Clinicians and researchers have long dreamed of accurate screening tools for preeclampsia — tools that could lead to detection before symptoms manifest and then targeted treatment.
The medical literature is replete with reports of preeclampsia predictors that were accurate but subsequently failed to take hold in clinical practice in the US. After years of rising incidence, preeclampsia now affects 1 in 12 pregnancies.
Some of these reports described studies that were small or not externally validated. Others described combinations of clinical factors and biochemical tests that were endorsed by professional bodies overseas but weren’t tested here or weren’t deemed practical enough for clinical practice in the US.
Now, there are signs of real progress — from growing attention to analytes such as placental growth factor (PlGF) to new studies of maternal circulating cell-free RNA (cfRNA) and cfDNA and new therapeutic studies.
“We’re moving [closer to] better identifying who is at risk and understanding the different pathways [to disease]. And as we do, we’ll move forward with more targeted approaches for prevention and treatment,” said Kara Rood, MD, a maternal-fetal medicine specialist at The Ohio State University College of Medicine, Columbus, Ohio.
The Problem With Current Risk Assessment
The current method of risk assessment and prevention falls short. The US Preventive Services Task Force (USPSTF) recommends the use of low-dose aspirin (LDA) between 12 and 28 weeks’ gestation (ideally at < 16 weeks) in people who are at increased risk for preeclampsia — defined as having one or more “high-risk” factors or two or more “moderate-risk” factors.
The problem is most pregnant individuals fall into the high-risk and especially the moderate-risk categories, the latter of which includes nulliparity, obesity, age 35 years or older, Black race, family history of preeclampsia, and lower income.
This has led to debates over possible universal LDA prophylaxis and discussion “about how to rule out who’s at such low risk they don’t need LDA,” said Ira M. Bernstein, MD, professor and chair of the Department of Obstetrics, Gynecology and Reproductive Sciences at the University of Vermont College of Medicine, Burlington, Vermont, and chair of the Preeclampsia Foundation’s medical advisory board.
A study just published in JAMA Network Open documents the problem. In the 11-center cohort study of 5684 pregnant individuals, almost 89% of participants were found to be at increased risk for preeclampsia, with 70.3% in the moderate-risk category and 18.5% in the high-risk category according to the 2021 USPSTF definitions.
High-risk factors had sufficient value in estimating risk, but except for nulliparity, moderate-risk factors for preeclampsia had “little or no value for preeclampsia risk assessment,” the investigators reported.
Molecular Subtyping and Preeclampsia Prediction With RNA Testing
The goal is to use biologic predictors rather than weakly predictive, sometimes ambiguous clinical and demographic characteristics to predict preeclampsia.
On one front, recent studies have shown promising predictive power with placental-derived cfRNA and cfDNA. In a large study sponsored by Mirvie (San Francisco), researchers analyzed transcriptomic data from blood collected at 17.5-22 weeks in a prospective cohort of over 9000 pregnant individuals who were 35 years or older and had no other preexisting high-risk conditions.
They identified distinct plasma cfRNA profiles capable of predicting preeclampsia — one reflecting the activation of placental genes like PAPPA2 that are associated with placental dysfunction, and the other correlating with “genes associated with maternal immune activity, probably inflammation, and probably some aspect of cardiovascular adaptation and systemic response,” said co-investigator Thomas F. McElrath, MD, PhD, professor of obstetrics, gynecology and reproductive biology at Harvard Medical School, Boston, and vice president for Clinical Development at Mirvie.
The two signatures align, respectively, with what researchers and clinicians have increasingly regarded as two distinct phenotypes of preeclampsia: an earlier form typically occurring before 34-35 weeks gestation and leading to preterm delivery or severe features, and a later form occurring at term.
Validation results show that the blood test identifies 91% of pregnancies that will develop preterm preeclampsia in this patient population. And those with low-risk test results had a 99.7% probability of not developing preterm preeclampsia.
Similar findings were reported by researchers at the annual meeting of the European Society of Human Reproduction and Embryology in June. Their preprint study analyzed cfRNA signatures in those who developed early-onset and late-onset preeclampsia in a cohort of approximately 9500 women and also found distinct profiles aligning with each phenotype.
Preeclampsia risk prediction using cfDNA testing, meanwhile, was described by National Institutes of Health-funded researchers in another paper published this April.
Mirvie’s research appears to be farthest along. Their blood test, branded Encompass, is available as a direct-to-consumer test for individuals aged over 35 years with no high-risk conditions for preeclampsia and singleton pregnancies (with a price tag of $1700). The company has formed partnerships with maternal health providers like Advantia Health, which offers the test.
