Blood testing identifies preeclampsia, disease risks in pregnancy months before symptoms
Researchers predicted preeclampsia in 75% of cases and preterm birth at nearly the same rate by analyzing maternal, fetal and placental RNA circulating in the mother’s blood during pregnancy, according to a study published in Nature.
“Over the years, what has become distressingly apparent is we just don’t have clinical biomarkers or good clinical risk stratification techniques or tools to try to tell someone that she may be at increased risk for spontaneous preterm birth or preeclampsia or any complications in pregnancy,” author Thomas McElrath, MD, PhD, an attending physician in the division of maternal-fetal medicine at Brigham and Women’s Hospital, told Healio.
By examining the progression of seven genes consistently involved in preeclampsia expressed in the mother and baby during pregnancy, the researchers said, they have developed a way to detect disease early and potentially address it therapeutically.
The researchers extracted cell-free RNA (cfRNA) via a single blood test from the mother and sequenced gene sets from this material at different time points in 1,840 pregnancies to confirm that their activity mirrored physiological changes expected at those time points, such as fetal heart development and changes in the mother’s uterus and cervix.
“Each week, there’s going to be an almost kaleidoscopic pattern of thousands of genes being expressed. And then the next week, there’s going to be a pattern that’s going to be slightly different,” said McElrath. “We’re able to look at what is the normal pattern of gene set expression across pregnancy.”
The researchers said the test could “robustly predict preeclampsia,” with a sensitivity of 75% and a positive predictive value of 32.3% (standard deviation, 3%), which is sevenfold higher than current clinical methods. The technique also performed as well as a second trimester ultrasound and better than a third trimester ultrasound in estimating pregnancy progression, the researchers said, making it an alternative for assessing gestational age when prenatal care is begun later in pregnancy.
“We’ve documented how these patterns change. That is that the real innovation here,” McElrath said. “Once you basically have a map of what normal RNA expression is with the progression of pregnancy, we can then start to look at what abnormal looks like.”
A positive test correctly identified 73% of individuals who later had a preterm birth more than 3 months ahead of the onset of clinical symptoms or delivery. Such a window could enable providers to design clinical interventions for women identified at risk.
“We could make sure she is on medical prophylaxis that is appropriate,” McElrath said. Providers could prescribe a low dose of aspirin to decrease the risk of preeclampsia, schedule these women for more frequent clinical visits or transfer them to settings more suitable for higher-risk patients, McElrath said. They could be trained to monitor their own blood pressure as well.
Improving preventive care
Clinical factors such as age, race and maternal body mass did not improve the screening model’s performance, the researchers added, indicating that cfRNA profiles are a robust predictor of preeclampsia by themselves and therefore may be more deeply rooted in the disease’s underlying mechanisms and more generalizable across human populations.
“We’re really beginning to explain things on a very fundamental biologic level,” McElrath said.
By aggregating eight independent study cohorts including multiple ethnicities, nationalities and socioeconomic contexts, the researchers said, they gathered the largest and most diverse set of maternal transcriptomes to date.
“In today’s world, where questions of discrimination and appropriate equity are very pertinent, the idea that we could remove a race variable from a clinical risk calculation was significant,” McElrath said.
Also, the researchers said they hope cfRNA sequencing can improve preventive care for preeclampsia, preterm birth, gestational diabetes and other maternal conditions and eventually advance the study of fetal complications as well.
“We can start to look at problems with growth with the baby or potentially metabolic or internal problems in the baby in ways we haven’t been able to look at thus far, noting that we’re getting RNA signals from the baby itself,” said McElrath. “It really allows us to enhance what we’re able to do with monitoring down the road.”
Additionally, the researchers said, the analysis of cfRNA profiles could enable researchers to develop new therapeutic strategies and more efficiently select candidates for clinical trials.
“If you have a disease that occurs in about 7% of all pregnancies, to get a thousand cases of preeclampsia, you really have to enroll tens of thousands of individuals,” McElrath said. “If we now identify who’s at increased risk, these studies can be done in a much more efficient and timely fashion.”