'What kind of changes do we make to our lives?'" says Chan.
Traditionally, the next step is to confirm the diagnosis through an amniocentesis or chronic villus sampling (CVS). Both procedures are invasive - a needle is inserted in the woman's uterus to draw out either amniotic fluid (amniocentesis) or tissue from the placenta (CVS) - and carry a risk of miscarriage of up to one in 100.
Chan wasn't too keen on either procedure as she didn't want to risk losing another baby. Her doctor suggested Non-Invasive Prenatal Testing (NIPT) instead, a relatively new DNA test that has shown in studies to be more than 99 per cent accurate in screening for Down's syndrome, Edwards syndrome and Patau syndrome.
A blood sample was taken and a week later she got a call from her doctor: the NIPT result was negative. "It was a huge relief," says Chan, who is now 32 weeks into her pregnancy.
The number of women in Hong Kong opting for NIPT has increased steadily since its introduction worldwide in 2011. At The Women's Clinic in Central, nearly 80 per cent of antenatal women choose to have NIPT says obstetrician Dr Charas Ong Yeu-theng.
At Central Health Medical Practice, about 60 per cent of pregnant women have the test, says obstetrician Dr Lucy Lord.
"Certainly, women are getting more aware of NIPT," says Dr Danny Leung Tse-ngong, director of Hong Kong Sanatorium & Hospital's maternal and fetal medicine department and president of the Obstetrical and Gynaecological Society of Hong Kong.
This is despite its cost - more than HK$6,000. The traditional test, Oscar (one-stop clinic for assessment of risk), costs about HK$2,000 in a private clinic; in public hospitals it's free as part of a universal Down's syndrome screening programme introduced by the Hospital Authority in 2010.
Chan paid HK$9,000 for her NIPT. "The price didn't hold us back because we would rather have peace of mind."
As the popularity of NIPT increases, fewer invasive procedures are being performed. At Hong Kong Sanatorium, Leung says about 4,000 NIPT cases have been performed since the test was introduced in December 2011. Prior to that, there were about 10 cases of invasive testing a week. "Now it's maybe once every one to two months," says Leung.
The Oscar test remains the most commonly used screening method for fetal abnormalities in Hong Kong, Leung says.
Done between the 11th and 14th week of gestation, the test computes the chance of a Down's syndrome fetus through a combination of maternal age, sonographic measurement of the fetal nuchal (skin at the back of the neck) translucency, and a blood test for maternal serum biochemical markers.
In a large local prospective audit, this approach achieved a detection rate of 91.2 per cent for Down's syndrome, with a screen-positive rate of 5.1 per cent and a false-positive rate of 4.9 per cent. Leung says the use of fetal or maternal serum markers for screening will always produce some errors because these markers merely reflect an association - but not a representation - with fetal chromosomal abnormalities.
NIPT, on the other hand, screens the fetus' DNA. Done as early as 10 weeks, it has near-perfect sensitivity and a very low false-positive rate.
The test is based on a discovery made in 1997 by Professor Dennis Lo Yuk-ming, Chinese University's Li Ka Shing Professor of Medicine, that the fetus releases its DNA into the mother's blood plasma.
Advancements in sequencing technologies make possible the precise determination of a relatively small difference in DNA concentrations. With Down's syndrome, for example, there's an elevated amount of chromosome 21 sequences in maternal blood.
The past couple of years have seen rapid growth in NIPT use. There are now about 10 different test providers worldwide, says Ong, with five or six being offered in Hong Kong.
The Prenetics verifi, or V, test - one of four brands offered at Ong's practice - was developed by Stanford University and is the latest to be launched in the city. Since its soft launch in May last year, more than 1,000 V tests have been sold, says Dr Lawrence Tzang Chi-hung, Prenetics co-founder and chief scientific officer. In Hong Kong, around 200 obstetrics and gynaecology centres use the V test, he says.
Other brands of tests available in Hong Kong include safeT21 developed by Chinese University; Nifty by Beijing Genomics Institute; Panorama by Natera in San Carlos, California; and Harmony by Ariosa Diagnostics in San Jose, California.
Competition is intense between the brands, with each claiming its test is the best. Prenetics markets its V test - with the help of Canto-pop star Gigi Leung Wing-kei as its brand ambassador - as "the most comprehensive in the industry".
