Maternal BMI Leaves Distinct Molecular Fingerprints in Placenta, Mother and Fetus

Higher body mass index in late pregnancy is linked to distinct molecular changes in the mother, the placenta, and the fetus at birth — and, strikingly, those changes do not follow a single uniform inflammatory pattern. That is the central finding of an exploratory multi-compartment study published in Frontiers in Cell and Developmental Biology, in which researchers profiled gene expression in maternal blood immune cells, placental tissue, and umbilical cord blood immune cells collected from the same pregnancies, alongside cytokine measurements in maternal and cord plasma. The work, led by Viviane Schuch and Erica L. Johnson at Morehouse School of Medicine, offers one of the most detailed cross-tissue snapshots to date of how maternal metabolic status is reflected across the maternal–placental–fetal axis.

The cohort consisted of 20 pregnant participants, all of whom self-identified as Black or African American — a population the authors note remains underrepresented in molecular studies of pregnancy biology. Samples were collected immediately after elective cesarean section without labor at Grady Memorial Hospital in Atlanta between June 2023 and April 2025. All deliveries occurred at term, with a median gestational age of 39 weeks, and the infants were evenly split between 10 girls and 10 boys. Third-trimester body mass index, the study’s primary exposure, was enriched toward higher values, with a median of 34.4 kg/m². RNA-sequencing data were available for 17 maternal peripheral blood mononuclear cell samples, 18 cord blood mononuclear cell samples, and 14 placental samples, while a larger plasma set of 31 maternal and 31 cord samples from 34 pregnancies was used for multiplex cytokine profiling.

The analytical strategy treated third-trimester BMI as a continuous variable within each compartment separately, using differential expression analysis, Hallmark pathway enrichment, and exploratory co-expression network analysis. Genes with adjusted P values below 0.10 were considered differentially expressed, and pathway enrichment was assessed at a stricter threshold of 0.05. The placenta emerged as the compartment with by far the strongest BMI-associated transcriptional signature, showing activation of metabolic and stress-response programs including oxidative phosphorylation, reactive oxygen species signaling, the unfolded protein response, DNA repair, MTORC1 signaling, and adipogenesis. Representative gene-level effects per five-unit increase in BMI included increased expression of ZFP57 (log2 fold change of 1.15) and decreased expression of MGA (log2 fold change of −0.11), both with false discovery rates of 0.021.

Maternal circulating immune cells told a subtler story. Rather than showing blanket inflammation, maternal peripheral blood mononuclear cells displayed what the authors describe as selective immune activation superimposed on broader attenuation of metabolic, inflammatory, and redox-related programs. Expression of PEG10, FCRL2, NIBAN3, FCER2, and SCN3A rose with higher BMI, while IL1R2, TARM1, CMBL, and CH25H fell. For example, each five-unit BMI increase was associated with a log2 fold change of 0.64 in PEG10 and −2.04 in IL1R2. The increased FCER2 and FCRL2 signals are compatible with B-cell-associated biology, whereas reduced IL1R2 and CH25H suggest dampening of selected innate immune regulatory and host-defense pathways. Pathway analysis reinforced this split picture: interferon gamma response was positively enriched in maternal immune cells but negatively enriched in placental tissue and cord blood cells, and oxidative phosphorylation was enriched in placenta but depleted in maternal blood cells.

The fetal compartment showed yet another pattern. In cord blood mononuclear cells, higher maternal third-trimester BMI was associated not with broad inflammatory activation but with proliferative and immune-developmental remodeling, including enrichment of cell-cycle programs and relative attenuation of inflammatory and immune-response signaling. Genes positively associated with BMI included GPR21, TACSTD2, and MFAP5, while XG, RBPMS2, SEC14L5, and DHRS9 were negatively associated. Exploratory co-expression modules in the fetal cells highlighted interleukin-10 signaling, a cytotoxic lymphoid-associated program featuring genes such as GZMB, PRF1, and NKG7, and relative reduction of heme biosynthesis-related modules at higher BMI strata.