“If someone is positive, it puts her at the same risk as someone who had preeclampsia in their last pregnancy early on. Or the same as someone who has diabetes, or kidney disease, or ongoing prepregnancy hypertension,” said McElrath, also professor of epidemiology at the Harvard T.H. Chan School of Public Health, Boston.
A Central Role for PlGF
Among the most well-studied biomarkers of preeclampsia risk are the proangiogenic PlGF and the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt1). Tests of the sFlt1/PlGF ratio are FDA-approved to help determine whether pregnant women with suspected preeclampsia — usually women who are hospitalized — are at high risk of developing severe disease within 2 weeks of testing.
Does PlGF itself have a role to play in more accurately identifying women at high risk for early-onset preeclampsia? In recent years, PlGF has been part of the first trimester “triple test” advocated by The Fetal Medicine Foundation (FMF) in London, England.
This test combines PlGF and maternal risk factors with mean arterial pressure and uterine artery pulsatility index (UtA-PI) to predict preeclampsia with both high sensitivity and specificity. It has been validated multiple times, more than other predictive models. But until now, interest in the US has been hindered largely by the inclusion of UtA-PI, which is not generally measured here.
In a study expected to yield results by the summer of 2026, researchers working under the auspices of the Foundation for the National Institutes of Health and its public-private Biomarkers Consortium are testing an algorithm similar to the FMF model. They are evaluating the first trimester predictive value of PlGF and one other circulating biomarker — pregnancy-associated plasma protein A (PAPP-A) — combined with maternal factors such as BMI and mean arterial blood pressure.
Research has already suggested that “PAPP-A when combined with PlGF gives similar performance as the FMF algorithm,” said principal investigator Ananth Karumanchi, MD, professor of medicine at Cedars-Sinai Medical Center, Los Angeles.
Other clinician-researchers, such as John Kingdom, MD, a maternal-fetal specialist at the University of Toronto, Toronto, Ontario, Canada, are documenting how PlGF offers a window into the health of the placenta at various points in gestation.
Kingdom uses real-time PlGF testing in high-risk patients to help diagnose preeclampsia and other problems after fetal viability (eg, fetal growth restriction). Upstream, in high-risk patients who start aspirin prophylaxis at 12 weeks to prevent preeclampsia, a 16-week PlGF test combined with placental ultrasound can guide management decisions, “providing reassurance when it’s normal” and prompting consideration of adjunctive therapies when it’s low, he said.
In patients without high-risk histories or conditions, PlGF testing can predict preeclampsia, Kingdom maintains. A screening study done over 10 years ago in the UK, he notes, showed that plasma PlGF at 14-16 weeks gestation in conjunction with clinical risk assessment improved the identification of preterm preeclampsia in nulliparous women over clinical risk factors alone.
In a prospective cohort study he recently led at Mount Sinai Hospital, Toronto, Ontario, Canada, of over 9000 unselected, predominantly low-risk patients, a low PlGF level (< 100 pg/mL) identified at the time of routine gestational diabetes screening (24-28 weeks) was associated with a 79.4-fold increased risk for preterm birth.
Screening for preeclampsia “needs high precision, but it also needs to be practical and easily and widely implemented,” Kingdom emphasized. PlGF testing in mid-pregnancy is “cheap, easily interpreted, unimodal…and can be tagged onto current diabetes screening.”
Needed Actions, Future Therapies
Experts believe that as risk assessment becomes more accurate, adherence to aspirin prophylaxis recommendations will increase, as will appreciation of evidence-based nonpharmacologic interventions.
But they also hope to see more data on the potentially prophylactic value of other agents such as heparin, metformin, and statins. “Even when used in the right patient, aspirin prevents only a portion of disease,” said Bernstein.
Questions about aspirin regimens continue to be explored, with reasonable data suggesting that higher doses are slightly more effective and just as safe, he said.
Metformin, Kingdom notes, has been shown in at least one randomized controlled trial to prolong pregnancy by at least 10 days in patients diagnosed with early-onset preeclampsia.
Low-molecular-weight heparin, which can improve vascular health through nonanticoagulant actions, “has been shown to boost the production of PlGF by placental tissues and by the endothelial cells,” he said.
McElrath said he has watched with interest the research on a potential role for statins in preventing preeclampsia that suggests the efficacy of pravastatin. With further study, it may be that “we start to see there are specific subgroups who will benefit [most],” McElrath said.
McElrath disclosed that he is an employee of Mirvie, Inc. Rood and Kingdom reported having no relevant disclosures. Karumanchi is an advisor to and has financial interest in Comanche Biopharma and Aggamin Pharmaceuticals and is a co-inventor on multiple patents related to preeclampsia biomarkers and therapy.