NEW YORK (360Dx) – Recent changes in professional guidelines regarding the use of cell-free DNA-based noninvasive prenatal screening for fetal aneuploidies are starting to have an effect in several large reference labs, which are seeing significant growth in the use of NIPT for screening average-risk patients.
"The vast majority of the volume we continue to receive is in the high-risk population, but we are seeing an increase in the frequency and adoption of testing in the average-risk population," said Mike Minahan, senior vice president and head of LabCorp's Integrated Genetics business. "The test performs just as well in that population. The incidence of disease is not the same with respect to chromosomal aneuploidy 13, 18, and 21, but the screening test is improving the overall sensitivity and specificity in that population. What we are seeing is, physicians don't want two levels of care for their patients."
While labs declined to disclose precise growth rates in test usage, Quest Diagnostics CEO Steve Rusckowski noted during a third quarter conference call that the company had made progress in noninvasive prenatal screening, with prenatal testing providing double-digit growth year over year.
"OB/GYN's are pretty conservative, and as a group, pretty guideline-driven," said Linda Mahoney, executive director of women's health at Quest. "As more clinical studies came to light, and as professional societies looked at the benefits of NIPS and the value it could bring diagnostically, they expanded their guidelines to support use in a broader population. That's when we saw physicians more interested. Certainly what we heard from our sales force was more of an interest in noninvasive prenatal exam and whether it would be appropriate for the broader pregnant population."
A broader view
Changes in guidelines were prompted by the publication of several clinical studies of NIPT among high-risk and average-risk pregnancies, the largest of which was published by Mary Norton and colleagues in the New England Journal of Medicine in 2015, according to Anthony Gregg, president-elect of the American College of Medical Genetics and Genomics, and chief of maternal-fetal medicine at the University of Florida. Those researchers studied nearly 19,000 women at 35 centers in the US, Canada, and Europe between March 2012 and April 2013.
"There was initially a thought that because the prevalence is very low in an average-risk patient, the test performance, and in particular the positive predictive value, would fall so low that the test would become useless. What people learned was that wasn't the case," Gregg said.
In fact, Gregg said, studies showed that the positive predictive value of serum analyte screening, which physicians had been using for years, was lower than NIPT for average-risk as well as high-risk patients.
The American Congress of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine revised their committee opinion on cell-free DNA screening in September of 2015, replacing an opinion that stated that NIPT should only be offered to high-risk women, to be more permissive, according to a spokesperson. ACOG still indicated that "conventional screening methods" are the most appropriate choice for reasons that include "limited data on cost-effectiveness in the low-risk population."
ACMG was more supportive in its position statement on NIPT, published in 2016, according to Gregg, who was the lead author of the statement.
"We say clearly that all pregnant women should be informed of this screening test. This test performs better than anything we do to date," Gregg said.
Reimbursement Challenges
While insurance companies are increasingly paying for NIPT, particularly in the high-risk category, insurance coverage is inconsistent when it comes to average-risk patients, the labs said.
"Coverage policies have not kept pace with the adoption in the average-risk population," Minahan said. "It depends on the plan and the coverage benefits, so we are adjudicating it appropriately given our relationships with managed care organizations, and in some cases, patients are paying out of pocket to gain access to screening."
To mitigate variations in insurance coverage, Quest has negotiated with health plans, and implemented financial assistance programs to support usage of the screen, according to Mahoney. The company is also working to take advantage of the loweing costs for of next-generation sequencing. Quest's NIPT, called QNatal Advanced, uses an Illumina sequencing platform.
"Frankly, where we saw growth, the other issue for us was not just having the offering but making sure that it is accessible to all patients," Mahoney said. "Making sure when patients with insurance and without insurance got bills, that prenatal exams are accessible, is something we really worked hard with our health plans and our internal teams to ensure, because everyone is concerned about out-of-pocket cost of healthcare."
