NEW YORK – Based on promising new data, developers of a cell isolation technology called NanoVelcro are hopeful that they can apply their platform in the clinical diagnosis of placenta accreta spectrum, or PAS, a collection of pregnancy complications in which placental trophoblast cells implant, invade, or adhere abnormally into the uterine muscle tissue.
In their study, published earlier this month in Nature Communications, investigators from NanoVelcro and their clinical collaborators demonstrated that detection of a combination of single and clustered circulating trophoblasts could reliably differentiate PAS from normal controls and other disorders like placenta previa, even in early gestation where current diagnostic tools struggle.
Developed initially for isolation of circulating tumor cells in cancer patients, NanoVelcro is a nanostructure-embedded microchip designed to capture and enrich specific target cells from a mixed sample. Several years ago, investigators explored the platform as a tool for noninvasive prenatal diagnosis — with early proof of concept that placenta-derived circulating trophoblast cells could be isolated from parental blood samples for chromosomal and other genetic testing.
Hsian-Rong Tseng, one of the inventors of NanoVelcro and a professor at the Crump Institute for Molecular Imaging at UCLA, said this week that although the NIPD work has met roadblocks in translation to the clinic, it did manage to catch the eye of physicians in the maternal/fetal medicine space who believe the platform could provide more accurate and timely diagnosis of PAS.
Yalda Afshar, the study's first author and a physician at UCLA, said that while clinicians who treat pregnant and birthing individuals aren't necessarily wringing their hands over PAS, there is a "very obvious need" for better and earlier diagnosis.
Current diagnostic tools for PAS include ultrasonography and magnetic resonance imaging, but these imaging-based methods are subjective, with accuracy dependent on the operator.
According to the study authors, MRI is also expensive and requires expertise that is rarely available in lower resource settings. Reflecting this, recent population studies have shown that as many as two-thirds of PAS cases remain undiagnosed before delivery.
"We know that maternal morbidity [and] severe outcomes are increasing," Afshar said. "Maternal mortality is increasing. And … this is especially true in rural areas and poor resource areas — centers without subspecialty surgeons, blood banks et cetera. … So I think there is just a glaring need to improve care."
"The two things that we know that are associated with significantly better outcomes are identifying [patients] earlier and sending them to expert centers," she added.
According to Margareta Pisarska, a reproductive endocrinologist and fertility specialist at Cedars-Sinai Medical Center and another clinical co-investigator on the study, part of this observed increase in PAS may reflect the fact that a larger proportion of individuals are now becoming pregnant later in life. Some fertility treatments can increase the risk of PAS, as can uterine surgery, she said.
"As we're seeing it more and more commonly, it could be game changing for our patients to be able to manage more successfully because, right now, it's often not diagnosed until the time of delivery, which is a really unfortunate situation. Facilities aren't necessarily prepared for this type of pregnancy [and] the significant morbidity that can result."
According to Afshar, her team's interest in the NanoVelcro platform was somewhat spontaneous. "The way I stumbled on this is that I saw some of their previous work on liquid biopsies, and I approached them cold turkey and said, 'How can we translate this to this disease that I am dealing with?'"
In the Nature Communications study investigators led by Afshar set out to test the hypothesis that the same circulating trophoblasts that the NanoVelcro team were interested in isolating for fetal diagnostics could serve as an indicator of PAS.
In their early experiments, the team saw not only higher levels of circulating trophoblasts, or cTBs, in PAS cases but also the presence of trophoblast cells clustered together. As a result, they retuned the NanoVelcro technology to preserve these clumps, or aggregates of cells, in addition to isolating single cTBs.
Using their optimized chips, the investigators analyzed samples from 168 pregnant individuals, divided between those with clinically confirmed PAS, placenta previa, or normal placentation. An additional 15 healthy non-pregnant female donors served as controls.
According to the authors, the numbers of both single and clustered cTBs were significantly higher in PAS than those in non-PAS participants.
Single cTBs were present in the majority of pregnant women, with detection rates of 98, 85, and 86 percent in PAS, placenta previa, and normal placentation, respectively. The presence of clustered cTBs was statistically significantly higher in PAS compared to the placenta previa group and the normal placentation group. More than 85 percent of PAS cases showed clustered cTBs, compared to about 20 percent of placenta previas and 14 percent of normal pregnancies.
The researchers then conducted statistical analyses, finding that both single and clustered cTBs contributed independently to prediction of PAS. They used these finding to build a logistic regression model that showed high accuracy when applied to an independent sample set. Overall, they calculated a positive predictive value of about 84 precent and a negative predictive value of 92 percent across the study's combined cohorts.
According to the authors, the fact that the NanoVelcro assay performed well even in samples from individuals at early stages of gestation was especially encouraging.
The authors cautioned that the current results are limited by the small size of the study.
"We're actively working on a larger clinical study now so that we can validate this in a larger cohort with [rigorous] systematic statistical design," Afshar said. "But what we've demonstrated is very solid pilot data that it's worth continuing to pursue," she added.
And even if the approach is validated more thoroughly, the magnitude of benefit offered by earlier and more definitive detection of PAS will still have to be borne out.
"In maternal health and delivery, we think of having a child and having a delivery as, overall a happy, healthy event," Pisarska said. "But in situations like this, these are very difficult times to try to manage through. And if we have a plan in place, schedule the delivery, have the right members on the team on board, have all the things prepared, that should lead to a more scheduled controlled delivery."
Another area for future study could be the potential of cTBs to serve as a readout of the progression of placental invasion. In other words, changes in the numbers of these cells might indicate worsening PAS. The current study hinted at this, with three individuals with very early stages of PAS presenting without the presence of clustered cTBs, but future studies will be needed to test this possibility.