Cell-Free Nucleic Acids in Pregnancy Complications

Cell-free nucleic acids, encompassing both DNA and RNA fragments released into the maternal circulation, provide a minimally invasive window onto placental and foetal health. Originating from apoptotic or active secretory processes within the trophoblast and maternal tissues, these molecules can be quantified and profiled to reveal dynamic changes across gestation. Measurements of total cell-free DNA, cell-free fetal DNA and cell-free RNA have transformed prenatal screening for chromosomal anomalies and are increasingly applied to predict and understand complications such as preeclampsia, spontaneous preterm birth and foetal growth restriction. Distinct patterns of gene expression in cell-free RNA reflect placental, vascular and immune alterations that precede clinical symptoms, while elevated levels of cell-free fetal DNA correlate with abnormal placental function and inflammatory pathways. Advances in sequencing and targeted assays now enable early identification of at-risk pregnancies, offering the prospect of personalised monitoring and timely intervention. Global studies underscore the utility of these biomarkers across diverse populations, although technical standardisation and cost considerations remain challenges for widespread clinical adoption.

Research from Nature Portfolio

Recent studies have employed plasma cell-free RNA to construct predictive models for preeclampsia. In one major investigation, longitudinal transcriptomic profiling of cell-free RNA in early gestation identified stable differentials in genes linked to endothelial, neuromuscular and immune cell types. An eighteen-gene panel measured between five and sixteen weeks of gestation demonstrated robust discrimination of later preeclampsia risk, enabling potential early-stage liquid biopsy testing. Complementary work across multiple cohorts tracked cell-free RNA signatures of normal pregnancy progression at placental, maternal and foetal levels and showed that deviations in this signature predicted preeclampsia with substantially higher sensitivity than conventional risk factors. Foundational analyses of total cell-free DNA levels in women who subsequently developed preeclampsia revealed that elevated methylated DNA fragments emerged before symptom onset in cases of early-onset disease or those complicated by small-for-gestational-age neonates, suggesting a placental origin and prognostic value for stratified clinical follow-up.

Cell-Free Nucleic Acids in Pregnancy Complications publication trend

The graph below shows the total number of articles in cell-free nucleic acids in pregnancy complications across all publications each year (not limited to Nature Index journals).

Technical terms

Cell-free nucleic acids: DNA or RNA fragments circulating freely in plasma, derived from apoptotic, necrotic or secretory processes in maternal and placental tissues.

Cell-free fetal DNA (cffDNA): Subset of cell-free DNA originating from placental trophoblasts that reflects foetal genetic information and placental health.

Cell-free RNA (cfRNA): Transcript fragments in maternal plasma representing gene expression from maternal, placental and foetal sources, used to monitor dynamic biological processes.

Fetal fraction: Proportion of total cell-free DNA in maternal plasma that is of foetal (placental) origin, influencing the accuracy of non-invasive tests.

Preeclampsia: A multi-organ hypertensive disorder of pregnancy characterised by new-onset hypertension and proteinuria or end-organ dysfunction after 20 weeks of gestation.

References

1. Fetal Fraction of Cell‐Free DNA in the Prediction of Adverse Pregnancy Outcomes: A Nationwide Retrospective Cohort Study. BJOG An International Journal of Obstetrics & Gynaecology (2024).
2. Early prediction of preeclampsia in pregnancy with cell-free RNA. Nature (2022).
3. RNA profiles reveal signatures of future health and disease in pregnancy. Nature (2022).
4. Cell-free fetal DNA and spontaneous preterm birth. Reproduction (2017).
5. Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation. Frontiers in Pediatrics (2020).
6. Maternal total cell-free DNA in preeclampsia with and without intrauterine growth restriction. Scientific Reports (2020).