Adversity in early life and pregnancy are immunologically distinct from total life adversity: macrophage-associated phenotypes in women exposed to interpersonal violence

Abstract

Early childhood and pregnancy are two sensitive periods of heightened immune plasticity, when exposure to adversity may disproportionately increase health risks. However, we need deeper phenotyping to disentangle the impact of adversity during sensitive periods from that across the total lifespan. This study examined whether retrospective reports of adversity during childhood or pregnancy were associated with inflammatory imbalance, in an ethnically diverse cohort of 53 low-income women seeking family-based trauma treatment following exposure to interpersonal violence. Structured interviews assessed early life adversity (trauma exposure ≤ age 5), pregnancy adversity, and total lifetime adversity. Blood serum was assayed for pro-inflammatory (TNF-a, IL-1ß, IL-6, and CRP) and anti-inflammatory (IL-1RA, IL-4, and IL-10) cytokines. CD14+ monocytes were isolated in a subsample (n = 42) and gene expression assayed by RNA sequencing (Illumina HiSeq 4000; TruSeq cDNA library). The primary outcome was a macrophage-associated M1/M2 gene expression phenotype. To evaluate sensitivity and specificity, we contrasted M1/M2 gene expression with a second, clinically-validated macrophage-associated immunosuppressive phenotype (endotoxin tolerance) and with pro-inflammatory and anti-inflammatory cytokine levels. Adjusting for demographics, socioeconomic status, and psychopathology, higher adversity in early life (ß = .337, p = 0.029) and pregnancy (ß = .332, p = 0.032) were each associated with higher M1/M2 gene expression, whereas higher lifetime adversity (ß = −.341, p = 0.031) was associated with lower immunosuppressive gene expression. Adversity during sensitive periods was uniquely associated with M1/M2 imbalance, among low-income women with interpersonal violence exposure. Given that M1/M2 imbalance is found in sepsis, severe COVID-19 and myriad chronic diseases, these findings implicate novel immune mechanisms underlying the impact of adversity on health.

Young children's traumatic stress reactions to the COVID-19 pandemic: The long reach of mothers' adverse childhood experiences

“…Research shows that maternal exposure to adverse childhood experiences (ACEs) significantly increases the odds of depression, anxiety, hyperactivity, or other serious emotional difficulties in their offspring ( Folger et al, 2018 ; Haynes et al, 2020 ; Schickedanz et al, 2018 ). Moreover, adversity experienced during a mother's childhood may have more longstanding impacts than trauma exposure that occurs later in her life ( Aschbacher et al, 2021 ; Steine et al, 2020 ) and may affect offspring outcomes by way of intergenerational biological embedding (i.e., adversity-related epigenetic or physiological alterations to maternal biology that are transmitted to offspring; for a review see Buss et al, 2017 ). As such, it is important to consider the contributions of maternal history of ACEs as well as more recent pandemic-related negative life events to children's adjustment during the pandemic.…”

Intergenerational Transmission of Effects of Women's Stressors During Pregnancy: Child Psychopathology and the Protective Role of Parenting

“…These include: emotional stressors (e.g., a family member being hospitalized or dying), financial stressors (e.g., moving, losing a job, being unable to pay rent/bills), partner-related stressors (e.g., separation/divorce), and traumatic stressors (e.g., becoming homeless) ( 12 ). Despite these alarming rates of exposure to stressors during pregnancy—a time when women's social and biological wellbeing is in flux and particularly vulnerable to stress ( 13 , 14 )— there has been limited focus on the intergenerational transmission of the effects of stressors, such as pSLE and pIPV, on offspring psychopathology and related developmental processes. The perinatal period is a critical time for offspring development, wherein such intergenerational risks pose a threat to offspring mental health across the lifespan.…”

“…A large body of research has documented the association of both pSLE and pIPV with deleterious outcomes for women, including maternal mortality, labor and delivery complications, poor perinatal mental health (such as depression, post-traumatic stress disorder, and substance use disorder), and enduring alterations to women's immune function ( 13 , 15 , 16 ). The intergenerational impact of pIPV and pSLE is seen in neonatal outcomes of higher rates of preterm birth and low birth weight, but also in longer-term neurodevelopmental problems that extend into childhood and beyond ( 17 – 20 ).…”

Stress-Related Mental Health Disorders and Inflammation in Pregnancy: The Current Landscape and the Need for Further Investigation

“…Taken together, studies to date suggest that stress/trauma exposure confers increased risk for higher inflammation in pregnant women and even altered expression of immune genes two to six years after pregnancy ( 66 ). This relationship may be due to glucocorticoid resistance.…”