When she was 4 months pregnant, Angela Crawley waited for 30 minutes in a private room to hear the results of her noninvasive prenatal testing. Her ultrasound had been flagged as high risk by the radiologist and she agreed to undergo further testing to gather information on the health of her unborn child.
As she waited for her genetic counseling appointment, she noticed somber expressions on the faces of her health team and picked up on hushed tones.
It had taken 2 years to become pregnant and the joy she felt attending prenatal care appointments was fading into a sense of dread as she sat in that small room and the minutes ticked by.
Crawley – a scientist in the chronic disease program at the Ottawa Hospital Research Institute, assistant professor at the University of Ottawa, and adjunct research professor at Carleton University in Ontario, Canada – is more qualified than most patients to absorb health information and make appropriate decisions.
And yet, “I was completely unprepared,” she told Medscape Medical News as she reflected on what she now refers to as some of the darkest days of her life. “It was a nightmare and it was such a confusing, scary time.”
Crawley is among the more than 6 million women from at least 90 countries who have undergone noninvasive prenatal testing. During pregnancy, a mother’s bloodstream contains a mix of cell-free DNA from her own cells and from placental cells, which is usually identical to the DNA of the fetus. Analysis of cell-free DNA can lead to the early detection of genetic disorders.
Testing is most often used to look for chromosomal disorders that are caused by the presence of an extra chromosome, like in trisomy 21 in the case of Down syndrome or extra or missing copies of the X and Y chromosomes in other disorders. The accuracy of the test tends to vary, depending on the condition being assessed.
Cell-free DNA testing has reduced the number of invasive prenatal diagnostic procedures, some of which can lead to miscarriage, and this noninvasive option made sense to Crawley and was covered by government health insurance.
With a market projected to surpass $13 billion by the year 2027, some experts speculate that prenatal genetic testing is the most rapidly adopted test in human history. Globally, noninvasive prenatal tests cost $500 to $3,000 for patients who pay out of pocket, and all those screening options are amassing valuable genetic data troves.
The pioneer of noninvasive prenatal testing, Dennis Lo, PhD, from the Chinese University of Hong Kong, told Medscape Medical News that the success of using cell-free DNA came after a long, winding road of rejected grant applications and scientific skepticism.
“Initially, people did not think this would be useful for assessing chromosomal abnormalities because the thinking at the time was that we would need to count them,” Lo said.
But he was enchanted by early glimpses of the capability of cell-free DNA, and felt driven to pursue unconventional research ideas even though there were significant hurdles to overcome in the lab.
“We were detecting fetal Y chromosomes in women. At first, it was just scientific curiosity,” said Lo. “At the time, people worried that fetal cells would persist from one pregnancy to the next, but we discovered that fetal DNA actually clears very quickly and does not progress into the next pregnancy,” he explained. “This is very important because it won’t alter the accuracy of the test.”
Gripped by the scientific mystery, the researcher put in long hours at the lab. “I’m fortunate I have a very understanding wife who is herself a scientist,” he said. After a particularly long stretch without quality time together, Lo and his spouse, Alice Wong, went to see a Harry Potter movie.
As Lo viewed the Harry Potter H through 3D glasses, he was suddenly reminded of the male human karyotype.
“I saw the vertical stripes of the H and it hit me,” he told Medscape Medical News. “There are two sets of chromosomes.” The average human karyotype contains 22 pairs of autosomal chromosomes and one pair of sex chromosomes.
“Our complex genetic conundrum was cracked in the middle of a Harry Potter movie in a moment when I felt completely relaxed,” he recalled. “My wife said: ‘You can’t even watch a movie properly.’ ”
Back at the lab, Lo shared his Harry Potter–inspired concept and the team got to work.
In December 2019, Lo received the Fudan-Zhongzhi Science Award in Shanghai from Nobel laureate physicist Samuel Chao Chung Ting, chair of the award committee. The prize honors fundamental and groundbreaking achievements in biomedicine, and the laureate receives ¥3 million (about U.S. $428,550), donated by Zhongzhi Enterprise Group.
This honor was 30 years in the making, Lo told Medscape Medical News. “I’m pleased to experience public recognition and this is a high honor in China,” he added.
“Noninvasive prenatal testing is better than anything we’ve ever had before,” said Ronald Wapner, MD, from the Columbia University Irving Medical Center in New York City, who taught a course on the transition of prenatal diagnostics from amniocentesis to whole-genome sequencing at the recent Society for Maternal–Fetal Medicine 2020 Annual Pregnancy Meeting.
“We now have the capability to improve healthcare decision-making in utero and at birth,” he told Medscape Medical News. “It’s remarkable.”
But, Wapner said, the market grew too fast. “The National Institutes of Health didn’t even play a role in these fast-paced developments. Traditional governing bodies and authorities were bypassed as cytogenetic labs marketed directly to physicians and patients,” he explained.
One of the major problems with the rapid uptake in testing is a lack of preparation for patients like Crawley.
The clinician who delivered her test results was not feeling well, so “she spoke through a surgical mask,” Crawley reported. “I was trying to understand what she was saying, but it was an uncomfortable exchange.”
Crawley had undergone prenatal genetic testing because her ultrasound had shown irregularities in fetal leg measurements. The genetic tests confirmed no anomalies in the chromosome count, but that was it.
“There was no prognosis, just vague numbers that no one seemed to know what to do with,” Crawley recalled.
With concern about growth measurements, the conversation moved quickly to options, including termination. Crawley said the dialogue felt jarring and moved too quickly for her to process all the information and possible courses of action.
She was told she could terminate and “try again to get pregnant.” But Crawley was 39 years old and had been trying to conceive for 2 years.
“It was devastating,” she said. “No one sat down with me before this appointment to learn about my values or preferences, and I left that conversation with more questions than I had before I arrived. I went home and had one the worst weekends of my life. My husband and I felt so overwhelmed, grieved, and alone.”
Pretest counseling can be as important as any subsequent genetic counseling, said Blair Stevens, a prenatal expert from the National Society of Genetic Counselors and a genetic counselor at the University of Texas Health Science Center in Houston.
“Information is valuable, but it can also be toxic, depending on what individuals intend to do with what they learn,” she explained. “We cannot unknow or unhear details, so it’s really important to work with patients in advance to make sure their preferences guide any planning.”
Uncertainty can be very unsettling, she acknowledged. “It’s important to help patients balance any ambiguity, so if there is a 20% risk, there is also an 80% chance of another, perhaps more favorable, outcome.”