Maternal Plasma Cell-Free RNA as a Predictor of Early and Late-Onset Preeclampsia Throughout Pregnancy

Maternal Plasma Cell-Free RNA as a Predictor of Early and Late-Onset Preeclampsia Throughout Pregnancy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Maternal Plasma Cell-Free RNA as a Predictor of Early and Late-Onset Preeclampsia Throughout Pregnancy Tamara Garrido-Gómez, Nerea Castillo-Marco, Teresa Cordero, Marina Igual, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5684050/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Oct, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Early-onset (EOPE) and late-onset preeclampsia (LOPE) pose significant challenges to maternal and child health, highlighting the need for early, non-invasive risk identification. In this prospective longitudinal study, we followed 9,586 pregnant women, collecting blood samples each trimester: 9-14 weeks (T1), 18-28 weeks (T2), and after 28 weeks or at preeclampsia diagnosis (T3). Plasma cell-free RNA (cfRNA) signatures were analyzed in women who developed EOPE (n=42) or LOPE (n=43) and compared to matched normotensive controls (n=75). Mapping cfRNA origins and performing differential abundance analysis provided insights into multi-organ impacts, revealing distinct transcriptional features of EOPE and LOPE. We developed a first-trimester EOPE predictive model using 36 transcripts, achieving 83% sensitivity, 88% specificity, and an AUC of 0.85, detecting risk 18.0 weeks before onset. A second-trimester model based on 87 cfRNA transcripts, predicted EOPE 8.5 weeks prior to onset with 87% sensitivity, 84% specificity, and an AUC of 0.85. For LOPE model, detecting risk 14.9 weeks before onset, used 92 cfRNAs, with 86% sensitivity, 89% specificity, and an AUC of 0.88. EOPE models were enriched for decidua-associated transcripts, highlighting the maternal involvement in this subtype, while LOPE models showed diverse tissue responses, paving the way for improved subtype differentiation and tailored interventions to mitigate preeclampsia risks. Health sciences/Biomarkers/Predictive markers Biological sciences/Biological techniques/Sequencing/RNA sequencing Biological sciences/Computational biology and bioinformatics/Predictive medicine Full Text Additional Declarations Table 1 is available in the Supplementary Files section. Yes there is potential Competing Interest. N.C-M., M.I., T.G-G., C.S. are inventors on a patent application (EP24383276.3) covering methods for determining the risk of preeclampsia. N.C-M., T.C., M.I., C.G-A., N.B-G., A.G-D., E.O-D., A.V., T.G-G. are employees of iPremom Pregnancy Healthcare Diagnostics. C.S. is a founder of iPremom Pregnancy Healthcare Diagnostics Supplementary Files Table1.xlsx Table 1. Maternal characteristics and pregnancy outcomes for the selected subset of participants. Supp.Table1.xlsx Supplementary Table 1. Gestational age at blood sample for patients and controls in the selected subset of participants. Supp.Table2.xlsx Supplementary Table 2. Differentially abundant cfRNA transcripts at diagnosis in early-onset preeclampsia patients compared to normotensive controls. Supp.Table3.xlsx Supplementary Table 3. Differentially abundant cfRNA transcripts at diagnosis in late-onset preeclampsia patients compared to normotensive controls. Supp.Table4.xlsx Supplementary Table 4. Gene ontology analysis for increased abundant cfRNA in early-onset preeclampsia and late-onset preeclampsia. Supp.Table5.xlsx Supplementary Table 5. cfRNAs composing the predictive models for early-onset preeclampsia and late-onset preeclampsia at the first and second trimester of pregnancy. Supp.Table6.xlsx Supplementary Table 6. Summary of predictive model performance metrics for early-onset preeclampsia and late-onset preeclampsia during the first and second trimesters of pregnancy Cite Share Download PDF Status: Published Journal Publication published 20 Oct, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5684050","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":394765271,"identity":"232f41d5-5b47-4706-bd16-0442829f1338","order_by":0,"name":"Tamara 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Maternal characteristics and pregnancy outcomes for the selected subset of participants.\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5684050/v1/39b6192cd70482130ba4e871.xlsx"},{"id":74015549,"identity":"8c4098cc-e124-4ffc-a64d-1fdc01dba0fb","added_by":"auto","created_at":"2025-01-17 03:52:48","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10345,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1. Gestational age at blood sample for patients and controls in the selected \u0026nbsp;subset of participants.\u003c/p\u003e","description":"","filename":"Supp.Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5684050/v1/8f6bc49cc56280a2ae5c90af.xlsx"},{"id":74015553,"identity":"d2bf8bb7-e70e-4285-a9c5-93620086a993","added_by":"auto","created_at":"2025-01-17 03:52:48","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1397726,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 2. Differentially abundant cfRNA transcripts at diagnosis in early-onset \u0026nbsp;preeclampsia patients compared to normotensive controls.