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OBJECTIVES: Chronic intervillositis of unknown etiology (CIUE) is the pathological influx of maternal inflammatory cells into the intervillous space of the placenta without demonstrable cause. CIUE is associated with placental damage and increased risk of pregnancy loss, fetal demise, and growth restriction. The pathogenic mechanism is unclear, and we lack biomarkers for detection, and treatments to prevent recurrence. DNA methylation (DNAme) is a biomarker altered in association with many disease states. We hypothesized that CIUE may be associated with a distinct signature placental DNAme signature. METHODS: DNAme was profiled using the Illumina Infinium MethylationEPIC v2.0 array on fresh-frozen placental tissue. After quality control, data were available for 24 CIUE (14 high grade, 10 low grade) and 27 non-CIUE placental samples, plus six independent decidua samples. CIUE was confirmed and graded by a perinatal pathologist. Contamination was assessed using the 65 array genotyping probes, placental cell composition and epigenetic age were estimated. After processing, DNAme data were available at 855,732 CpGs. RESULTS: Several lines of evidence indicated maternal DNA in CIUE placentas. Genetic contamination metrics were higher in CIUE than non-CIUE cases. In XY samples, X chromosome copy number increased with CIUE grade, suggesting XX contaminating DNA. Principal components analysis placed CIUE samples closer to decidua along PC1 than non-CIUE samples, cell composition showed elevated Hofbauer cells, monocytes, and neutrophils in CIUE. Epigenetic age was higher in CIUE versus non-CIUE samples. Together, these findings suggested an increased concentration of non-self XX DNA in CIUE cases, likely originating from an adult, macrophage-rich source, suggesting a maternal origin. An epigenome-wide association study found that all significant differentially methylated loci associated with CIUE were attenuated after adjusting for cell composition. CONCLUSIONS: Our results illustrate that placental DNAme patterns in CIUE reflect signatures of maternal infiltration rather than intrinsic DNAme alterations. This study also highlights the value of integrating the diverse molecular data outputs of DNAme arrays to explore the presence of maternal cells in placental tissue.
Inkster et al. (Fri,) studied this question.