Using a cell-free RNA (cfRNA) “liquid biopsy” of maternal plasma, researchers at the Carlos Simon Foundation and iPremom enrolled 9,586 pregnant women from 14 hospitals across Spain between September 2021 and June 2024. In a nested case-control analysis of 216 participants, they successfully predicted both early-onset and late-onset preeclampsia well before the onset of symptoms.
Preeclampsia, a complication marked by high blood pressure and organ damage in pregnancy, is a leading cause of maternal and infant illness worldwide.[2] Current first-trimester screening methods rely on maternal risk factors or placental biomarkers but miss over half of impending cases and often detect risk only after the disorder is already developing. By contrast, the cfRNA approach can capture subtle molecular signals from multiple maternal tissues, including the uterus and placenta, months before symptoms appear.
Blood samples were collected at multiple timepoints during pregnancy (9–14 weeks, 18–28 weeks, and >28 weeks or at diagnosis). cfRNA was extracted from 548 plasma samples across the 216 selected participants and sequenced using Illumina technology. Using machine learning, researchers identified cfRNA “signatures” that signalled future development of preeclampsia.
In the first trimester, a cfRNA model predicted early-onset preeclampsia (EOPE) with 83% sensitivity, 90% specificity, and an AUC of 0.88, on average 18 weeks prior to diagnosis.
“For the first time, we’ve shown that a routine blood sample in the first trimester can give an early warning for preeclampsia with high accuracy, well before symptoms appear”, said biomedical researcher Dr. Nerea Castillo Marco, first author of the study. “Identifying high-risk pregnancies this early opens a crucial window for preventive treatment and closer monitoring to protect mothers and babies.”
Notably, 47.2% of the predictive transcripts were linked to genes associated with the maternal endometrium, specifically decidualisation resistance, a failure of the uterine lining to properly adapt in early pregnancy. This supports the theory that uterine dysfunction plays a key role in EOPE.[3]
Late-onset preeclampsia (LOPE) was also predicted, on average 14.9 weeks before onset, using a distinct cfRNA signature with minimal overlap to that of EOPE. In contrast to EOPE, LOPE signatures included few decidualisation-related transcripts and instead reflected broader systemic biological signals. These findings confirm that EOPE and LOPE are biologically and temporally distinct conditions.
“Our transcriptomic analyses showed that EOPE involves widespread molecular changes across organs, including liver, kidney, placenta, brain, and lungs”, explained Dr. Castillo Marco. “In contrast, LOPE displayed later-onset and more localised patterns, particularly in immune and hepatic pathways.”
Looking ahead, the project leader Dr. Tamara Garrido said, “We are currently conducting a prospective clinical study designed to validate the utility and feasibility of cfRNA screening in standard prenatal care. With validation and regulatory efforts already underway, we anticipate that cfRNA-based screening could become available in clinical practice within the next year, offering an unprecedented opportunity for early, non-invasive identification of high-risk pregnancies and timely intervention.”
Commenting on the study, Prof. Dr. Karen Sermon, Chair of ESHRE, said, “Besides offering a major breakthrough in preventive prenatal care for a common and often dangerous condition during pregnancy, this research increases our understanding at a molecular level of a complex pathology that remains poorly understood.
The study abstract will be published today in Human Reproduction, one of the world’s leading reproductive medicine journals.
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Notes to editors:
A reference to the ESHRE Annual Meeting must be included in all coverage and/or articles associated with this study.
For more information or to arrange an expert interview, please contact the ESHRE Press Office at: press@eshre.eu
About the study author:
Dr. Tamara Garrido Gómez, PhD, is a senior principal investigator at the Carlos Simón Foundation and Scientific Director at iPremom in Valencia, Spain, where she coordinates the multicentre PREMOM consortium, which has recruited more than 9,500 pregnant women from 14 Spanish hospitals for prospective cfRNA studies. Dr. Nerea Castillo Marco PhD is the first author of the study and led the experimental work and data generation that underpin the main findings. Both researchers have co-authored numerous peer-reviewed publications in leading journals such as Human Reproduction, Nature Communications, and Nature Medicine, and are committed to translating omics-based discoveries into routine prenatal care to improve maternal and fetal health.
About Carlos Simon Foundation:
The Carlos Simón Foundation (CSF) is a non-profit organisation dedicated to translational research in women’s health.
About the European Society of Human Reproduction and Embryology
The main aim of ESHRE is to promote interest in infertility care and to aim for a holistic understanding of reproductive biology and medicine.
ESHRE collaborates world-wide and advocates universal improvements in scientific research, encourages and evaluates new developments in the field, and fosters harmonisation in clinical practice. It also provides guidance to enhance effectiveness, safety and quality assurance in clinical and laboratory procedures, psychosocial care, and promotes ethical practice. ESHRE also fosters prevention of infertility and related educational programmes and promotes reproductive rights regardless of the individual’s background. ESHRE’s activities include teaching, training, professional accreditations, mentoring and career planning for junior professionals, as well as developing and maintaining data registries. It also facilitates and disseminates research in human reproduction and embryology to the general public, scientists, clinicians, allied personnel, and patient associations.
Website: https://www.eshre.eu/
About Human Reproduction
Human Reproduction is a monthly journal of ESHRE and is one of the top three journals in the world in the field of reproductive biology, obstetrics and gynaecology. It is published by Oxford Journals, a division of Oxford University Press.
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: https://www.researchsquare.com/article/rs-5684050/latest] & Human Reproduction. [insert link when available]
[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.
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