Inflammation: A Proposed Intermediary Between Maternal Stress and Offspring Neuropsychiatric Risk

Abstract

During pregnancy, programming of the fetal central nervous system (CNS) establishes vulnerabilities for emergence of neuropsychiatric phenotypes later in life. Psychosocial influences during pregnancy, such as stressful life events or chronic stress, correlate with offspring neuropsychiatric disorders and with inflammation, respectively. Stress promotes inflammation, but the role of inflammation as a mediator between maternal psychosocial stress and offspring neuropsychiatric outcomes has not been extensively studied in humans. This review summarizes clinical evidence linking specific types of stress to maternal inflammatory load during pregnancy. We propose that inflammation is a mediator in the relationship between psychosocial stress and offspring neuropsychiatric outcomes, potentially influenced by poor maternal glucocorticoidimmune coordination. We present relevant experimental animal research supporting this hypothesis. We conclude that clinical and preclinical research support the premise that stressinduced maternal immune activation (MIA) contributes in part to prenatal programming of risk. Programming of risk is likely due to a combination of vulnerabilities, including multiple or repeated inflammatory events, timing of such events, poor maternal regulation of inflammation, genetic vulnerability, and lifestyle contributors.

Unique maternal immune and functional microbial profiles during prenatal stress

“…Exposure to prenatal stress can have life-long negative impacts on offspring mental health and wellbeing, and the mechanisms underlying these risks have yet to be completely defined. Maternal immune and glucocorticoid responses have repeatedly been demonstrated to be two of the primary drivers of poor infant outcomes 49,50 , although variability in stress severity and duration of exposure make it difficult to pinpoint critical activation thresholds of these cellular and molecular signaling pathways. Expanding investigations of the maternal microbiome during stress and gestation also highlight microbes as primary mediators of immune status and infant neurodevelopment 51 .…”

“…An increase in circulating pro-inflammatory cytokines is one of the hallmarks of pregnancy complications 55,56 and can be detected in pregnant women experiencing psychological stress 50,57,58 . In animal models, systemic administration of particular cytokines in circulation, such as IL-6 and IL-1β, is sufficient to recapitulate specific offspring neuroimmune abnormalities seen with prenatal stress 59,60 .…”

What does immunology have to do with brain development and neuropsychiatric disorders?

“…This crosstalk in the neuro-immune network can then, in turn, contribute to a number of somatic, neurodevelopmental and neuropsychiatric disorders 4,68,69 . Remarkably, in the case of mothers, stressful events occurring during a child's gestation can set the stage for adverse outcomes much later in the child's life 4,15,67,68,70,71 . In the case of fathers, it also appears that stressful events occurring pre-conception can have an adverse long-term impact 72 .…”

“…Epidemiological studies provide compelling evidence that perturbations in the prenatal and perinatal environments are associated with an increased risk of offspring developing neuropsychiatric disorders including ASD 71,[73][74][75][76][77][78][79][80] , schizophrenia 68,71,[81][82][83][84][85] , mood and affective disorders 71,[86][87][88][89][90][91][92] , OCD [93][94][95] , ADHD [96][97][98] , and TS [99][100][101][102] . These studies have identified a number of factors that can contribute to an individual's risk of developing one or more of these disorders.…”

Worries and concerns about COVID-19 lockdown aggravate stress reactions among pregnant women

“…Several studies have indicated that infections caused by viruses such as the In uenza A virus subtype H1N1 (A/H1N1) (The ANZIC In uenza Investigators and Australasian Maternity Outcomes Surveillance System 2010); Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) (Mullins et al 2020); and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (Alfaraj et al 2019), posed risks of severe maternal and neonatal morbidities. Moreover, pandemics can induce high levels of maternal psychological stress (Lee et al 2007), which can be a risk factor for poor pregnancy outcomes (Woods et al 2010) and child neurodevelopmental disorders (Hantsoo et al 2019). Moreover, a systematic review substantiated that disasters impact maternal mental health as well as child development (Harville et al 2010).…”