Predicting preeclampsia from a blood test holds promise for pregnancy complications

Preeclampsia is a potentially serious problem that usually surfaces late in pregnancy, posing an immediate risk of preterm birth, stillbirth, and death as well a later danger of stroke for the mother. New research published Wednesday in Nature shows how RNA molecules sequenced from a single blood sample could predict preeclampsia months before symptoms appear, holding promise for detecting and treating this and other pregnancy complications before they cause harm.

Circulating RNA drawn from mothers’ blood has been sequenced and tied to preeclampsia before, as a July 2020 Science Translational Medicine paper from the sequencing company Illumina showed in 113 people. Four genes have previously been implicated in preeclampsia, too. But the new Nature paper analyzed what is known as cell-free RNA in blood from mother, placenta, and fetus in more than 1,840 pregnancies in participants from North America, Europe, and Africa. The geographic and racial diversity of participants (55.1% white, 32.6% Black, 5.4% Hispanic, 3.8% Asian, and 3.1% mixed/unknown/not reported) lends strength to its conclusion that race, body mass index, and age were irrelevant to preeclampsia risk.

To create their test, an international team of scientists from academic medical centers and from Mirvie, a San Francisco biotech developing RNA tests for pregnancy complications, first established a genetic timeline of a normal pregnancy and then, week by week, compared what was different in the patterns of gene activation. That’s how they spotted preeclampsia (and three more genes tied to it).

To study co-author Thomas McElrath, an OB-GYN at Brigham and Women’s Hospital in Boston, detecting preeclampsia could be just the beginning.

“I think the real impact of this technology we’re looking at is a little bit bigger than just preeclampsia,” he told STAT. He sits on the scientific advisory board of Mirvie, where some of the paper’s co-authors work and whose RNA technology was used in the study.

“This is really more about a platform that for the first time has been able to look at what are the transcriptomes of gene set expressions as pregnancy progresses, and we looked at preeclampsia as a test case,” McElrath said. “We hope to look at other clinically meaningful deviations, such as, potentially, gestational diabetes or growth restriction or other areas. Once we basically have a road map of normal cases, where there’s a deviation off of that map then becomes much easier to discern.”

The researchers say that about one-third of the patients predicted by their model to develop preeclampsia were later diagnosed with the condition. That’s seven times better than existing methods that rely on ultrasound testing in patients considered at risk because they already have high blood pressure or other problems. And the model had 75% sensitivity, meaning it could identify three-quarters of the eventual cases of preeclampsia. The test is still under development and will undergo further studies but won praise in a companion Nature editorial.

“Not only have the authors developed a predictive test for pre-eclampsia, but the study’s findings also have the potential to provide insights into typical pregnancies and fetal development, and to advance the design of rational, precision therapeutics that can improve pregnancy care,” OB-GYNs Lydia Shook and Andrea Edlow of Massachusetts General Hospital wrote.

Preeclampsia’s hallmark symptom is high blood pressure. It occurs in about 1 in 12 pregnancies but tools to treat or prevent it are few: the U.S. Preventive Services Task Force recommends low-dose aspirin for elevated blood pressure during pregnancy, but identifying who should follow that advice has been challenging, particularly in first pregnancies. Knowing who’s at risk could tailor that treatment and prompt a higher level of care — and maybe inspire future therapeutics.

Lauren Theilen, who practices maternal-fetal medicine at University of Utah Health in Salt Lake City and has studied stroke risk after preeclampsia, welcomes any step that might bring basic biology to bear on what has been an intractable problem. She was not involved in the study.

“It’s groundbreaking stuff in terms of furthering the understanding of preeclampsia,” she said.

Theilen also sees the potential to predict other pregnancy complications related to whether the placenta is implanting normally, including fetal growth restriction, placental abruption (when the placenta separates from the inner wall of the uterus before birth), and preterm birth.

“This paper is very exciting from a biological standpoint, being able to actually identify the path of a physiologic process as it is happening before it manifests clinically in an individual person without needing to rely on additional clinical information,” she said.

By “additional clinical information,” Theilen means social constructs that are not grounded in biology, such as race, access to care, and access to resources to support one’s own health. A study published in JAMA in December found that low-income U.S.-born Black women were at higher risk for preeclampsia than Black women who had immigrated to the United States.

The new Nature study found that the patient’s BMI, age, and race were irrelevant to risk of preeclampsia. When the researchers included the genes they linked to preeclampsia in their analysis, the variables for race, BMI, and age were no longer significant.

McElrath called that getting down to the underlying biology. The editorial’s authors went further.

“This lends further support to abandoning racially biased approaches for diagnosis and treatment that have been found to have little or no utility and that perpetuate racial disparities in health care,” they wrote.