Beyond the gene-level results, exploratory network analysis nominated candidate modules tied to tissue structure and the maternal–fetal interface. In placental tissue, one module enriched for extracellular matrix organization and integrin interactions showed lower activity at higher BMI, while another, more active at high BMI, was enriched for cell-surface interactions at the vascular wall and erythroid oxygen-transport pathways, containing placental endocrine-associated nodes such as LEP, PSG1, and CSH1. In maternal immune cells, modules pointed to interleukin-10 signaling and platelet activation and adhesion pathways. The authors stress that, given the modest sample sizes, these network findings are hypothesis-generating context rather than confirmatory evidence.

Supportive validation came from targeted quantitative PCR on villous placental tissue from 15 donors. Third-trimester BMI was inversely correlated with ΔCt values — where lower values indicate higher transcript abundance relative to β-actin — for FDXR (Pearson r = −0.57, p = 0.028), NMNAT2 (r = −0.71, p = 0.003), and ZFP57 (r = −0.68, p = 0.005), consistent with the sequencing results for these mitochondrial, redox-regulatory, and imprinting-related genes. Estimated cell-composition analyses using CIBERSORTx and placental marker scores found no associations with BMI that survived correction, and adjusting for the dominant composition axis preserved the direction of all key gene associations, suggesting the signals were not simply driven by shifts in cell proportions — although bulk RNA sequencing cannot definitively separate cell-intrinsic regulation from compositional or activation-state changes.

The plasma cytokine results, by contrast, were largely negative. Of 71 analytes measured in each compartment, four maternal-plasma and three cord-plasma analytes showed nominal associations with BMI — including nominally higher MDC/CCL22 and lower IL-28A, Eotaxin/CCL11, and IL-9 in maternal plasma, and nominally higher MIP-1β/CCL4 and lower FLT-3L and IL-9 in cord plasma — but none remained significant after Benjamini–Hochberg correction, with minimum false discovery rates of 0.577 and 0.547 respectively. The authors interpret these as strictly hypothesis-generating signals that do not support a uniform systemic inflammatory response to increasing BMI.

Important caveats frame the entire study. The sample sizes are small, limiting statistical power, and sparse pregnancy complications — one case of gestational diabetes, three of hypertension, and zero recorded preeclampsia cases — prevented reliable multivariable adjustment for clinical confounding. Sensitivity analyses adding maternal age, gestational age, infant sex, or a complication composite retained the direction of key BMI associations in all estimable models, but the authors emphasize this demonstrates directional consistency, not definitive confounder control. Third-trimester BMI also reflects pre-pregnancy adiposity, gestational weight gain, and fetal and placental mass together, so the associations cannot be attributed specifically to pre-pregnancy obesity, and the cross-sectional design cannot capture longitudinal change.

Within those limits, the study’s contribution is a systems-level view: increasing late-pregnancy BMI was associated with coordinated but compartment-specific molecular programs — maternal immune-metabolic remodeling, placental metabolic and oxidative-stress adaptation, and fetal immune-developmental changes — rather than a single inflammatory signature. The authors conclude that the candidate mitochondrial, inflammatory, vascular-interface, extracellular matrix, and placental endocrine-associated pathways they identified now require validation in larger independent cohorts, ideally with single-cell transcriptomics and functional studies, before any claims about causality, clinical significance, or effects on offspring health can be made.

Subject of Research: Molecular signatures associated with maternal late-pregnancy BMI across the maternal–placental–fetal axis

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

Article References: Schuch, V., Bashi, A., Hossack, D., Adekambi, T., Joseph, T., Wilson, C., Olanrewaju, R., Dawning, A., Johnson, A., Jones, S., Sintim-Aboagye, E., Enninga, E. A. L., Chakraborty, R., & Johnson, E. L. (2026). Maternal late-pregnancy BMI is associated with compartment-specific immune-metabolic signatures across the maternal–placental–fetal axis. Frontiers in Cell and Developmental Biology, 14, Article 1899628. https://doi.org/10.3389/fcell.2026.1899628

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1899628

Keywords: maternal BMI, placenta, cord blood, transcriptomics, RNA-seq, pregnancy, obesity, cytokines, fetal immune development, oxidative phosphorylation, co-expression networks, maternal–fetal interface