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Second-trimester blood test predicts preterm birth



A new blood test performed in the second trimester could help identify pregnancies at risk of early and very early spontaneous preterm birth (sPTB), based on a prospective cohort trial.

The cell-free RNA (cfRNA) profiling tool could guide patient and provider decision-making, while the underlying research illuminates biological pathways that may facilitate novel interventions, reported lead author Joan Camunas-Soler, PhD, of Mirvie, South San Francisco, and colleagues.

“Given the complex etiology of this heterogeneous syndrome, it would be advantageous to develop predictive tests that provide insight on the specific pathophysiology leading to preterm birth for each particular pregnancy,” Dr. Camunas-Soler and colleagues wrote in the American Journal of Obstetrics and Gynecology. “Such an approach could inform the development of preventive treatments and targeted therapeutics that are currently lacking/difficult to implement due to the heterogeneous etiology of sPTB.”

Currently, the best predictor of sPTB is previous sPTB, according to the investigators. Although a combination approach that incorporates cervical length and fetal fibronectin in cervicovaginal fluid is “of use,” they noted, “this is not standard of care in the U.S.A. nor recommended by the American College of Obstetricians and Gynecologists or the Society for Maternal-Fetal Medicine.” Existing molecular tests lack clinical data and may be inaccurate across diverse patient populations, they added.

The present study aimed to address these shortcomings by creating a second-trimester blood test for predicting sPTB. To identify relevant biomarkers, the investigators compared RNA profiles that were differentially expressed in three types of cases: term birth, early sPTB, and very early sPTB.

Among 242 women who contributed second-trimester blood samples for analysis, 194 went on to have a term birth. Of the remaining 48 women who gave birth spontaneously before 35 weeks’ gestation, 32 delivered between 25 and 35 weeks (early sPTB), while 16 delivered before 25 weeks’ gestation (very early sPTB). Slightly more than half of the patients were White, about one-third were Black, approximately 10% were Asian, and the remainder were of unknown race/ethnicity. Cases of preeclampsia were excluded.

The gene discovery and modeling process revealed 25 distinct genes that were significantly associated with early sPTB, offering a risk model with a sensitivity of 76% and a specificity of 72% (area under the curve, 0.80; 95% confidence interval, 0.72-0.87). Very early sPTB was associated with a set of 39 genes, giving a model with a sensitivity of 64% and a specificity of 80% (area under the curve = 0.76; 95% CI, 0.63-0.87).

Characterization of the two RNA profiles offered a glimpse into the underlying biological processes driving preterm birth. The genes predicting early sPTB are largely responsible for extracellular matrix degradation and remodeling, which could, “in terms of mechanism, reflect ongoing processes associated with cervical shortening, a feature often detected some weeks prior to sPTB,” the investigators wrote. In contrast, genes associated with very early sPTB are linked with insulinlike growth factor transport, which drives fetal growth and placentation. These findings could lead to development of pathway-specific interventions, Dr. Camunas-Soler and colleagues suggested.

According to coauthor Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health at the University of Pennsylvania, Philadelphia, and chief medical advisor at Mirvie, the proprietary RNA platform moves beyond “unreliable and at times biased clinical factors such as race, BMI, and maternal age” to offer a “precision-based approach to pregnancy health.”

Excluding traditional risk factors also “promises more equitable care than the use of broad sociodemographic factors that often result in bias,” she added, noting that this may help address the higher rate of pregnancy complications among Black patients.

When asked about the potential for false-positive results, considering reported specificity rates of 72%-80%, Dr. Elovitz suggested that such concerns among pregnant women are an “unfortunate misconception.”

“It is not reflective of what women want regarding knowledge about the health of their pregnancy,” she said in a written comment. “Rather than be left in the dark, women want to be prepared for what is to come in their pregnancy journey.”

In support of this statement, Dr. Elovitz cited a recent study involving women with preeclampsia and other hypertensive disorders in pregnancy. A questionnaire showed that women appreciated pregnancy risk models when making decisions, and reported that they would have greater peace of mind if such tests were available.

Laura Jelliffe-Pawlowski, PhD, of the UCSF California Preterm Birth Initiative, San Francisco

Dr. Laura Jelliffe-Pawlowski

Laura Jelliffe-Pawlowski, PhD, of the University of California, San Francisco, California Preterm Birth Initiative, supported Dr. Elovitz’s viewpoint.

“If you talk to women who have delivered preterm most (but not all) say that they would have wanted to know their risk so they could have been better prepared,” she said in a written comment. “I think we need to shift the narrative to empowerment away from fear.”

Dr. Jelliffe-Pawlowski, who holds a patent for a separate test predicting preterm birth, said that the Mirvie RNA platform is “promising,” although she expressed concern that excluding patients with preeclampsia – representing approximately 4% of pregnancies in the United States – may have clouded accuracy results.

“What is unclear is how the test would perform more generally when a sample of all pregnancies was included,” she said. “Without that information, it is hard to compare their findings with other predictive models without such exclusions.”

Regardless of the model used, Dr. Jelliffe-Pawlowski said that more research is needed to determine best clinical responses when risk of sPTB is increased.

“Ultimately we want to connect action with results,” she said. “Okay, so [a woman] is at high risk for delivering preterm – now what? There is a lot of untapped potential once you start to focus more with women and birthing people you know have a high likelihood of preterm birth.”

The study was supported by Mirvie, Tommy’s Charity, and the National Institute for Health Research Biomedical Research Centre. The investigators disclosed financial relationships with Mirvie, including equity interest and/or intellectual property rights. Cohort contributors were remunerated for sample collection and/or shipping. Dr. Jelliffe-Pawlowski holds a patent for a different preterm birth prediction blood test.

*This story was updated on 4/26/2022.

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