The remarkably high incidence of child maltreatment in the United States and worldwide is astounding. Estimates have revealed that nearly 3.6 million cases of child abuse and neglect are reported annually in the United States. According to the U.S. Department of Health and Human Services Children’s Bureau (NCANDS), more than 700,000 of these were found to be severe in nature, with nearly 2,000 cases resulting in fatalities in 2007 alone. However, it is important to recognize that many experts in the field consider these figures to be a gross underestimate because childhood maltreatment is often not reported or difficult to confirm. A growing database indicates that early life stress, defined as verbal, physical or sexual abuse, or neglect, including, for example, separation from a primary caregiver, or living with a primary caregiver with severe mental illness, increases the risk of developing psychiatric disorders, including mood disorders, anxiety disorders, attention-deficit hyperactivity disorder (ADHD), substance abuse, and schizophrenia.1–4 Moreover, the long-term effects of early-life trauma are not limited to increased vulnerability for syndromal psychiatric disorders but also appear to result in impaired cognitive abilities, increased obesity, and long-term effects on a number of biological systems that result in increased disease burden in adults. It is this subject that comprises the major subject matter of this article, an area previously, to the best of our knowledge, not summarized. Understanding the biological consequences of early-life stress is of paramount importance, not only in advocacy for protection of our youth but also as a pathophysiologic guide to develop novel treatments for this population. As will be described below, multiple biological mechanisms have been demonstrated to be dysregulated in adults who were victims of child abuse and neglect. These include effects on the endocrine, nervous, immune, and cardiovascular systems, all of which are known to be involved in the innate acute stress response. This article is an effort to consolidate the data available involving the long-term medical consequences of childhood trauma.
The acute stress response involves multiple organ systems acting in concert, resulting in the “fight or flight” response, which allows an individual’s internal resources to be optimized to respond to a threat. Major neurobiological components of the stress response system include the hypothalamic-pituitary-adrenal axis (HPA), the locus coeruleus-norepinephrine (LC-NE) system, and the extrahypothalamic corticotropin-releasing factor (CRF) system.5–8 Our group and others have hypothesized that the marked activation of the stress response in children experiencing trauma during a critical period in brain development results in persistent abnormalities that lead to adult dysregulation of multiple biological systems, including the immune, endocrine, and autonomic nervous systems.
Physiologic Systems Involved in the Stress Response and Early-Life Trauma
The Hypothalamic-Pituitary-Adrenal Axis (HPA Axis)
In response to a stressful life event, CRF is released from median eminence nerve terminals into the hypothalamo-hypophysial portal circulation and is transported to the anterior pituitary, where it binds to CRF receptors on corticotropes. Activation of the CRF receptor stimulates the production and release of adrenocorticotropin (ACTH), as well as proopiomelanocortin (POMC) and its end products, including beta-endorphin. ACTH is secreted into the systemic circulation and acts upon the adrenal cortex, where it stimulates the synthesis and release of glucocorticoids. Glucocorticoids act upon high-affinity mineralocorticoid receptors (MR) and low-affinity glucocorticoid receptors (GR). MRs are located in high density in the hippocampus, and GRs are located throughout the central nervous system (CNS). High concentrations of glucocorticoids exert negative feedback effects on CRF and ACTH secretion, thereby limiting HPA axis hyperactivity in usual physiological situations. The HPA axis is an integral component of the stress response, as is the sympathetic nervous system, both also affecting the immune system.
Early-life stress, in various forms, is associated with persistent alterations in the adult HPA axis. The same pattern of data has been observed in rodents, non-human primates, and in humans.7,8 A number of studies have measured plasma, salivary, and urinary cortisol concentrations, as well as various provocative tests of HPA axis function, such as the ACTH response to CRF, the so-called CRF stimulation test.7 Significant differences in ACTH and cortisol concentrations have been documented in adults exposed to early trauma, compared with demographically matched controls. Unfortunately, the findings are not entirely concordant. For example, some studies have found a blunted HPA axis response in adults who had experienced child abuse, whereas others, including our group, have reported a hyperresponsive HPA axis. We believe that the discrepancies in these studies highlight, in part, differences in study designs, (cortisol levels exhibit a diurnal rhythm), gender-related effects, the timing and nature of the early adverse experience, the age of the individual at the time of abuse, and the number of years since the abuse, as well as several critical genetic variables. What is abundantly clear is that early-life trauma results in persistent changes in the HPA axis regulation; in some, it results in hyperresponsiveness, and in others, it results in hyporesponsiveness. This dysregulation of the HPA axis may contribute to the increased risk for psychiatric and medical disorders in this population.
