Maternal late-pregnancy BMI is associated with compartment-specific immune-metabolic signatures across the maternal–placental–fetal axis

Introduction Elevated maternal body mass index (BMI) during pregnancy is associated with adverse maternal and offspring outcomes; yet the molecular pathways linking maternal metabolic status to placental function and fetal immune development remain poorly understood. Methods We performed multi-compartment transcriptomic profiling across the maternal–placental–fetal axis, complemented by exploratory cytokine profiling in a larger available plasma sample set. Maternal peripheral blood mononuclear cells (PBMCs), placental villous tissue, cord blood mononuclear cells (CBMCs), maternal plasma, and cord plasma were collected at delivery when available. RNA-seq data were available for 17 maternal PBMC samples, 18 CBMC samples, and 14 placental samples from 20 term pregnancies, while Luminex profiling was performed in 31 maternal plasma and 31 cord plasma samples, comprising available plasma from the RNA-seq cohort plus additional plasma-only samples. RNA-seq analyses were performed separately within each compartment using third-trimester BMI as a continuous variable, followed by Hallmark pathway enrichment, co-expression network analysis, cytokine/chemokine profiling and targeted placental qRT-PCR validation. Results Higher maternal third-trimester BMI was associated with distinct transcriptional programs across maternal, placental, and fetal compartments. In maternal PBMCs, higher third-trimester BMI was associated with a modest but coordinated gene-level signature and pathway patterns consistent with selective immune activation, alongside broader attenuation of metabolic, inflammatory, and redox-related programs. Placental tissue exhibited the strongest BMI-associated transcriptomic signature, characterized by metabolic and stress-response activation, including enrichment of oxidative phosphorylation, reactive oxygen species signaling, unfolded protein response, DNA repair, MTORC1 signaling, and adipogenesis. Exploratory co-expression analyses further highlighted candidate extracellular matrix, vascular-interface, and placental endocrine-associated modules. In CBMCs, higher third-trimester BMI was associated with fetal immune-developmental remodeling, including proliferative pathway enrichment and relative attenuation of inflammatory and immune-response signaling. Exploratory plasma cytokine profiling identified nominal compartment-specific associations with higher third-trimester BMI; however, none remained significant after multiple-testing correction. Discussion Collectively, the multi-compartment findings nominate candidate mitochondrial, inflammatory, vascular-interface, extracellular matrix, and placental endocrine-associated pathways for validation in larger independent cohorts.