LabCorp's NIPT is called InformaSeq, and the company has added screening options acquired through its 2016 acquisition of NIPT provider Sequenom. Both Quest and LabCorp offer screens for the common fetal aneuploidies of chromosomes 13, 18, 21, as well as for sex chromosome aneuploidies and certain microdeletions.
Many patients and physicians aren't aware of conditions that are caused by microdeletions screened by NIPT, but the conditions are associated with severe disabilities, according to Gregg. Microdeletion screens are for the general population, rather than for high-risk groups, and they look for syndromes that are less common, with lower predictive value, meaning there may be more false positive results. Without NIPT microdeletion screens, these debilitating diseases can only be detected through diagnostic tests, Gregg noted.
"There is no other way to screen for these conditions. I think they will have even greater uptake once providers really understand what these additional microdeletion and -duplication screens offer the patients," he said.
Some of the most common syndromes detected through microdeletions include DiGeorge syndrome, which occurs in one in 3,000 pregnancies; 1p36 deletion syndrome, with an occurrence of one in 5,000; Prader-Willi syndrome, which has a frequency of one in 10,000; and Cri-du-chat syndrome, which occurs in around one in 20,000 pregnancies, he said.
"If you add up microdeletion/-duplication conditions, before you know it, they have a combined frequency that starts to be more common than trisomy 13 or 18," he said.
As with other screens for average-risk pregnancies, however, there is inconsistent coverage by insurers, Gregg said.
"Who is going to pay for it? There are two barriers to widespread use. Insurance companies are not uniformly paying for this in average-risk patients. Cost is much higher than traditionally used analyte screening. This poses a barrier for patients whose insurance companies have not yet recognized the advantage of this technology," he said.
Increasing awareness
While some of the rise in usage of the test may be guideline-driven, a PiperJaffray survey of more than 1,300 consumers suggests some of the growth in use of NIPT may be resulting from increased awareness of the test among patients.
"We found more average-risk patients hear about noninvasive prenatal testing through friends or from expectant mother websites compared to the high-risk group," PiperJaffray analyst William Quick wrote in the report.
Maroney noted that the awareness among patients is not surprising, given how actively pregnant women seek information.
"Most pregnant women are hungry for information. More and more women are coming to understand that NIPS is a way to get some unique information about the health of their baby and physicians have come to understand how NIPS works and what the clinical benefits are," she said.
A key benefit, Minahan noted, is that NIPT offers fewer false positives than previously used screens, and as a result, it has reduced the number of invasive diagnostic tests like amniocentesis.
"I'd say it's a push-pull scenario. We are seeing patients asking for it and we are seeing physicians adopt it because they know it's a very good test and it's replacing biochemical screening which had its limitations."
Meanwhile, growth in NIPT is coinciding with growth in other tests for expectant parents, particularly carrier screening, a DNA test for genetic diseases that parents might pass on to children, Maroney said. Earlier this year, ACOG expanded its recommendations for carrier screening, stating that both spinal muscular atrophy (SMA) and cystic fibrosis testing should be offered to all women who are considering pregnancy or are currently pregnant, not just those with family histories of the diseases.
The new guidelines, as well as the fact that advances in next-generation sequencing have brought down the cost of carrier screening, has resulted in increased use of SMA screening as well as expanded carrier screening, which looks for multiple diseases at once. Quest offers Q-Herit, which screens for 22 diseases.
LabCorp Integrated Genetics has seen similar growth in SMA screening and expanded carrier screening, Minehan said. He cautioned, however, that physicians have to act on all data that may be abnormal, and suggested the industry needs to carefully weigh how data will impact pregnancies.
"The platform is limitless, meaning we can get tremendous amounts of data, but we can't get too far ahead of coverage," he said. "I envision a time where physicians are going to want to know as much as they can, and patients are going to want to know as much as they can, and payors are going to be very thoughtful about where the ROI is in what we are paying for from a screening perspective and whether it makes sense. I think there has to be an ongoing dialog between societies, the payor population, commercial organizations, as well as patient advocacy groups to make sure we are all aligned and being thoughtful and appropriate as we introduce new tests."