Corticotropin-Releasing Factor (CRF) System
In addition to its seminal role in endocrine regulation, CRF also serves as a neurotransmitter within the CNS, mediating the autonomic, immune, and behavioral stress response. Stress activates CRF secretion, not only in the hypothalamic neurons but also in the neocortex, limbic system, locus coeruleus, spinal cord, and central nucleus of the amygdala. CRF in the amygdala and brainstem has been implicated in the emotional response to stress, and CRF neurons in the neocortex have been implicated in the cognitive response to stress.8 In addition, CRF receptors are found not only in the CNS but in peripheral tissues as well, including the heart, testes, gastrointestinal tract, adrenal medulla, and spleen.
Maternal separation is a well-established model of early-life stress in animals resulting in long-lasting changes in the CNS and the stress response. The CRF system is profoundly altered in adult rats exposed to early trauma. For example, Ladd et al9 observed a persistent change in CRF neurons, including an increase in immunoreactive CRF concentrations, and changes in the density of CRF receptor binding sites in hypothalamic and extrahypothalamic areas in rats that were separated from their mothers as neonates, as compared with controls.
Additionally, CRF hypersecretion may, at least in part, mediate structural alterations in the brain as well, evidenced by the reduction in hippocampal volume in rats that had received chronic CRF treatment. These findings are concordant with the reduction in hippocampal volume in depressed women who had suffered from child abuse.10
The Locus Coeruleus-Norepinephrine System (LC-NE)
The locus coeruleus is a compact nucleus in the pons, which contains a dense collection of norepinephrine (NE) containing neurons. These LC cells project to widespread CNS areas, including to the neocortex, thalamus, limbic system, hypothalamus, and spinal cord. In addition to HPA axis activation, stress excites the LC-NE system, releasing NE. Laboratory animal studies have revealed that stressful events activate the release of NE from the LC, resulting in activation of the sympathetic nervous system (SNS) and initiation of the “fight or flight” reaction. This is associated with increased catecholamine turnover in the CNS and adrenal medulla, as well as NE release from the peripheral sympathetic nerve endings. The physiological consequences include increased blood pressure, heart rate, alertness, and pupillary dilation. Considerable evidence exists to suggest that childhood trauma results in alterations of catecholamine systems. For example, an increase in 24-hour urinary catecholamine concentration was noted in girls who had experienced sexual trauma, as compared with demographically matched controls.6 In a study of police academy recruits, salivary 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite of NE, was found to be elevated in recruits, who had experienced childhood trauma 14 years, after watching a stressful video, as compared with recruits who had no childhood trauma.11
The Immune System
Because of the close relationship between neural circuits, the endocrine system, and the immune system, it is not surprising that chronic early-life stress can lead to alterations in immune function. This area has been surprisingly well studied.12–22 Danese et al found a “dose-dependent” increase in inflammatory markers, including high-sensitivity C-reactive protein (hsCRP), fibrinogen, and white blood cell count (chosen because they are all well-documented markers of inflammation and show significant association with cardiovascular disease). The study was conducted in adults (32 years) with two or more types of childhood maltreatment, versus one type of childhood maltreatment, versus no child maltreatment (maltreatment measures included maternal rejection, harsh discipline, disruptive caregiver changes, physical abuse, and/or sexual abuse). Subjects in the study were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behavior in a complete birth cohort. Child maltreatment (and other) data were collected at 11 time points between the 3 years and 32 years. Adults with two or more forms of maltreatment during childhood were 1.86 times more likely to have elevated hsCRP than those with no maltreatment. Despite controlling for potential confounding factors, such as low birth weight, child social economic status, child IQ, adult stress, major depression, smoking, low physical activity, poor fruit and vegetable intake, and markers of the metabolic syndrome, the association between childhood maltreatment and inflammation remained significant (RR = 1.61). Similar trends for white blood cell count and fibrinogen levels were also noted.17
Preclinical studies have also contributed to our understanding of the immune system consequences of early-life stress. Avitsur et al reported that female mice exposed to early-life stress and subsequently infected with influenza virus as adults exhibited elevated IL-1alpha, IL-6, TNF-alpha, IL12, IFN-gamma, and IL-18 cytokine gene expression and IL-1alpha, IL-6, IL-12, and IFN-gamma cytokine lung protein concentrations. Viral replication in lung tissue was also increased in mice exposed to early maternal separation. Moreover, glucocorticoid secretion was blunted in the maternally separated mice, further demonstrating a role for both endocrine and immune dysregulation by early stress.23
