Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes

Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes | 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 Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes Kathleen Fisch, Molly Huang, Cindy Barba, Hector Chavez, Avery Williams, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7419733/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Preeclampsia is a leading cause of pregnancy-related death, accounting for over 50,000 maternal and 500,000 fetal deaths worldwide each year. Preeclampsia has been linked to confined placental mosaicism, which underscores a potential role of placental genomic instability in driving adverse pregnancy outcomes. Here, using bulk RNA sequencing from 59 preeclamptic and 53 normotensive pregnancies, we explored somatic genomic instability and hypoxia with respect to clinical maternal-placental-neonatal outcomes. We found that genomic instability increased the probability of delivering at an earlier gestational age with a diagnosis of preeclampsia, maternal vascular malperfusion placental lesions, and small for gestational age neonates. Notably, genomic instability and hypoxia are predictive biomarkers for all three adverse pregnancy outcomes. In an induced pluripotent stem cell-derived trophoblast stem cell model, we observed increased genomic instability in trophoblast stem cells obtained from placentas demonstrating maternal vascular malperfusion with preeclampsia. Additionally, increased genomic instability correlated with reduced extravillous trophoblast invasion, implicating a functional role for genomic instability. These findings provide promising insights into the underlying mechanisms of genomic instability in the placenta which may be useful biomarkers for early clinical diagnosis of placental injury underlying preeclampsia. Health sciences/Biomarkers/Predictive markers Health sciences/Diseases/Cardiovascular diseases/Hypertension/Pre-eclampsia Health sciences/Pathogenesis/Clinical genetics/Chromosome abnormality Biological sciences/Computational biology and bioinformatics/Predictive medicine Biological sciences/Genetics/Genomic instability Full Text Additional Declarations Yes there is potential Competing Interest. A provisional patent application has been filed by the institution (University of California, San Diego) on behalf of inventors Kathleen Fisch, Mariko Horii, and Molly Huang covering all aspects of the manuscript (Application # 63/806,796). Cite Share Download PDF Status: Under Review 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7419733","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":505410251,"identity":"bb283cfe-6be4-4ae5-9d2d-c860949e23aa","order_by":0,"name":"Kathleen Fisch","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBACCeaDDQyMDTYJDAzMDcwQMSCbB58WtkSQljSgMsbGZiK1gBQ3HCZBi2Qbc/OHnzvO5/GzH2x/XMBwWF6+PYHxwds23Fqk2RjbJHvP3C6W7ElsbJ7BcNhww5kHzIZz8WiRk29sY2Zsu5244QBQCw/D4QQDiQQ2aV58WtgYmz8ztp1L3H/+IUSL/IwE9t/4tAAd1iDN2HYgcYME1BaGGwlszPi0SLaB/NKWnDjjxsPG2TwG6UC/PGyWnHMOtxaJY+yPP/xss0vs708+8JmnwhoYYskHP7wpw60FDRiACMYGotWPglEwCkbBKMAOAAN1VWQENZo/AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-0117-7444","institution":"University of California, San Diego","correspondingAuthor":true,"prefix":"","firstName":"Kathleen","middleName":"","lastName":"Fisch","suffix":""},{"id":505410252,"identity":"e406048a-d02f-4106-81ce-76845738218d","order_by":1,"name":"Molly Huang","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Molly","middleName":"","lastName":"Huang","suffix":""},{"id":505410253,"identity":"5a5ad0f1-19ef-4a33-8ee1-4fbcf1003eef","order_by":2,"name":"Cindy Barba","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Cindy","middleName":"","lastName":"Barba","suffix":""},{"id":505410254,"identity":"d44c7d0f-b91a-4c30-8504-ce10f83da1bb","order_by":3,"name":"Hector Chavez","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Hector","middleName":"","lastName":"Chavez","suffix":""},{"id":505410255,"identity":"73309dc2-52cb-413f-8b54-d5968e9f02a3","order_by":4,"name":"Avery Williams","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Avery","middleName":"","lastName":"Williams","suffix":""},{"id":505410256,"identity":"a3c597cc-defe-4e19-95cc-0d747327d44a","order_by":5,"name":"Nicholas Guo","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Guo","suffix":""},{"id":505410257,"identity":"43496d8f-c587-4c97-855e-460a16584fa8","order_by":6,"name":"Rhea Robertson","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Rhea","middleName":"","lastName":"Robertson","suffix":""},{"id":505410258,"identity":"0d20b7fa-f62f-4bba-832d-28f54ef8946d","order_by":7,"name":"Emily Zhang","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"","lastName":"Zhang","suffix":""},{"id":505410259,"identity":"c1bd3edc-68bf-4cec-af65-4056535b0b03","order_by":8,"name":"Arundhati