A groundbreaking study unveiled at the 41st Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) this week marks a new era in prenatal care, revealing that a simple blood test conducted during the first trimester of pregnancy can predict the development of preeclampsia months before any clinical symptoms arise. This molecular “liquid biopsy” uses cell-free RNA (cfRNA) extracted from maternal plasma to detect subtle and early signals of this life-threatening pregnancy disorder, offering a transformative approach to early diagnosis and intervention.
Preeclampsia, characterized by dangerously high blood pressure and organ damage during pregnancy, remains a leading cause of maternal and neonatal morbidity and mortality worldwide. Traditional screening methods in the first trimester primarily rely on maternal risk factors and placental biomarkers, which unfortunately fail to identify over 50% of at-risk pregnancies before the disease’s clinical manifestation. Recognizing this diagnostic gap, the collaborative research initiative spearheaded by the Carlos Simón Foundation and iPremom set out to harness advanced genomics and machine learning for more sensitive, timely detection.
The study enrolled an unprecedented cohort of 9,586 pregnant women across 14 major Spanish hospitals between September 2021 and June 2024. Out of these, a nested case-control subset of 216 participants was meticulously selected for intensive molecular profiling. Researchers collected multiple plasma samples at critical gestational windows—specifically between 9 and 14 weeks, 18 to 28 weeks, and beyond 28 weeks or at diagnosis—to assay circulating cfRNA molecules which serve as dynamic indicators of gene expression changes in maternal and placental tissues.
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Employing cutting-edge next-generation sequencing on 548 plasma samples using Illumina technology, the team decoded complex cfRNA profiles. These molecular signatures were then analyzed through sophisticated machine learning algorithms to develop predictive models capable of discerning pregnancies at risk for both early-onset (EOPE) and late-onset preeclampsia (LOPE), well in advance of symptomatic detection.
Remarkably, the first-trimester cfRNA model flagged EOPE with 83% sensitivity and 90% specificity, boasting an average area under the curve (AUC) of 0.88. This implies that on average, the test predicted EOPE approximately 18 weeks—nearly five months—prior to clinical diagnosis. Such temporal advantage presents a compelling opportunity to commence preventative therapies and heightened surveillance protocols, potentially averting severe complications for both mother and child.
Molecular investigation into the predictive transcripts revealed close links to genes involved in maternal endometrial function, particularly those associated with decidualisation resistance. Decidualisation refers to the vital transformation of the uterine lining facilitating embryo implantation and placental development, and its impairment is increasingly implicated in EOPE pathogenesis. Nearly half of the identified cfRNA transcripts corresponded to these uterine remodeling pathways, underscoring a key mechanistic role of uterine dysfunction.
In contrast, cfRNA signatures predictive of LOPE emerged as distinct, with minimal overlap in decidualisation-related transcripts. Instead, late-onset preeclampsia exhibited systemic biological signatures involving immune response and hepatic pathways, emphasizing a more localized and temporally delayed pathophysiology. On average, LOPE was predicted roughly 14.9 weeks before symptom onset, allowing a critical window for early detection despite its complex biological roots.
Dr. Nerea Castillo Marco, the study’s lead author, emphasized the novelty of this approach in prenatal medicine: “Our findings demonstrate for the first time that a routine maternal blood draw during early pregnancy can deliver highly accurate forecasts of preeclampsia, creating an invaluable window for intervention before clinical manifestations.” The precision and non-invasiveness of cfRNA liquid biopsy herald a paradigm shift in maternal-fetal medicine, particularly for a condition historically challenging to diagnose preemptively.
Beyond the predictive capabilities, the transcriptomic landscape mapped in this study provides unprecedented molecular insights into the diverse organ systems impacted during EOPE, including liver, kidney, brain, lungs, and placenta. This multisystem involvement confirms that EOPE encompasses widespread systemic dysregulation rather than isolated placental pathology. Conversely, LOPE’s molecular footprint concentrated on immune and liver-related processes further delineates the two forms as distinct clinical and biological entities.
Project leader Dr. Tamara Garrido highlighted the immediate translational potential: “With ongoing prospective clinical validation underway, we anticipate that cfRNA-based screening will soon integrate seamlessly into routine prenatal care, providing obstetricians worldwide with a robust tool to identify high-risk pregnancies proactively.” Regulatory reviews and clinical deployment efforts are progressing rapidly, with potential availability of this revolutionary screening method expected within the next year.
The implications of this study extend far beyond diagnostics. By elucidating molecular pathways implicated in preeclampsia development, it paves the way for targeted therapeutic research and personalized medicine approaches, aiming to improve maternal and neonatal outcomes on a global scale. This aligns closely with broader public health goals to reduce preventable pregnancy complications and enhance reproductive healthcare equity.
Commenting on these seminal findings, Prof. Dr. Karen Sermon, Chair of ESHRE, stated, “This research not only marks a formidable advance in prenatal disease prevention but also deepens our molecular understanding of preeclampsia—a complex and often enigmatic pregnancy disorder—thus fostering future innovation both in science and clinical practice.”
The study abstract is set to be published imminently in Human Reproduction, one of the world’s foremost journals dedicated to reproductive biology and medicine. This milestone discovery underscores the power of integrating omics technologies with clinical obstetrics, heralding an era where early molecular diagnostics will become central to safeguarding maternal and fetal health worldwide.
Subject of Research: Early detection of preeclampsia using cell-free RNA liquid biopsy in maternal plasma during the first trimester.
Article Title: (Not provided)
News Publication Date: Monday, 30 June 2025
References:
[1] Castillo Marco, N., et al. (2025) Maternal plasma cell-free RNA as a liquid biopsy for first-trimester screening of early and late-onset preeclampsia. Nature Communications (Under review) [preprint] & Human Reproduction (abstract forthcoming)
[2] World Health Organization. (2025). Pre-eclampsia – Fact Sheet.
[3] Muñoz-Blat, R., Pérez-Moraga, R., Castillo Marco, N., et al. (2025). Multi-omics-based mapping of decidualisation resistance in patients with a history of severe preeclampsia. Nature Medicine.
Keywords: Human reproduction, Pregnancy, Preeclampsia, Cell-free RNA, Liquid biopsy, First-trimester screening, Prenatal diagnostics, Maternal plasma, Decidualisation resistance, Obstetrics, Molecular biomarkers, Machine learning
Tags: cell-free RNA analysis in pregnancycollaborative research in women’s healthearly diagnosis of pregnancy complicationsESHRE annual meeting insightsgenomic approaches to pregnancy disordersliquid biopsy technology in obstetricsmachine learning in prenatal carematernal health advancementsmaternal plasma testing for preeclampsiapreeclampsia risk predictionprenatal blood test innovationreducing maternal morbidity through early detection
