Blood Cell-Free RNA Signatures Can Predict Preterm Birth Four Months Before Delivery

4 million babies are born prematurely worldwide, accounting for roughly one in ten of all live births. Of these, nearly one million preterm infants die annually, and preterm birth (PTB) remains the leading cause of death for children under five. Infants born prematurely often face higher risks of complications because their organs are not fully developed for life outside the womb. These complications can include respiratory issues, jaundice, feeding problems, and infections. Long-term health problems such as cerebral palsy, epilepsy, and blindness can also arise, placing significant emotional and financial strain on families. Furthermore, children born before 37 weeks of gestation have a considerably higher likelihood of dying before reaching five years of age. Predicting the risk of preterm birth and implementing preventive measures is challenging due to the condition's heterogeneity, the many unknown mechanisms at play, and the absence of reliable predictive tools. Now, researchers have demonstrated that blood cell-free RNA (cfRNA) signatures can predict PTB up to four months before the expected delivery date.

In their study, researchers from Fudan University (Shanghai, China) and BGI Genomics (Shenzhen, China) analyzed blood plasma samples from 851 pregnancies (299 PTB cases and 552 controls) taken at around 16 weeks of gestation to identify cfRNA markers associated with spontaneous PTB. They found significant differences in cfRNA between PTB cases and term births. The study included both preterm births with intact membranes and those with premature rupture of membranes (when the water breaks before labor begins), with fewer than 3% of the participants having a previous preterm birth. Unlike DNA or immune-focused cellular biomarkers, circulating RNA offers dynamic, tissue-specific insights. The researchers noted distinct patterns—infection and inflammation markers in cases with membrane rupture, compared to metabolic dysregulation and trophoblast issues in cases with intact membranes. These findings were supported by clinical parameters.

Before this technique can be implemented widely, the researchers emphasize the need to develop standardized protocols for sample handling, as RNA is more unstable than DNA. Prediction algorithms also need to be established through diverse population studies, and the causes of various PTB subtypes must be further explored to guide targeted interventions. The team is actively pursuing these goals and seeking collaborations with other institutions to speed up the application of their findings in clinical practice.

“Being able to detect these predictive signals over four months suggests early biological priming for PTB, far earlier than current clinical recognition. This extended window could revolutionize prevention strategies,” said Dr. Wen-Jing Wang, an associate researcher at BGI Research. “Practically, our method uses the same blood draw timing as routine Non-Invasive Prenatal Testing (NIPT), enabling dual testing. Current cfRNA sequencing costs are similar to NIPT pricing, but future optimization using targeted qRT-PCR panels could reduce expenses significantly. This creates a potential route to both monitoring patients at high risk and for wider population-level screening.”