Calambur","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Arundhati","middleName":"","lastName":"Calambur","suffix":""},{"id":505410260,"identity":"d0c60937-7900-47d1-a27b-c9a774d9efaf","order_by":9,"name":"Cayla Mason","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Cayla","middleName":"","lastName":"Mason","suffix":""},{"id":505410261,"identity":"245fa49e-c78e-451a-ba87-cbb19adf6c9e","order_by":10,"name":"Katharine Nelson","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Katharine","middleName":"","lastName":"Nelson","suffix":""},{"id":505410262,"identity":"9707a5af-e55c-4642-9d6c-a9235b01722f","order_by":11,"name":"Morgan Meads","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Morgan","middleName":"","lastName":"Meads","suffix":""},{"id":505410263,"identity":"f7ae6386-eb8a-4bd8-adc0-74bffec173ae","order_by":12,"name":"Omonigho Aisagbonhi","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Omonigho","middleName":"","lastName":"Aisagbonhi","suffix":""},{"id":505410264,"identity":"8470b398-3561-4d30-af4f-6f38a7f239d2","order_by":13,"name":"Mariko Horii","email":"","orcid":"https://orcid.org/0000-0002-4996-6792","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Mariko","middleName":"","lastName":"Horii","suffix":""}],"badges":[],"createdAt":"2025-08-20 17:35:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7419733/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7419733/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90798048,"identity":"befe4e89-cf10-4e1d-8c74-20c2b6b8bd95","added_by":"auto","created_at":"2025-09-08 09:31:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2530654,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Huangetalmanuscriptfigures20250820.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7419733/v1_covered_16af2c1c-b393-443e-bd29-ccd27e7ad9c1.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nA provisional patent application has been filed by the institution (University of California, San Diego) on behalf of inventors Kathleen Fisch, Mariko Horii, and Molly Huang covering all aspects of the manuscript (Application # 63/806,796).","formattedTitle":"Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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-7419733/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7419733/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Preeclampsia is a leading cause of pregnancy-related death, accounting for over 50,000 maternal and 500,000 fetal deaths worldwide each year. Preeclampsia has been linked to confined placental mosaicism, which underscores a potential role of placental genomic instability in driving adverse pregnancy outcomes. Here, using bulk RNA sequencing from 59 preeclamptic and 53 normotensive pregnancies, we explored somatic genomic instability and hypoxia with respect to clinical maternal-placental-neonatal outcomes. We found that genomic instability increased the probability of delivering at an earlier gestational age with a diagnosis of preeclampsia, maternal vascular malperfusion placental lesions, and small for gestational age neonates. Notably, genomic instability and hypoxia are predictive biomarkers for all three adverse pregnancy outcomes. In an induced pluripotent stem cell-derived trophoblast stem cell model, we observed increased genomic instability in trophoblast stem cells obtained from placentas demonstrating maternal vascular malperfusion with preeclampsia. Additionally, increased genomic instability correlated with reduced extravillous trophoblast invasion, implicating a functional role for genomic instability. These findings provide promising insights into the underlying mechanisms of genomic instability in the placenta which may be useful biomarkers for early clinical diagnosis of placental injury underlying preeclampsia.","manuscriptTitle":"Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 09:23:03","doi":"10.21203/rs.3.rs-7419733/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":"d34eea14-59eb-4526-90ae-5742dab5854c","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":53682288,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":53682289,"name":"Health sciences/Diseases/Cardiovascular diseases/Hypertension/Pre-eclampsia"},{"id":53682290,"name":"Health sciences/Pathogenesis/Clinical genetics/Chromosome abnormality"},{"id":53682291,"name":"Biological sciences/Computational biology and bioinformatics/Predictive medicine"},{"id":53682292,"name":"Biological sciences/Genetics/Genomic instability"}],"tags":[],"updatedAt":"2025-09-08T09:23:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-08 09:23:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7419733","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7419733","identity":"rs-7419733","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}