Associations of Serum Inflammatory Biomarkers During Pregnancy With Placental Pathology and Placental Gene Expression at Delivery

Problem: We sought to investigate whether maternal inflammatory cytokines during pregnancy are associated with histologic inflammatory or vascular lesions in the placenta and/or correlated with gene expression patterns in the placenta.

Method of Study: We leveraged data from a large randomized controlled trial (RCT) at a single site. Maternal serum was collected in the second and third trimesters, and a composite inflammatory score was created using five measured biomarkers (CRP, IL-6, IL-1ra, IL-10, and TNF-α). Placentas were collected at delivery for histological analysis and four major patterns of placental injury were characterized. Fresh small chorionic villous biopsies were collected for placental genome-wide mRNA profiling. Transcripts showing >2-fold differential expression over the 4-SD range of circulating inflammatory biomarkers were reported, adjusting for potential confounders.

Results: The primary analysis included 601 participants. A one standard deviation increase in the third-trimester inflammatory composite was associated with increased odds of chronic inflammation in the placenta (OR: 1.23, 95% CI 1.01, 1.51;). This was driven primarily by elevations in IL-10 (OR: 1.37; 99% CI: 1.06, 1.77). Higher maternal IL-10 in circulation was associated with bioinformatic indications of reduced pro-inflammatory gene regulation pathways in the placenta (AP1 decreased 25%, p = 0.003; NF-kB decreased 53%, p = 0.003) and indications of increased STAT family signaling pathways which mediate signaling through the IL-10 receptor (increased 73%, p = 0.002).

Conclusions: Our results indicate that elevated maternal circulating IL-10 during pregnancy is associated with chronic inflammatory lesions in the placenta at delivery. Additionally, higher levels of circulating IL-10 are associated with upregulated STAT signaling pathways in placental tissues.