{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:04:31Z","timestamp":1789830271282,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,15]]},"group-title":"Epidemiology","reference-count":24,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["24CDA1260466"],"award-info":[{"award-number":["24CDA1260466"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>Psychosocial exposures in early pregnancy are associated with worse maternal cardiovascular health (CVH), but the biological pathways linking early-pregnancy stressors to long-term CVH are not defined.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To determine whether plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stressors and CVH 2 to 7 years after delivery.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design, Setting, and Participants<\/jats:title>\n                  <jats:p>This was a secondary analysis of the prospective multicenter Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study (nuMoM2b-HHS), which enrolled nulliparous individuals at eight US academic centers (2010-2014) and followed them 2 to 7 years after delivery. The analytic sample comprised participants with first-trimester plasma proteomics. Analyses were conducted from January to June 2026.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposures<\/jats:title>\n                  <jats:p>Perceived stress (Perceived Stress Scale-10 &gt;13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale &gt;10) and anxiety (State-Trait Anxiety Inventory &gt;37) as secondary exposures.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>Post-pregnancy CVH quantified by the American Heart Association Life\u2019s Essential 8 (LE8) composite score (0-100) and its clinical components: blood pressure, lipid, glucose, and body mass index (BMI) scores. A four-way decomposition partitioned the total effect of stress into a controlled direct effect, reference interaction, mediated interaction, and pure indirect effect operating through a proteomic mediator.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 1662 participants (mean [SD] age, 27.1 [5.5] years), 41.6% screened positive for stress. Of 6874 aptamers, 17 (representing 14 unique, predominantly neuronal and synaptic proteins) were associated with both stress and the LE8 composite as well as four clinical components after false discovery rate correction. No aptamers met criteria for depression or anxiety. Stress was associated with lower levels of all 14 proteins, and higher protein levels were associated with better CVH scores. The 14 proteins reduced to a single principal component (57% of variance) used as the mediator. Stress was associated with a lower post-pregnancy LE8 composite score (total effect, \u22123.74 [95% CI, \u22125.03 to \u22122.45]); the proteomic factor accounted for a pure indirect effect of \u22121.20 (95% CI, \u22121.68 to \u22120.72), approximately 32% of the total effect, and approximately 56% of the larger association with the BMI score. Significant indirect effects through the proteomic factor were also observed for the blood pressure, lipid, and glucose scores despite nonsignificant total effects.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions and Relevance<\/jats:title>\n                  <jats:p>A coherent neuronal and synaptic plasma protein signature in early pregnancy mediated a substantial share of the association between maternal psychosocial stress and cardiovascular health years after delivery, identifying a candidate biological pathway for further study.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Question<\/jats:title>\n                    <jats:p>Do plasma proteins measured in early pregnancy mediate the association between early-pregnancy psychosocial stress and cardiovascular health (CVH) 2 to 7 years after delivery?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>In this analysis of 1662 nulliparous individuals, early-pregnancy perceived stress was associated with lower post-pregnancy Life\u2019s Essential 8 CVH. A single factor derived from 14 predominantly neuronal and synaptic plasma proteins mediated approximately one-third of this association and more than half of the association with body mass index.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Meaning<\/jats:title>\n                    <jats:p>A coherent neuronal and synaptic plasma protein signature in early pregnancy may represent a biological pathway linking maternal psychosocial stress to long-term cardiovascular health.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.14.26363041","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:10:28Z","timestamp":1789521028000},"source":"Crossref","is-referenced-by-count":0,"title":["Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5813-5993","authenticated-orcid":false,"given":"Xiaoning","family":"Huang","sequence":"first","affiliation":[{"name":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-1219","authenticated-orcid":false,"given":"Lucia C.","family":"Petito","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Guan","sequence":"additional","affiliation":[{"name":"University of Minnesota, School of Public Health, Division of Biostatistics & Health Data Science"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6274-0544","authenticated-orcid":false,"given":"Lynn M.","family":"Yee","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8379-0743","authenticated-orcid":false,"given":"David M.","family":"Haas","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Department of Obstetrics and Gynecology, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Mercer","sequence":"additional","affiliation":[{"name":"Case Western Reserve University School of Medicine, Department of Obstetrics and Gynecology, Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Parry","sequence":"additional","affiliation":[{"name":"University of Pennsylvania School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George