Background
Defining early life adversity
Biological embedding
Methodological challenges
Search strategy
Biological embedding by physiological axis
Examples of physiological changes observed after ELA | Overall clinical and functional effects | Key reviews |
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Brain structure and activity
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Structural variation in gray and white matter | Increased risk of: - Impairments in executive functioning (e.g., working memory, cognitive control) - Impaired emotion regulation and social functioning - Adverse effects on reward processing and stress regulation (e.g., hippocampus, amygdala, PFC) may increase risk of mood and substance use disorders | Bick & Nelson, 2016 [21] Hart & Rubia, 2012 [24] McEwen, 2013 [50] Nemeroff et al., 2016 [25] |
1) Changes in local/global gray matter volumes a) Some evidence for widespread, global gray matter change b) Decreased gray matter volume of PFC and hippocampus c) Complex volumetric changes in amygdala | ||
2) Changes in local/global white matter volume and microstructure | ||
a) Complex white matter volumetric changes in frontal lobes b) Microstructural variation in various white matter tracts that may impair communication between brain regions | ||
Functional variation in brain activity and functional connectivity | ||
3) Aberrant amygdala reactivity to emotional stimuli | ||
4) Alterations in amygdala-PFC connectivity | ||
Altered neurotransmitter metabolism or production | ||
5) Potential altered neurotransmitter levels/signaling involving key molecules, e.g., serotonin, dopamine, GABA, glutamate | ||
Neuroendocrine (HPA) stress response axes
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Hyper-responsiveness | - Both HPA hyper- or hypo- reactivity are characteristic patterns generating excess “allostatic load,” linked to cardiovascular disease, metabolic syndrome, accelerated cellular aging, and various psychopathologies - Downstream effects of aberrant cortisol levels (e.g., neurotoxicity, heightened inflammation, metabolic dysregulation) may drive pathology across other axes | Doom & Gunnar, 2015 [36] Heim & Binder, 2012 [87] |
1) Enhanced ACTH and cortisol response to stress/stimulation | ||
2) Evidence of impaired GR-mediated feedback inhibition | ||
Hypo-responsiveness | ||
4) Blunted HPA response (ACTH and cortisol) to stress/stimulation | ||
5) Heightened ACTH response with inappropriately blunted cortisol (normal or low) | ||
Altered basal diurnal rhythms | ||
3) Elevated, or suppressed, average cortisol/CRF | ||
6) Complex changes to diurnal cortisol rhythms (e.g., lower morning and flatter decline, or higher morning and steeper decline) | ||
Autonomic functioning
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1) Complex patterns of sympathetic- or parasympathetic-predominant imbalance of reactivity to acute stress, with alterations in responsiveness and counter-regulatory control | - Both parasympathetic- or sympathetic-predominant autonomic imbalances are linked to diseases of elevated “allostatic load” (discussed above) | Alkon et al., 2012 [55] El-Sheikh et al., 2009 [56] |
2) Elevated or decreased sympathetic or parasympathetic basal tone | ||
Immunity and inflammation
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1) Systemic immune suppression (e.g., impaired cellular immunity) | - Chronic inflammation linked to increased cardiometabolic and other disease risk - Immunosuppression linked to impaired control of infectious/neoplastic threats | Slopen et al., 2012 [66] Baumeister et al., 2016 [67] |
2) Chronic basal inflammation (e.g., elevated CRP, TNF- α, IL-6) 3) Heightened inflammatory reactivity | ||
Metabolism
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1) Impaired peripheral glucose handling with insulin resistance | - Heightened risk of type 2 diabetes, obesity, hyperlipidemia, or other metabolic disease | Maniam et al., 2014 [70] |
2) Altered fat metabolism with dyslipidemia | ||
Microbiome functioning (emergent evidence, animal models only to date)
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1) Transient microbiome perturbations after stress in infancy linked to aberrant immune development | - May contribute to inflammation, immune-suppression, and/or neurodevelopmental risk | O’Mahony et al., 2015 [74] |
2) Possible durable microbiome changes in adults after early stress |
Axis 1: The brain
Axis 2: Neuroendocrine stress regulation
HPA axis
Autonomic axis
Axis 3: Immune functioning
Axis 4: Metabolic health
Axis 5: The microbiome
Interactive effects across axes
Differential susceptibility to adversity
Modifier | Examples of findings | Further reading |
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Genetic variability | • Genetic polymorphisms found to moderate associations between ELA and various outcomes; Specific examples of outcomes impacted with implicated genes include: | |