It claims to detect common chromosomal abnormalities such as Down's syndrome at 99.9 per cent sensitivity and a 0.02 per cent false-positive rate.
SafeT21, the first NIPT test available in Hong Kong, gives three different rates: 99.1 per cent sensitivity and 0.1 per cent false-positive rate for Down's syndrome; greater than 99.9 per cent sensitivity and 0.4 per cent false-positive rate for Edwards syndrome; and 91.7 per cent sensitivity and a 0.3 per cent false-positive rate for Patau syndrome.
If you're confused by all these figures, Leung says all the tests are "roughly the same. I generally believe that NIPT is a test that's very mature and is working very well", he says. "All the brands will probably do a good job."
Leung, who previously worked at Chinese University, says Hong Kong Sanatorium only offers the safeT21 test. At Central Health Medical Practice, Lord uses Panorama as her main provider, but also Harmony because she says the test is better for multiple pregnancies.
If there's one key similarity among all the brands, it's that NIPT is only a screening tool.
In the US, a report published last month by the New England Centre for Investigative Reporting revealed that some women were aborting babies based on NIPT tests alone.
The report cited a recent study by Natera that found 6.2 per cent of women who received high-risk test results terminated pregnancies without getting confirmation through invasive tests.
"NIPT is not diagnostic," Ong stresses. "Amniocentesis or CVS is still the gold standard for diagnosis. So if one is screened positive by NIPT, it doesn't mean the baby has Down's syndrome and you go ahead with termination of the pregnancy.
"One should always be counselled by an obstetrician, have an ultrasound scan and be offered the option of CVS or amniocentesis to make the diagnosis because there could be the possibility of a false-positive."
False-negatives, too, can happen. Among the 4,000 NIPT cases at Hong Kong Sanatorium, Leung says there was one case of Down's syndrome missed. After the patient's Oscar test had produced a high-risk score, a follow-up safeT21 test came back negative.
However, an ultrasound later revealed that the fetus had some Down's syndrome features. The woman decided to keep the baby.
Ong shares a recent case in which a woman had three NIPT tests done: the patient had done a test at another clinic and it was inconclusive for Edwards syndrome, so she repeated the same test, which was inconclusive for all conditions.
She was then offered a CVS or amniocentesis, or another brand of NIPT. She opted for NIPT, and this time the result was normal for Down's, Edwards and Patau syndromes. At 19 weeks gestation, the patient then saw Ong for her second trimester anomaly scan, which showed the fetus had a severe brain problem. Given the findings, Ong suggested the patient have an amniocentesis to find out if the chromosomal make-up of the baby was normal.
"The patient asked why she needed an amniocentesis since NIPT showed that everything was normal," says Ong. "When I explained that NIPT was just a screening test, that there could be false-negatives and that other chromosomal abnormalities were not tested, she was in shock. Obviously, she hadn't had proper pre-test counselling."
Eventually an amniocentesis showed the baby's brain abnormalities were so severe that the mother opted for termination of pregnancy.
Certainly, as Ong's case shows, NIPT has its limitations and misconceptions.
Leung adds that NIPT requires a certain concentration of fetal DNA within the maternal blood for it to be accurate. Low concentrations are related to false-negative test results. Twin pregnancies - in particular non-identical twins - also affect test accuracy.
Further, there is a small possibility that test results might not reflect the chromosomes of the fetus, but instead the chromosomal changes to the placenta or of the mother.
As technology advances, NIPT could become more accurate and as cover a wider rage of abnormalities. Experts also think the test will become more affordable. The first sequenced human genome cost nearly US$3 billion in 2001; now, it's US$1,000 or less.
"There's no doubt that one day NIPT will be offered as primary screening," says Lord. "I think it'll be soon - two to five years - once they've worked out ways to make it cheaper."
Leung, however, questions the ethics of NIPT.
"In my opinion, if the woman knows too much about the baby, it might not necessarily be a good thing: some people might terminate a potentially viable baby," he says.
"For example, with XXY (Klinefelter) syndrome, the baby may be infertile, a tall and thin adult, and sometimes might have behavioural or learning difficulties. But some babies turn out to be absolutely normal. However, the woman might not understand this. Ethically, should we know more?"