The birth of a revolution in prenatal screening

Andrea Owens was 17 weeks and five days into her second pregnancy when her obstetrician called to say something might be wrong with the baby.

The routine prenatal screening that Ontario offered at the time, in 2012, suggested that she had a higher-than-expected risk of carrying a baby with Down syndrome.

To verify the findings, Ms. Owens, then 32, underwent an amniocentesis, a diagnostic test that required inserting a long needle into her stomach to retrieve a sample of her amniotic fluid.

The findings were heartbreaking. The baby had already died in utero. Had the child lived, further testing revealed, he or she would have had Down syndrome. (Ms. Owens and her husband decided not to find out if their lost baby was a boy or a girl.)

As Ms. Owens, a hospital communications specialist in Pickering, Ont., recalls it now, the hardest part of the experience was discovering that her pregnancy was at risk when she was well into her second trimester. She was showing. She had already told her family and friends that her one-year-old son was going to be a big brother.

A few months after the loss, Ms. Owens got pregnant again. This time, her doctor offered her a new test called Harmony.

For about $800, an American lab would analyze the fetal DNA circulating in Ms. Owens's blood and tell her as early as 10 weeks into her pregnancy if she was carrying a baby with the chromosomal anomalies that cause Down syndrome and a few other, less common, conditions.

"Once I found out about this test," Ms. Owens said, "I refused to wait until I was in my second trimester. I had to know right away."

The desire of women like Ms. Owens to know as much as possible about their pregnancies as early as possible is behind a quiet revolution in prenatal screening in Canada and other developed countries.

A new generation of simple blood tests is allowing would-be parents to learn about the sex and potential genetic anomalies of their babies in the first trimester, a stage of the pregnancy when it's relatively easy to get an abortion in Canada.

Known as non-invasive prenatal testing (NIPT), the approach has the advantage of giving some women more time to make decisions about their pregnancies, while helping others to avoid unnecessary invasive procedures such as amniocentesis, which carry a small risk of miscarriage.

But NIPT also raises difficult ethical questions, especially among opponents of sex-selective abortion and people with Down syndrome, who fear NIPT will make it easier to screen their condition out of future generations.

Complicating matters further, for-profit genetic testing companies are, in some cases, offering to screen for conditions that are much rarer than Down syndrome and therefore harder to reliably detect.

At least half a dozen companies already sell their testing services to Canadian women; one report on the lucrative NIPT market found 76 different versions of the tests are available around the world.

The NIPT market is "moving very, very quickly and the interest is high," said Tim Caulfield, a University of Alberta professor who is studying the ethical and legal implications of NIPT as part of a Canada-wide research project called PEGASUS, short for PErsonalized Genomics for prenatal Aneuploidy Screening USing maternal blood.

"It's surprising [NIPT] hasn't received as much attention in the media and popular culture more broadly," he said, "because it is a potentially very powerful tool." Available since 2011 to Canadian women willing to pay out of pocket, NIPT is now starting to be picked up by public health insurance, with little in the way of public debate.

Ontario and British Columbia already fund the tests for some women, primarily those who have been flagged as high-risk through traditional prenatal screening.

Women who have had a previous pregnancy or child with a chromosomal anomaly and women over the age of 40 can also be considered high risk.

Ontario covered 8,066 of the tests in 2016-17, up 55 per cent from 5,204 the year before.

In Quebec, an expert committee recently studied NIPT, and the provincial government there is expected to decide on public funding of the testing this year.

In Saskatchewan, a group of clinical leaders and physicians is working on a proposal to add the testing to its existing maternal screening program.

Most significantly, the Ontario committee that reviews new medical technologies and makes recommendations about their public coverage is currently studying NIPT to see if it should be offered to all pregnant women as a first-line test, regardless of their risk status.

If Canada's most populous province took that approach, it would mean all Ontario women could see the results of their NIPT as early as 10 weeks into their pregnancy, not just those with the means to pay a fee that today ranges from about $500 to a few thousand dollars, depending on the test.

Even without widespread public funding, NIPT "has really been a game-changer in our practice of prenatal diagnosis," said François Audibert, the head of maternal-fetal medicine at Centre Hospitalier Universitaire Sainte-Justine, a Montreal pediatric hospital.

Unlike traditional prenatal screening, which uses a combination of ultrasound and biomarkers in a pregnant woman's blood to make a good guess about whether a fetus is at elevated risk of having an extra chromosome, NIPT is conducted on a genetic level.

The tests, also known as cell-free fetal DNA(cfDNA) screening, use different algorithms to analyze DNA fragments that originate in the placenta and circulate in maternal blood.

The PEGASUS project, a $10.5-million, four-year effort involving more than 30 Canadian researchers, including Prof. Caulfield, found cell-free DNA testing to be impressively accurate at detecting Down syndrome in the high-risk women recruited for the study.

The project, the bulk of which was publicly funded, builds on years of research about cfDNA's reliability, most of it funded by test makers.

The official findings of PEGASUS are expected to be published in a peer-reviewed journal this year, but preliminary results presented at two conferences last summer showed that two versions of a cfDNA test developed by publicly funded labs in Canada were highly accurate and performed as well as Harmony, the commercial prenatal screening test that is marketed by California-based Roche Sequencing.

In tests of 1,947 high-risk women, the two in-house cfDNA tests had a positive predictive value of about 96 per cent when it came to detecting Down syndrome; one of the tests caught 145 cases of Down syndrome and missed five, the other caught 146 and missed three.

