Early prediction of preterm birth in cell-free RNA could reshape prevention strategies

Children born before 37 weeks of gestation have a considerably increased risk of dying before they reach the age of five. Predicting the risk of preterm birth (PTB) and hence implementing preventive strategies is complicated by the heterogeneity of the condition, the many unknown mechanisms involved, and the lack of reliable predictive tools.

Now, however, researchers have been able to show that blood cell-free RNA (cfRNA) signatures can predict PTB over four months before delivery date. The research was presented at the annual conference of the European Society of Human Genetics.

Dr. Wen-Jing Wang, an associate researcher at BGI Research in Shenzhen, China, together with team leader Professor Chemming Xu from the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, and colleagues analyzed blood plasma samples from 851 pregnancies (299 PTB cases and 552 controls) at about 16 weeks gestation to identify cfRNA markers associated with spontaneous PTB, and found significant alterations in cfRNA between PTB and birth at term.

The study included both preterm births with intact membranes and premature rupture of membranes (when the waters break before labor starts), with fewer than 3% having a prior preterm birth.

“Being able to detect these predictive signals over four months suggests early biological priming for PTB, far earlier than current clinical recognition,” she says. “This extended window could revolutionize prevention strategies.”

Annually, about 13.4 million newborns worldwide are delivered prematurely, accounting for approximately one in 10 of all live births. Nearly one million of these preterm infants die each year, and PTB remains the primary cause of mortality in children under five.

Because children born preterm have immature organs that are not yet prepared for life outside the womb, it means that they will have a far higher risk of complications than those born at term. This can lead to a range of health issues such as respiratory problems, jaundice, feeding difficulties, and infections.

Long-term health problems for these children include cerebral palsy, epilepsy, and blindness, and impose substantial emotional and financial burdens on families.

“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,” says Dr. Wang.

Unlike static DNA or immune-focused cellular biomarkers, circulating RNA can provide dynamic, tissue-specific insights. The researchers say that they have already observed distinct patterns—infection and inflammation signatures in preterm cases with rupture of the membranes as opposed to dysregulation of metabolism and trophoblasts in intact membrane cases, and that these findings were corroborated by clinical parameters.

“The liquid biopsy approach could transform our understanding and management of pregnancy complications,” says Dr. Wang.

Before this diagnostic technique can be used more widely, the researchers say that standardized protocols for sample handling need to be developed, given RNA’s instability compared with DNA.

Prediction algorithms need to be developed in diverse population studies, and the causes of different PTB subtypes explored to be able to guide targeted interventions. The team is pursuing these goals and seeking to collaborate with other institutions in order to accelerate the use of their findings in clinical practice.

Chair of the conference, Professor Alexandre Reymond, said, “Advances in sequencing and analysis technologies are now offering many new diagnostic possibilities. This is a fascinating example of the use of sequencing readouts to evaluate risk, rather than assessing genetic background to assess predisposition.”

Children born before 37 weeks of gestation have a considerably increased risk of dying before they reach the age of five. Predicting the risk of preterm birth (PTB) and hence implementing preventive strategies is complicated by the heterogeneity of the condition, the many unknown mechanisms involved, and the lack of reliable predictive tools.

Now, however, researchers have been able to show that blood cell-free RNA (cfRNA) signatures can predict PTB over four months before delivery date. The research was presented at the annual conference of the European Society of Human Genetics.

Dr. Wen-Jing Wang, an associate researcher at BGI Research in Shenzhen, China, together with team leader Professor Chemming Xu from the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, and colleagues analyzed blood plasma samples from 851 pregnancies (299 PTB cases and 552 controls) at about 16 weeks gestation to identify cfRNA markers associated with spontaneous PTB, and found significant alterations in cfRNA between PTB and birth at term.

The study included both preterm births with intact membranes and premature rupture of membranes (when the waters break before labor starts), with fewer than 3% having a prior preterm birth.

“Being able to detect these predictive signals over four months suggests early biological priming for PTB, far earlier than current clinical recognition,” she says. “This extended window could revolutionize prevention strategies.”

Annually, about 13.4 million newborns worldwide are delivered prematurely, accounting for approximately one in 10 of all live births. Nearly one million of these preterm infants die each year, and PTB remains the primary cause of mortality in children under five.

Because children born preterm have immature organs that are not yet prepared for life outside the womb, it means that they will have a far higher risk of complications than those born at term. This can lead to a range of health issues such as respiratory problems, jaundice, feeding difficulties, and infections.

Long-term health problems for these children include cerebral palsy, epilepsy, and blindness, and impose substantial emotional and financial burdens on families.

“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,” says Dr. Wang.

Unlike static DNA or immune-focused cellular biomarkers, circulating RNA can provide dynamic, tissue-specific insights. The researchers say that they have already observed distinct patterns—infection and inflammation signatures in preterm cases with rupture of the membranes as opposed to dysregulation of metabolism and trophoblasts in intact membrane cases, and that these findings were corroborated by clinical parameters.

“The liquid biopsy approach could transform our understanding and management of pregnancy complications,” says Dr. Wang.

Before this diagnostic technique can be used more widely, the researchers say that standardized protocols for sample handling need to be developed, given RNA’s instability compared with DNA.

Prediction algorithms need to be developed in diverse population studies, and the causes of different PTB subtypes explored to be able to guide targeted interventions. The team is pursuing these goals and seeking to collaborate with other institutions in order to accelerate the use of their findings in clinical practice.

Chair of the conference, Professor Alexandre Reymond, said, “Advances in sequencing and analysis technologies are now offering many new diagnostic possibilities. This is a fascinating example of the use of sequencing readouts to evaluate risk, rather than assessing genetic background to assess predisposition.”