R.","family":"Saade","sequence":"additional","affiliation":[{"name":"University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5794-3152","authenticated-orcid":false,"given":"Robert M.","family":"Silver","sequence":"additional","affiliation":[{"name":"University of Utah Health Sciences Center, Department of Obstetrics and Gynecology, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Qiao","sequence":"additional","affiliation":[{"name":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Huang","sequence":"additional","affiliation":[{"name":"Utah Center for Genetics Discovery, University of Utah School of Medicine, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyagriv N.","family":"Simhan","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine, Magee-Women\u2019s Research Institute & Foundation, Department of Obstetrics and Gynecology, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma M.","family":"Reddy","sequence":"additional","affiliation":[{"name":"Columbia University Irving Medical Center, Department of Obstetrics and Gynecology, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Chung","sequence":"additional","affiliation":[{"name":"University of California Irvine School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6327-2439","authenticated-orcid":false,"given":"Philip","family":"Greenland","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"name":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0847-6110","authenticated-orcid":false,"given":"Donald M.","family":"Lloyd-Jones","sequence":"additional","affiliation":[{"name":"Preventive Medicine & Epidemiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Grobman","sequence":"additional","affiliation":[{"name":"The Warren Alpert Medical School of Brown University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Providence, RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0643-1859","authenticated-orcid":false,"given":"Sadiya S.","family":"Khan","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine, Department of Medicine, Division of Cardiology, Chicago, IL"},{"name":"Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091907300706000_2026.09.14.26363041v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001124"},{"key":"2026091907300706000_2026.09.14.26363041v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.19192"},{"key":"2026091907300706000_2026.09.14.26363041v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.322001"},{"key":"2026091907300706000_2026.09.14.26363041v1.4","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001078"},{"key":"2026091907300706000_2026.09.14.26363041v1.5","doi-asserted-by":"publisher","DOI":"10.1161\/circoutcomes.124.011217"},{"key":"2026091907300706000_2026.09.14.26363041v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2025.102501"},{"key":"2026091907300706000_2026.09.14.26363041v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.125.25991"},{"key":"2026091907300706000_2026.09.14.26363041v1.8","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2024.1621"},{"key":"2026091907300706000_2026.09.14.26363041v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2015.01.019"},{"key":"2026091907300706000_2026.09.14.26363041v1.10","doi-asserted-by":"publisher","DOI":"10.2307\/2136404"},{"key":"2026091907300706000_2026.09.14.26363041v1.11","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.150.6.782"},{"key":"2026091907300706000_2026.09.14.26363041v1.12","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m4022"},{"key":"2026091907300706000_2026.09.14.26363041v1.13","doi-asserted-by":"crossref","unstructured":"Spielberger CD. State-trait anxiety inventory for adults. 1983;","DOI":"10.1037\/t06496-000"},{"key":"2026091907300706000_2026.09.14.26363041v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.Cd015292"},{"key":"2026091907300706000_2026.09.14.26363041v1.15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015004"},{"key":"2026091907300706000_2026.09.14.26363041v1.16","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v045.i04"},{"key":"2026091907300706000_2026.09.14.26363041v1.17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-9-57"},{"key":"2026091907300706000_2026.09.14.26363041v1.18","doi-asserted-by":"publisher","DOI":"10.2307\/2346101"},{"issue":"6","key":"2026091907300706000_2026.09.14.26363041v1.19","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1093\/aje\/kwx355","article-title":"Decomposition of the total effect in the presence of multiple mediators and interactions","volume":"187","year":"2018","journal-title":"American journal of epidemiology"},{"key":"2026091907300706000_2026.09.14.26363041v1.20","doi-asserted-by":"crossref","unstructured":"Discacciati A , Bellavia A , Lee JJ , Mazumdar M , Valeri L . Med4way: a Stata command to investigate mediating and interactive mechanisms using the four-way effect decomposition. Oxford University Press; 2019.","DOI":"10.1093\/ije\/dyy236"},{"key":"2026091907300706000_2026.09.14.26363041v1.21","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0000000000000121"},{"key":"2026091907300706000_2026.09.14.26363041v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s11886-023-01990-8"},{"issue":"28","key":"2026091907300706000_2026.09.14.26363041v1.23","first-page":"179","article-title":"Adipose tissue-derived nerve growth factor and brain-derived neurotrophic factor: results from experimental stress and diabetes","volume":"28","year":"2009","journal-title":"Gen Physiol Biophys"},{"key":"2026091907300706000_2026.09.14.26363041v1.24","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.125.325580"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.14.26363041","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T14:30:15Z","timestamp":1789828215000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.14.26363041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":24,"URL":"https:\/\/doi.org\/10.64898\/2026.09.14.26363041","relation":{},"subject":[],"published":{"date-parts":[[2026,9,15]]},"subtype":"preprint"}}