The tests' negative predictive value – a measure of how often they correctly predict that a fetus does not have Down syndrome – was 99.9 per cent when the test produced an interpretable result. (In 3.5 per cent to 4 per cent of cases, the analysis couldn't be completed because there was not enough fetal DNA in the women's blood to produce clear results.)

François Rousseau, a co-leader of the PEGASUS project and the head of laboratory medicine at Centre Hospitalier Universitaire de Quebec-Université Laval, says NIPT would likely be cost-neutral for the public-health-care system if used to weed out false positives found through conventional screening, which could in turn reduce the number of invasive tests "by probably 90 per cent."

Still, Dr. Rousseau and his peers are quick to point out that NIPT is not accurate enough to be considered diagnostic.

They say no woman should terminate a pregnancy without undergoing an invasive test to confirm the abnormal findings of an NIPT.

"There is some concern that because it's a very good test, doctors and patients would consider it a 100-per-cent reliable test that could replace amniocentesis or other invasive tests, which is not true," said Dr. Audibert, who is also one of the lead authors of a new prenatal screening guideline published in September by the Society of Obstetricians and Gynaecologists of Canada and the Canadian College of Medical Geneticists.

That caveat is even more important when NIPT is used to detect rarer genetic conditions such as trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome) or Turner syndrome, a condition that arises when a female is missing all or part of the X chromosome, which helps to determine the sex of a fetus.

The PEGASUS study found the positive predictive value was lower for all three of those conditions than it was for Down syndrome.

The waters get even murkier when it comes to screening for a slew of different microdeletion syndromes, which occur when a small segment of a chromosome is missing.

Several companies already offer microdeletion screening to women who can pay, but the new Canadian guidelines recommend against it, saying there isn't enough good evidence that cfDNA can reliably detect microdeletions.

Some of the tests fall into a regulatory grey zone in Canada.

After The Globe and Mail inquired about the Harmony and Panorama tests, the two brands that appear to be most popular in this country, Health Canada opened an investigation into whether they should be licensed as medical devices.

Right now, they're not, although Roche Sequencing and Natera, the U.S. companies that market the tests, stressed that the Canadian labs that now perform them are strictly regulated at the provincial level.

"Our lab is accredited in three different ways. We have to be," said Ron Carter, laboratory director at LifeLabs Genetics, which conducts the Panorama test on Natera's behalf at a lab near Toronto's Pearson International Airport. "In the last three assessments, we've received 100-per-cent compliance. We haven't even received recommendations."

He added that all of their data is sent to BORN, the Ontario government body that collects data on pregnancy and birth outcomes, for extra oversight.

Vardit Ravitsky, a professor of bioethics at the University of Montreal and another member of the PEGASUS team, predicted it won't be long before the companies vying for dominance of the NIPT market begin to offer screening for dozens more potential genetic flaws whose effects on a baby's future health are unclear.

"I'm not usually looking for sensationalist language," she said, "but it's going to be an avalanche of information – very confusing information at a very vulnerable time. Every day, your pregnancy is one day older. The information is complex and the test's reliability is evolving every week. It's a bit of a nightmare."

In the meantime, doctors, ethicists, pregnant women and their partners are wrestling with the choices NIPT already provides.

"NIPT certainly makes sex selection possible," said Meredith Vanstone, a professor in the department of family medicine at Hamilton's McMaster University, who is contributing to Ontario's review of potential expanded funding for NIPT. "This information is available, [through] private pay, early enough in pregnancy that a woman can access abortion quite easily. There's no way of tracking that."

Nor is there a way to control it, she added, without infringing on a woman's right to choose.

Mary Casagrande, 36, of Guelph, Ont., took the Harmony NIPT during her second pregnancy in 2013, after conventional screening identified her as at high-risk for carrying a baby with Down syndrome.

The Harmony results were positive for Down syndrome. Rather than proceed to an amniocentesis and risk a miscarriage, she and her husband, Ed, pushed past their initial devastation and sought out families raising children with Down syndrome, many of whom were thriving in a way that belied what the Casagrandes heard from their doctors.

By the time Ms. Casagrande gave birth to her daughter, Emma – now a happy four-year-old who rides the bus to junior kindergarten with her big brother – Ms. Casagrande was emotionally ready to raise a child with Down syndrome.

For Ms. Casagrande, NIPT cuts two ways: She is thankful for the extra time it gave her to prepare for Emma's birth, but she is keenly aware that other women in her situation could use that time to terminate their pregnancies.

"I think that if the number of people with Down syndrome is dramatically reduced, that the supports are not going to be there for people who have an intellectual disability because the need won't be there as much," she said. "[Down syndrome] is definitely not a disease and I don't think it's something that needs to be eradicated."

Ms. Owens, the Pickering, Ont., mother who miscarried a second pregnancy with Down syndrome, does not know what she would have done if faced with the same choice as the Casagrande family.

As it turned out, the Harmony test she paid for early in her third pregnancy revealed the baby had no chromosomal anomalies.

When Ms. Owens received the results, she sobbed with relief. "I cried. Tears of joy," she said. "It was really emotional because from the time that we lost our baby to the time I became pregnant again, it was sort of a short window. I feel like I was still working through all of those emotions and the grief."

On Sept. 21, 2013, a year to the day after losing her second pregnancy, Ms. Owens gave birth to a healthy baby girl.