NEW YORK – Researchers at the University of Virginia School of Medicine and elsewhere are building evidence they believe could pave the way for a blood-based biomarker test to screen pregnant patients for risk of developing preeclampsia.
Preeclampsia is a serious pregnancy complication and a leading cause of maternal death, responsible for 70,000 mother and 500,000 fetus deaths globally each year. It's characterized by high blood pressure, problems with blood clotting, and kidney dysfunction, and it can result in various poor outcomes, including premature delivery.
The condition is diagnosed by symptoms including hypertension, proteinuria, low blood platelet count, and edema, but those symptoms don't tend to appear until midway through pregnancy, after 20 weeks. To prevent preeclampsia, aspirin is commonly prescribed in low doses to women thought to be at risk. However, the drug only works at preventing the condition in about half of patients, and to be most effective, it must be started within the first 16 weeks of pregnancy, before symptoms arise.
Knowledge of a patient's likelihood of developing the condition is critical to inform whether they need such preventive treatment or could benefit from additional monitoring for symptoms.
"There's a need to identify ways of predicting women who will develop preeclampsia during a pregnancy so that could be averted, if possible, with prophylactic treatments," said Jerome Strauss, an emeritus professor of obstetrics and gynecology at the University of Pennsylvania's Perelman School of Medicine.
Today, that risk assessment involves whether a patient has chronic hypertension, diabetes, kidney disease, autoimmune disease, or a combination of moderate risk factors, such as obesity or family history, according to guidelines from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. "There's interest in biomarkers that can identify women who are at risk earlier than the onset of symptoms," in addition to those clinical factors, Strauss said. But while some research has suggested certain bioactive lipids can be predictive of preeclampsia, that hasn't been validated, and there isn't an accepted method for identifying those lipids as part of clinical care.
Strauss and colleagues recently identified multiple lipid-based biomarkers in patients' blood during pregnancy that they say could predict risk of developing preeclampsia, findings they reported in the Journal of Lipid Research this summer. Though, they noted, validation studies are needed.
For the study, investigators analyzed plasma derived from blood samples of 57 women seen at Virginia Commonwealth University Medical Center using targeted ultra-performance liquid chromatography and electrospray ionization mass spectrometry. They found significant differences in the levels of various lipids between those who did and those who did not develop preeclampsia: For example, decreased levels of dihydroxyeicosatrienoic acids and of certain ceramides were linked with developing the pregnancy complication. Investigators were able to predict risk based on those biomarkers regardless of whether patients were already on the standard of care for at-risk patients.
"We were able to read out lipids that would be independent of the current therapy, which is aspirin," said Charles Chalfant, senior author on the paper and a professor at UVA's medical school who studies molecular biology and bioactive lipid signaling.
Investigators also found that stratifying patients based on levels of eicosanoids — specifically, decreased levels of 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid as well as increased levels of resolvins — could identify those at risk for preeclampsia and associated preterm birth.
These findings are based on early research, confirmation of which is dependent on getting additional blood samples from patients, Chalfant said. Study authors also recommended that the field standardize practices for sample collection and processing, to ensure comparisons across studies are possible.
Additional retrospective analysis is critical before considering a prospective study. The authors are hoping to do another small study on blood samples from the University of Pennsylvania and are also exploring whether they can confirm their findings using data from a biorepository at UVA's obstetrics and gynecology department, Chalfant said.
The recent paper, while a small study, "provide[s] an expanded menu, if you will, of potential biomarkers that could be used to specify individuals who would develop certain phenotypes of preeclampsia," Strauss said. But validation is needed to establish which biomarkers are high-performing indicators, he added.
Strauss believes that lipid-based biomarkers could one day complement emerging protein biomarkers that are picking up steam in the field. In May, the first blood-based tests to aid in risk assessment for preeclampsia were cleared by the US Food and Drug Administration. The tests, developed by Thermo Fisher Scientific, measure two types of proteins: soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF).
Lipids "need to be part of the equation," Strauss said. "Hopefully, [lipids] will give some refined information that will help us understand the diversity of symptoms."
If additional studies pinpoint a set of lipid-based biomarkers that can predict development of preeclampsia, a next step could involve developing a blood test for screening patients.
In the analysis in the Journal of Lipid Research, investigators also found that lipid-based biomarkers varied based on patients' self-reported race — another area for future study, researchers said. Thromboxane levels, for example, were significantly lower in Black patients with preeclampsia, while white patients tended to have lower levels of 12-hydroxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, eicosapentaenoic acid, and docosahexaenoic acid. Hispanic patients had a significant increase in levels of prostaglandin A2.
That's an important area to dig into, given massive maternal mortality disparities between Black and white patients in the US.
Strauss underscored that it's still unclear if the biomarkers identified in specific ancestry groups are drivers of healthcare disparities and that additional research is needed in a large and multiethnic patient population. In the analysis described in the paper, 58 percent of patients reported African ancestry, 21 percent reported European ancestry, and 21 percent reported Hispanic ancestry.
Even if the lipids are confirmed to be risk factors, they might be related to ancestry or they could be related to lifestyle factors like diet or metabolic disorders linked with preeclampsia. "We're not quite sure what that means in terms of pathophysiology," Strauss said of the lipids that varied by ethnicity. "But it shows that there are potential ancestry-related differences in lipid metabolism that may play into this."