Early-life stress has also been found to alter the brain-gut axis (neural, immune, and endocrine communication between the brain and the gut), in the maternal separation paradigm.20 Specifically, the lipopolysaccharide (LPS) stimulation of the proinflammatory cytokine TNF-alpha was elevated in animals exposed to maternal separation, as compared with controls. Additional findings in this study included increased plasma corticosterone concentrations, increased sensitivity to visceral sensation, and alteration in the bacterial DNA found in the fecal pellets of the maternally deprived animals. These data are concordant with the known association between so-called functional bowels disorders (such as irritable bowel syndrome) and early life stress, an observation validated in clinical studies.24
In addition to specific immune markers, an association between childhood trauma and increased rates of hospitalization in adults with autoimmune disease has been established in the Adverse Childhood Experiences (ACE) study.18 Approximately 15,000 adults in an HMO in the San Diego area enrolled in the ACE study from 1995–1997 in the prospective phase. Eight ACEs were assessed: emotional, physical, and/or sexual abuse, witnessing domestic violence, and growing up with an adult with substance abuse, mental illness, and/or criminal history. In this study, 21 selected autoimmune disease hospitalizations were assessed in the ACE cohort. Compared with no ACEs, those with more than two ACEs were 70% to 100% more likely to be hospitalized depending on the stratification of disease (T helper cells; Th1, Th2, versus mixed Th1/Th2 mediated autoimmune disease). Inflammation is a well-documented component of the stress response with activation of pro-inflammatory cytokines and activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB). As noted earlier, the HPA axis is dysregulated in adults with early life trauma, which may contribute to proinflammatory dysregulation as well. Increased proinflammatory cytokines may be, in part, responsible for the association between child abuse and neglect and autoimmune disorders.
The Autonomic Nervous System (ANS)
Activation of the autonomic nervous system is one of the central components of the stress response and is characterized by increases in heart rate, blood pressure, and respiratory rate, increasing metabolic rate. A number of studies have scrutinized alterations in the cardiovascular response to stress in adults who had been exposed to child abuse.25–27 Although heart rate and blood pressure were found to be elevated in these patients and matched controls in response to stress, the magnitude of the elevation was significantly greater in the early childhood trauma group. In the ACE study, individuals with a history of early life trauma exhibited a greater incidence of ischemic heart disease (IHD).28 Chronic alterations of the immune and neuroendocrine systems and/or the ANS may contribute to the increased risk of cardiovascular disease. Moreover, depression is associated with an increased risk for IHD, and child abuse and neglect are associated with an increased risk for depression. Thus, depression might, in part, mediate the increased risk for IHD in victims of child abuse and neglect.
Other Clinical Measures
In addition to the well-documented increased incidence of psychiatric illness in those exposed to adverse early-life events are a number of other morbidities, including low IQ and obesity. Lower cognitive functioning in children who experience trauma may be the result of increased anxiety and/or poor attention to schoolwork, given their home environment. Unfortunately, this deficit has been found to be persistent in at least one study comparing adults who had experienced neglect or abuse as a child, with both decreased IQ and reading abilities, despite controlling for age, sex, race, and social class.29 These effects might be due to the accumulation of reduced school attendance and/or neurodevelopmental consequences. Moreover, physical abuse is associated with head trauma, and neglect can impair normal brain development secondary to poor nutrition. Further studies will be necessary to understand the mechanisms underlying cognitive dysfunction in individuals with childhood trauma.
A number of studies have focused on the association between increased rates of obesity and/or eating disorders in adults exposed to child abuse.30–32 In the general population, obesity rates have reached epidemic proportions and continue to rise. The morbidity and mortality resulting from obesity has been well documented and include but are not limited to, metabolic syndrome, diabetes and heart disease.33 Early-life trauma, including sexual, emotional, and physical abuse, as well as neglect, has been found to be associated with increased rates of obesity, in addition to eating disorders, in adults and adolescents. Poor nutrition modeling, decreased social status, and poor education may also, at least in part, account for this association but are surely unable to fully account for obesity rates found in the adult victims of child abuse.