o Emotional and neuroendocrine stress reactivity: 5-HTTLPR | Lester et al., 2006 [86] | |
o Inflammatory response to stress: 5-HTTLPR | Fredericks et al., 2010 [88] | |
o Common forms of psychopathology, including depression, ADHD, and substance addiction: NR3C1, CRHR1, OXTR, 5-HTTLPR, HTR3A, DRD2, MAOA, BDNF, COMT o Atherosclerosis risk: MAOA | Nemeroff et al., 2016 [25] Heim & Binder, 2012 [87] Zhao et al., 2013 [89] | |
Child sex and gender | • Complex sex differences in HPA and autonomic dysregulation after early stress observed in animals and humans | Essex et al., 2013 [19] |
• Differential effects of maternal vs. paternal stress on boys vs. girls leads some to posit ELA effect moderation by socially embedded gender roles | ||
• Genetic moderators of the effects of ELA may be sex and/or gender specific o Meta-analysis found stronger effect of MAOA genotype on psychopathology in boys o Different polymorphism on the 5-HTTLPR gene have been linked with increased risk of depression following ELA in males vs. females | Kim-Cohen et al., 2006 [90] Brummet et al., 2008 [91] | |
Other child characteristics | • Pre-existing health conditions, e.g., prematurity, poor physical health status, etc. alter social and physiological consequences of ELA | Doom & Gunnar, 2015 [36] |
• Child temperament, sensitivity to the environment, and emotion processing are associated with risk for psychopathology and may affect the ways in which children respond to adversity | Lester et al., 2006 [86] | |
Exposure characteristics | • Characteristics of the exposure, including type (e.g., sexual, physical, emotional abuse, or neglect), chronicity, and intensity, modify associations with physical and mental health outcomes | Nemeroff et al., 2016 [25] |
• Exposures occurring during early sensitive periods can have heightened impacts on specific developmental domains leading to “timing effects” | Bick & Nelson, 2016 [21] | |
Social context and caregiving | • Family structure and stability, birth order, caregiver stress and social support, community and societal context may modify effects of specific adversities | Doom & Gunnar, 2015 [36] |
• Presence of a dependable, supportive caregiver may “buffer” children from effects of otherwise adverse environment | ||
Cumulative occurrence | • Dose-response relationship between number of adversities and health and social effects are observed in large epidemiological studies | Felitti et al., 1998 [1] Danese et al., 2009 [3] |
Clinical, research, and public health applications
Practitioner activity | Recommendations | Recommended resources |
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Understanding disease etiology and risk | Consider how ELA contributes to a patient’s risk of common health problems, e.g.: • Mental health disorders: Depression, anxiety, substance use disorders, post-traumatic stress disorder, psychosis • Cardiovascular disease: Ischemic heart disease, hypertension, atherosclerosis • Metabolic pathology: Obesity, type 2 diabetes, dyslipidemia, metabolic syndrome • Neoplasm: Breast, liver, lung cancers | Further reading suggested throughout |
Screening | • Screen for ELA history • Assess social service and protection needs • Consider ELA history when assessing risk and screening for ELA-related diseases or developmental needs | Adverse Childhood Experiences Questionnaire [1] WHO Adverse Childhood Experiences International Questionnaire [104] American Academy of Pediatrics Resilience Project Clinical Screening Tools [105] |
Intervention |
General practice
Provide access to: • Mental healthcare • Early prevention and treatment for other ELA-related diseases • Social services and poverty alleviation • Violence response and prevention interventions
Pediatric practice
• Family and caregiver support programs • Early development interventions • Services to prevent or respond to ELA exposures, including child protection services | WHO Preventing Child Maltreatment guide [106] WHO mhGAP Intervention Guide [107] Interventions resources to support healthy child development from Frontiers of Innovation – Center on the Developing Child at Harvard University [108] |
Transforming care models | Adopt best-practices from “medical home models” to support ELA-exposed patients, including strategies promoting: • Patient- and family-centered wraparound care • Cultural competency • Enhanced access and follow-up | National Center for Medical Home Implementation Tools & Resources [109] |
Advocacy | Incorporate evidence on ELA into advocacy relating to: • Access to mental health services • Poverty alleviation, criminal justice reform, and violence prevention • Fair parental leave and high-quality child care • Immigration and refugee policies protecting children and families | WHO guidance package on Advocacy for Mental Health [110] United Nations Children’s Fund policy advocacy and children's rights tools [111] Children’s Defense Fund policy campaign resources [112] |