New blood test predicts preterm birth risk early in pregnancy
A new study found that cell-free DNA from routine prenatal testing can accurately identify preterm birth risk without added cost or procedures.
New blood test predicts preterm birth risk early in pregnancy | Image Credit: © angellodeco - © angellodeco - stock.adobe.com.
Non-invasive test for preterm birth assessment
A cheap, non-invasive test using cell-free DNA (cfDNA) collected during standard early pregnancy testing may be used to predict preterm birth (PTB) risk, according to a recent study published in PLOS Medicine.1
Approximately 11% of births occur preterm, causing significant maternal and neonatal morbidity and mortality. This highlights a need for early identification to implement strategies that reduce the risk of PTB.2 As a dynamic indicator of biological processes in pregnancy, plasma cfDNA has been considered for PTB risk.
“These properties establish cfDNA as a valuable biomarker for investigating pregnancy complications, including PTB,” wrote investigators.
Sample collection and gene profiling
A large, multi-center case-control study was conducted to evaluate PTB prediction from cfDNA. Investigators collected cfDNA through whole-genome sequencing, with a focus on promoter profiling.
Samples were collected from 12- to 28-weeks’ gestation at 1 of 3 independent hospitals in China. Exclusion criteria included multiple pregnancies, chorioamnionitis, uterine fibroids, congenital abnormalities, and assisted reproductive technology use.
Participants were assigned to a birth outcome group based on their delivery time, including spontaneous PTB before 37-weeks’ gestation and full term after 38-weeks’ gestation. These patients were matched based on gestational age at sampling, maternal age, and body mass index.
The Ref-Seq of the University of California Santa Cruz Genome Browser Database provided necessary gene information, with a promoter region ranging from -1 to 1 kb for each transcript. Bwa-mem (ver. 3.5.0) was used to align raw reads to the human reference genome.
The Gene Expression Omnibus database was assessed for placenta and whole blood expression profiles. Expression profiles were evaluated to determine the top 500 highly expressed and 500 least expressed genes.
Findings on gene expression and read depth
A P-value was calculated from primary transcription start site (pTSS) coverages between pre and full term samples. Using functional relationships from the String database, investigators developed a gene correlation network. Whole-genome sequencing allowed classifiers for predicting sPTB to also be constructed.
Whole-genome sequencing data from 20 preterm pregnancies and 20 full term pregnancies was included in the analysis, alongside RNA expression profiles from preterm pregnancies. When comparing the pTSS of the 500 most expressed genes to the 500 least expressed genes, the most expressed genes had reduced depth at the pTSS regions.
Lower read depth was also reported in housekeeping genes with highly expressed levels, while higher read depth was reported in unexpressed genes. Maternal whole blood data displayed similar trends, highlighting a correlation of plasma cfDNA coverage at the pTSS regions with expression profiles of original tissues.
Platelet gene profiling and PTB indicators
The cfDNA profiles of platelet-enriched genes were also evaluated. Assessments indicated reduced coverage at the pTSS regions of these genes in PTB pregnancies vs full term pregnancies. This indicates the promoter profiling may significantly differ between these 2 groups.
When comparing cfDNA promoter profiling, there were 277 genes with differential coverages at the pTSS. Of these genes, 146 had increased coverage and 131 had decreased coverage. Key genes linked to PTB incidence include ERBB2, ESR1, NFKBIA, HSPA5, PRKCB, RAF1, NFE2LE, SNAI1, GSN, and ATF3.
Potential clinical utility
These results indicated potential from the promoter-profiling-based classifier (PTerm) in predicting PTB risk early in pregnancy. Investigators concluded this method may be easily applied to non-invasive prenatal testing data without the need for additional tests or increased costs.
“Currently, PTerm can distinguishing PTB pregnancies from full-term pregnancies with high accuracy. Moving forward, leveraging additional data on promoter profiles across different gestational ages could facilitate developing a model for accurately predicting delivery time,” wrote investigators.
References
- Preterm birth might be predicted with high accuracy with new cheap, non-invasive test, based on cell-free DNA collected in standard early pregnancy testing. PLOS. April 15, 2025. Accessed April 15, 2025. https://www.eurekalert.org/news-releases/1079902
- Guo Z, Wang K, Huang X. Genome-wide nucleosome footprints of plasma cfDNA predict preterm birth: A case-control study. PLOS Medicine. 2025. doi:10.1371/journal.pmed.1004571
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