Plasma Proteomic Mediators of the Association Between Early-Pregnancy Psychosocial Stress and Cardiovascular Health 2 to 7 Years After Delivery: The nuMoM2b-HHS Study

Importance: 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. Objective: 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. Design Setting and Participants: 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. Exposures: Perceived stress (Perceived Stress Scale-10 >13) as the primary exposure; Early-pregnancy depression (Edinburgh Postnatal Depression Scale >10) and anxiety (State-Trait Anxiety Inventory >37) as secondary exposures. Main Outcomes and Measures: Post-pregnancy CVH quantified by the American Heart Association Life's 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. Results: 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, -3.74 [95% CI, -5.03 to -2.45]); the proteomic factor accounted for a pure indirect effect of -1.20 (95% CI, -1.68 to -0.72), 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. Conclusions and Relevance: 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. Key Points: 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.