Prenatal stress exposures and fetal inflammation during mid-gestation

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ABSTRACT Maternal experiences of psychosocial stress (e.g., stressful life events, perceived stress, job strain, poor social support) are associated with an increased risk of preterm birth and inflammation during pregnancy has been implicated as a key mechanistic pathway. Epidemiologic studies have observed positive relationships between psychosocial stressors and maternal inflammation levels. Similarly, inflammatory biomarkers, measured in maternal samples during the second and third trimesters, have been associated with preterm birth. However, how psychosocial stress and maternal inflammation both influence fetal inflammation during early to mid- gestation remains unknown. This is problematic because most studies rely on maternal samples as proxies of fetal health during mid-pregnancy. This knowledge gap persists in large part due to logistical and ethical challenges in obtaining fetal tissue samples during mid-gestation. Closing this knowledge gap has implications for improving fetal health across pregnancy, as elevated levels of maternal inflammation during early pregnancy may lead to elevated levels of fetal inflammation later in gestation, which in turn can affect fetal development and child health outcomes. Communities of color and low socioeconomic status individuals experience the highest burden of multiple psychosocial stressors and are disproportionately affected by structural discrimination. Accordingly, we will utilize a unique cohort of pregnant people who underwent elective pregnancy terminations during the second trimester in San Francisco, CA between 2010 and 2016. This study population is racially, ethnically, and demographically diverse, serving primarily low-income women of color with public health insurance. We will, for the first time, measure a comprehensive panel of 24 inflammatory biomarkers in 114 previously banked maternal and cord sera and placenta samples. In parallel, we will quantify levels of corticotropin-releasing hormone (CRH), FMS-like tyrosine kinase receptor (FLT1), and placental growth factor (PlGF) in maternal sera. Our study, which leverages hard to obtain biospecimens from a critically important time period, will be the first to examine the relationship between psychosocial stress and fetal inflammation during mid-gestation. We will determine differences in abundances and assess correlations among biomarkers across the three matrices (Aim 1). Further, we will examine relationships between psychosocial stress and maternal and fetal inflammation and create inflammation scores for each matrix using factor analysis (Aim 2). We will also use structural equation modeling to assess whether inflammation measured in cord serum is influenced by and associated with maternal and placenta inflammation levels (Aim 3). Importantly, results from our study will provide important insights on the health effects of historically marginalized populations during a time period that is difficult to study. Understanding the origins of fetal inflammation during mid-gestation and its relationship with maternal inflammation can inform future studies that must rely on maternal measures as proxies for fetal inflammation and elucidate intervention opportunities at biologically relevant time periods to improve fetal growth.