A new blood test to identify individuals at risk of preterm birth

There’s currently no universal screening strategy to determine the likelihood of delivering a baby preterm, but a University of Toronto research team led by fourth-year ob-gyn resident Rachel Gladstone and John Kingdom, a professor of obstetrics and gynaecology, may have found one.

Their study concludes that a low circulating blood level of placental growth factor (PlGF) — a protein that signals placental development — is associated with an early preterm birth, defined as a birth before 34 weeks’ gestation. A low level would alert physicians to a need for enhanced monitoring and delivery planning.

The team, which includes a number of faculty members from the Temerty Faculty of Medicine, recently published the study in JAMA Network Open. 

PlGF levels rise as the healthy placenta develops, reaching a peak by 28 weeks as the third trimester commences. The study found that when the level of PlGF is below 100 picograms per millilitre between 24- and 28-weeks’ gestation, the risk of birth before 34 weeks’ gestation is almost 50-fold higher. Since only about 1.5 per cent of the population falls in this range, a PlGF screening test is highly specific, and few people would have false-positive results.

If you know in advance that you’re high risk, says Gladstone, there are ways to improve pregnancy outcomes.

“It starts with self-monitoring for elevated blood pressure and perhaps taking anti-hypertensive medications to keep it under control. And if you originally had plans to deliver at a community hospital or remote location, you could decide to receive care at a tertiary centre, which may be safer for both mother and baby than emergency transport to such centres for unanticipated complications.” 

The study was conducted from 2020 to 2023 and involved over 9,000 pregnant participants who intended to deliver their baby at Mount Sinai Hospital. They were tested by their health care provider for PlGF levels (through a blood sample) at the same time as their routine screening blood test for gestational diabetes, between 24 to 28 weeks.  

PlGF is a protein released by the placenta into maternal blood. It acts to promote relaxation of the maternal blood vessels. This helps normalize the mother’s blood pressure despite the large increase in blood volume and cardiac output needed to support growth of the baby. It also protects the mother from blood loss at delivery. 

Research from Mount Sinai Hospital and other centres shows that low levels of PlGF contribute to the development of a potentially dangerous type of hypertension called preeclampsia. Ultimately, preeclampsia necessitates physician-initiated early delivery in two-thirds of patients with low PlGF levels. 

A second complication, fetal growth restriction, accounts for the majority of other medically indicated preterm births, to prevent stillbirth.

For each of the 9,000 patients, says Gladstone, “we went back into their medical record and looked at their birth outcomes, such as birth weight and gestational age at birth. We could also ascertain whether they developed preeclampsia by looking at their bloodwork and blood pressure, to define the relationship between low PlGF and key complications.”

This prospective observational study was able to show that other factors, such as weight, race or previous pregnancy outcomes, did not affect the association of low PlGF with preterm birth. This makes the PlGF screening a unimodal test, unlike most pregnancy screening programs, which require multiple data inputs before algorithmic analysis.

“This means it’s a very simple test to interpret,” says Kingdom, who is an obstetrician and clinician-scientist at Sinai Health. “It doesn’t matter how tall you are, whether you’re Black or white, or if you’ve had a baby before, the test interpretation remains valid regardless of those inputs.”

Many hospitals in Canada currently have the laboratory technology and the expertise to accommodate such a test because PlGF is included in early pregnancy risk assessment for Down’s syndrome (trisomy 21). Rollout across Canada would come down to a budgetary decision, says Kingdom.

“It is very obvious based on the data that large-scale screening would deliver health systems cost savings. I’m optimistic we’ll see this happen within three to five years.”

Both Gladstone and Kingdom acknowledge that the next step is a randomized controlled trial, one that reliably measures the maternal and fetal health benefits of screening and costs. It would provide critical evidence to the provincial and territorial governments that implementation of a PlGF test could be worth the allocation of resources. 

To start the dialogue, Kingdom, Gladstone and two members of the research team — Kelsey McLaughlin and John Snelgrove, both assistant professors of obstetrics and gynaecology and on staff at Mount Sinai — met with regional representatives from across Canada in late 2024. (The meeting was made possible by funding from both the Canadian Institutes of Health Research and the Morra Family and Deluxe Foundation.)

For Gladstone, it had been a winding journey to arrive at such a high-profile knowledge translation meeting, presenting a paper’s findings as lead author. 

“During med school, I was deciding between internal medicine and ob-gyn and found a project on preeclampsia, which was a perfect merger of the two,” she says. “Then this study generously fell into my lap by way of Dr. Kingdom, and I stepped away from residency to do a master’s in clinical epidemiology.”

She also recently finished the Surgeon-Scientist Training Program this past June.

“She’s well-poised now for a clinical-academic career,” says Kingdom. “This is a great example of empowering smart people to deliver their full potential.”