19 Feb 2025
Low levels of a protein that signals placental development could alert physicians to need for enhanced monitoring, researchers say
A research team from Sinai Health and the University of Toronto has identified a way to determine which mothers are more likely to deliver a baby preterm, raising the possibility of developing a universal screening strategy.
The study, published recently in JAMA Network Open, found that low levels of placental growth factor (PlGF), a protein that signals placental development, is associated with a preterm birth, defined as a birth before 34 weeks’ gestation. It also suggests that a simple blood test to detect the level in expectant mothers could alert physicians to a need for enhanced monitoring and delivery planning.
A protein released by the placenta into maternal blood, PIGF acts to promote relaxation of the maternal blood vessels and helps normalize the mother’s blood pressure despite the large increase in blood volume and cardiac output needed to support the 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, which ultimately 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.
If you know in advance that you’re high risk, there are ways to improve pregnancy outcomes, says fourth-year obstetrics and gynaecology resident Rachel Gladstone, who led the study with John Kingdom, a clinician-scientist at the Lunenfeld-Tanenbaum Research Institute at Sinai Health and U of T professor of obstetrics and gynaecology.
“It starts with self-monitoring for elevated blood pressure and perhaps taking anti-hypertensive medications to keep it under control,” Gladstone says. “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.”
PlGF levels rise as the healthy placenta develops, reaching a peak by 28 weeks as the third trimester commences. The study found that if 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.
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.
For each of the 9,000 patients, Gladstone says “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.”
The prospective observational study was able to show that other factors, including 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. “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).
“It is very obvious based on the data that large-scale screening would deliver health systems cost savings,” says Kingdom. “I’m optimistic we’ll see this happen within three to five years.”
Gladstone and Kingdom say the next step is a randomized controlled trial that reliably measures the maternal and fetal health benefits of PlGF screening as well as its associated costs, which could help convince provincial and territorial governments to implement such a test.
To start the dialogue, Kingdom, Gladstone along with two other members of the research team – Kelsey McLaughlin and John Snelgrove, both staff members at Mount Sinai and U of T assistant professors of obstetrics and gynaecology – met with regional representatives from across Canada in late 2024 with the support of the Canadian Institutes of Health Research, the Morra family and Deluxe Corporation Foundation.
For Gladstone, it had been a winding journey to arrive at such a high-profile knowledge translation meeting, where she presented the 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.”