Maternal socioeconomic disadvantage is associated with transcriptional indications of greater immune activation and slower tissue maturation in placental biopsies and newborn cord blood

Abstract

Children from economically disadvantaged families experience worse cognitive, psychiatric, and medical outcomes compared to more affluent youth. Preclinical models suggest some of the adverse influence of disadvantage could be transmitted during gestation via maternal immune activation, but this hypothesis has not been tested in humans. It also remains unclear whether prenatal interventions can mitigate such effects. To fill these gaps, we conducted two studies. Study 1 characterized the socioeconomic conditions of 79 women during pregnancy. At delivery, placenta biopsies and umbilical blood were collected for transcriptional profiling. Maternal disadvantage was associated with a transcriptional profile indicative of higher immune activation and slower fetal maturation, particularly in pathways related to brain, heart, and immune development. Cord blood cells of disadvantaged newborns also showed indications of immaturity, as reflected in down-regulation of pathways that coordinate myeloid cell development. These associations were independent of fetal sex, and characteristics of mothers (age, race, adiposity, diabetes, pre-eclampsia) and babies (delivery method, gestational age). Study 2 performed the same transcriptional analyses in specimens from 20 women participating in CenteringPregnancy, a group-based psychosocial intervention, and 20 women in traditional prenatal care. In both placenta biopsies and cord blood, women in CenteringPregnancy showed up-regulation of transcripts found in Study 1 to be most down-regulated in conjunction with disadvantage. Collectively, these results suggest socioeconomic disparities in placental biology are evident at birth, and provide clues about the mechanistic origins of health disparities. They also suggest the possibility that psychosocial interventions could have mitigating influences.

Keywords: Early life stress; Inflammation; Neurodevelopment; Placenta; Poverty.

Figure 1. Placenta transcriptome

Genome-wide expression profiling was performed on biopsies of placental chorionic villi. Linear mixed models were used to estimate the magnitude of differential gene expression as a function of maternal socioeconomic disadvantage, adjusting for a panel of a priori selected covariates, with false discovery rate held at 5 percent. Genes showing ≥ 1.25-fold differential expression over the range from lowest to highest disadvantage served as input into higher-order bioinformatics analyses using the Transcription Factor Element Listening System. This platform quantified the prevalence of transcription factor binding motifs (TFBMs) in promoters of differentially expressed genes. TFBM ratios > 1 indicate specified transcriptional pathway is up-regulated with maternal disadvantage; ratios < 1 indicate converse.

Figure 2. Cord blood transcriptome

Genome-wide expression profiling was performed on bulk cord blood cells (i.e., un-separated) from newborns. Linear mixed models were used to estimate the magnitude of differential gene expression as a function of maternal socioeconomic disadvantage, adjusting for a panel of a priori selected covariates, with false discovery rate held at 5 percent. Genes showing ≥ 1.25-fold differential expression over the range from lowest to highest disadvantage served as input into higher-order bioinformatics analyses using the Transcription Factor Element Listening System. This platform quantified the prevalence of transcription factor binding motifs (TFBMs) in promoters of differentially expressed genes. TFBM ratios > 1 indicate specified transcriptional pathway is up-regulated with maternal disadvantage; ratios < 1 indicate converse.

Figure 3. CenteringPregnancy Intervention

Relative to comparison subjects, women who participated in the intervention displayed higher expression of transcripts that were down-regulated in concert with disadvantage in Study 1. These patterns were apparent in both (A) biopsies of the placenta’s chorionic villous layer and (B) bulk cord blood cells (i.e., un-separated) from newborns.