Maternal Cell-Free RNA Can Gauge Preeclampsia Risk Months Before Symptoms, Study Finds

NEW YORK — Cell-free RNA found in the blood plasma of expectant mothers may be able to gauge their risk of developing preeclampsia months before symptoms arise, a new study from the startup Mirvie has found.

Preeclampsia, a pregnancy complication marked by the onset of hypertension, affects about 8 percent of pregnancies and contributes to maternal and neonatal morbidity and mortality. Signs of preeclampsia tend to arise late in pregnancy, and the disease is thought to originate with the establishment of the placenta in pregnancy.

By comparing the cell-free RNA profiles of pregnant women with and without preeclampsia, the Mirvie-led team developed a model to predict who might develop the condition. As they reported in Nature on Wednesday, the researchers found the model could identify three-quarters of women who would later develop preeclampsia early in their pregnancies.

"The results demonstrate that we can predict preeclampsia early in pregnancy, before it becomes a threat to the mother and baby," senior author Thomas McElrath, an attending physician in maternal-fetal medicine at Brigham and Women's Hospital, said in a statement.

The researchers gathered maternal transcriptome data from eight different prospective cohorts, pulling together data that encompassed 2,539 plasma samples and 1,840 pregnancies. This cohort included women of a range of ethnic, national, geographical, and socioeconomic backgrounds.

After first establishing that the cfRNA signature could accurately predict gestational age and that cfRNA profiles can reflect a normal pregnancy progression, the researchers compared cfRNA profiles of pregnant women who later developed preeclampsia to those who did not.

In particular, the researchers conducted a case-control study of 72 individuals with preeclampsia and 452 controls, including individuals with chronic hypertension and gestational hypertension using blood samples taken during the second trimester. They identified seven genes whose signatures consistently separated cases and controls. Four of the genes — PAPPA2, CLDN7, TLE6, and FABP1 — have functions linked to preeclampsia or to placental development and the three others — SNORD14A, PLEKHH1, and MAGEA10 — have been tied bioinformatically to preeclampsia, though their functions are unclear.

At a sensitivity of 75 percent, a model based on these gene signatures had a positive predictive value of 32.3 percent, with a preeclampsia prevalence of 13.7 percent in the study. This, according to the researchers, is better than currently used clinical models, which have positive predictive values of 4.4 percent, and rely on maternal factors.

The test also detected preeclampsia risk early in pregnancy. It correctly identified 73 percent of expectant mothers who later had a medically indicated preterm birth three months before the onset of clinical symptoms or delivery, the researchers noted.

In a related commentary appearing in Nature, Lydia Shook and Andrea Edlow from Harvard Medical School noted that this model does not include, and was not affected by the inclusion of, maternal race as a factor. "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 healthcare," they wrote.

Shook and Edlow additionally noted some limitations of the study, particularly that the prevalence of preeclampsia in the study was higher at nearly 14 percent than the reported global prevalence of between 2 percent and 8 percent. This, they said, could mean the positive predictive value of the test might be lower in groups with lower preeclampsia rates.

They further added that a key next step would be to gauge whether cfRNA samples obtained during the first trimester could also predict preeclampsia risk, as that is when preventative treatments are likely to have the greatest effect.

In a statement, South San Francisco, California-based Mirvie said it is currently further validating these results.