\u003c/p\u003e","description":"","filename":"Supp.Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5684050/v1/f3ab4ad34f7d464e83b850d7.xlsx"},{"id":74016249,"identity":"08871723-9a00-40a3-b27f-6d69e7a24514","added_by":"auto","created_at":"2025-01-17 04:00:48","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":665212,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 3. Differentially abundant cfRNA transcripts at diagnosis in late-onset preeclampsia patients compared to normotensive controls.\u003c/p\u003e","description":"","filename":"Supp.Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5684050/v1/9e953def4142655d65cb2430.xlsx"},{"id":74016253,"identity":"65585944-6bdf-4063-b488-26815accdf82","added_by":"auto","created_at":"2025-01-17 04:00:48","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":19123,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 4. Gene ontology analysis for increased abundant cfRNA in early-onset preeclampsia and late-onset preeclampsia.\u003c/p\u003e","description":"","filename":"Supp.Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5684050/v1/dffc9b308a72c9a9fcedbf35.xlsx"},{"id":74015557,"identity":"a4f9d7e5-9584-4dfd-9f8d-bb5eef10da32","added_by":"auto","created_at":"2025-01-17 03:52:48","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":12306,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 5. cfRNAs composing the predictive models for early-onset preeclampsia and late-onset preeclampsia at the first and second trimester of pregnancy.\u003c/p\u003e","description":"","filename":"Supp.Table5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5684050/v1/1ed3c1f4664f2383e92dcbc9.xlsx"},{"id":74015563,"identity":"e4b554e9-d174-43d7-a11f-c00f96e62c54","added_by":"auto","created_at":"2025-01-17 03:52:48","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":18632,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 6. 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C.S. is a founder of iPremom Pregnancy Healthcare Diagnostics\u003c/p\u003e","formattedTitle":"Maternal Plasma Cell-Free RNA as a Predictor of Early and Late-Onset Preeclampsia Throughout Pregnancy","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5684050/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5684050/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Early-onset (EOPE) and late-onset preeclampsia (LOPE) pose significant challenges to maternal and child health, highlighting the need for early, non-invasive risk identification. In this prospective longitudinal study, we followed 9,586 pregnant women, collecting blood samples each trimester: 9-14 weeks (T1), 18-28 weeks (T2), and after 28 weeks or at preeclampsia diagnosis (T3). Plasma cell-free RNA (cfRNA) signatures were analyzed in women who developed EOPE (n=42) or LOPE (n=43) and compared to matched normotensive controls (n=75). Mapping cfRNA origins and performing differential abundance analysis provided insights into multi-organ impacts, revealing distinct transcriptional features of EOPE and LOPE. We developed a first-trimester EOPE predictive model using 36 transcripts, achieving 83% sensitivity, 88% specificity, and an AUC of 0.85, detecting risk 18.0 weeks before onset. A second-trimester model based on 87 cfRNA transcripts, predicted EOPE 8.5 weeks prior to onset with 87% sensitivity, 84% specificity, and an AUC of 0.85. For LOPE model, detecting risk 14.9 weeks before onset, used 92 cfRNAs, with 86% sensitivity, 89% specificity, and an AUC of 0.88. EOPE models were enriched for decidua-associated transcripts, highlighting the maternal involvement in this subtype, while LOPE models showed diverse tissue responses, paving the way for improved subtype differentiation and tailored interventions to mitigate preeclampsia risks.","manuscriptTitle":"Maternal Plasma Cell-Free RNA as a Predictor of Early and Late-Onset Preeclampsia Throughout Pregnancy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-17 03:52:43","doi":"10.21203/rs.3.rs-5684050/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"70375abf-2622-4efd-80ad-8ea27d7c5155","owner":[],"postedDate":"January 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":42068592,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":42068593,"name":"Biological sciences/Biological techniques/Sequencing/RNA sequencing"},{"id":42068594,"name":"Biological sciences/Computational biology and bioinformatics/Predictive medicine"}],"tags":[],"updatedAt":"2025-10-21T07:05:52+00:00","versionOfRecord":{"articleIdentity":"rs-5684050","link":"https://doi.org/10.1038/s41467-025-64215-2","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-10-20 04:00:00","publishedOnDateReadable":"October 20th, 2025"},"versionCreatedAt":"2025-01-17 03:52:43","video":"","vorDoi":"10.1038/s41467-025-64215-2","vorDoiUrl":"https://doi.org/10.1038/s41467-025-64215-2","workflowStages":[]},"version":"v1","identity":"rs-5684050","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5684050","identity":"rs-5684050","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}