Elsevier

Psychoneuroendocrinology

Volume 38, Issue 2, February 2013, Pages 188-200
Psychoneuroendocrinology

Childhood adversity and inflammatory processes in youth: A prospective study

https://doi.org/10.1016/j.psyneuen.2012.05.013Get rights and content

Summary

Background

Retrospective studies show that childhood adversity is associated with systemic inflammation in adulthood. Few prospective studies have examined whether childhood adversity influences inflammation in an observable manner during childhood or adolescence and if these effects are sustained over time.

Methods

Using longitudinal data from the Avon Longitudinal Study of Parents and Children, we examined associations between acute adverse events at seven time points prior to age 8 and inflammation at ages 10 and 15. Inflammatory markers at age 10 included interleukin-6 (IL-6; N = 4655) and C-reactive protein (CRP; N = 4647), and CRP was measured again at age 15 (N = 3286). We further evaluated whether body mass index (BMI), depression, or cigarette smoking mediated associations between adverse events and inflammation.

Results

Adverse events in middle childhood (occurring between ages 6 to 8), as well as cumulative adversity from birth to 8 years, were associated with higher levels of IL-6 and CRP at age 10. Adverse events reported in early childhood (1.5 years) or middle childhood, and cumulative adversity from birth through 8 years predicted increased levels of CRP at age 15, and these associations persisted after adjustment for CRP at age 10. Some, but not all, of these associations were mediated by BMI.

Conclusions

This study documents that exposure to adverse events prior to age 8 is associated with elevated inflammation at age 10 and in mid-adolescence. These findings provide prospective evidence for a biological mechanism by which early experiences may shape long-term health. Future studies with earlier assessments of inflammation are necessary in order to elucidate potential sensitive periods and mechanisms that link childhood adversity to later disease vulnerability.

Introduction

Early life experiences have lasting effects on neurobiological functioning and health outcomes across the life course (Shonkoff et al., 2009, Taylor et al., 2011). Adverse childhood experiences — including low socioeconomic status (SES), maltreatment, or maladaptive early family environments — are associated with a broad spectrum of subsequent health problems in adulthood, including cardiovascular disorders (CVD) (Dong et al., 2004, Galobardes et al., 2006), metabolic abnormalities (Thomas et al., 2008, Danese et al., 2009), cancers (Felitti et al., 1998), arthritis (Dube et al., 2009, Von Korff et al., 2009) and mental illnesses (Chapman et al., 2004, Kessler et al., 2010). Evidence from both animal and human studies suggests that inflammation may be a central biological mechanism linking early adversity to a variety of health outcomes (Miller et al., 2009a). Although numerous studies show that low childhood SES and harsh early family environments are associated with elevated concentrations of inflammatory markers like circulating levels of C-reactive protein (CRP) and pro-inflammatory cytokines such as interleukin-6 (IL-6) among adults (Taylor et al., 2006, Danese et al., 2007, Pollitt et al., 2007), relatively few studies have examined whether childhood adversity is associated with inflammation during childhood or adolescence (Slopen et al., 2011). It is important to characterize the developmental progression of inflammatory processes in relation to adversity in children and adolescents in order to understand how exposure to childhood adversity may engender disease vulnerability over time (Danese et al., 2011). The aim of this study is to examine prospectively the relationship between adverse events that occur during childhood and inflammation in both childhood and adolescence.

Increasing evidence suggests that elevated levels of inflammation in childhood may provide an early marker of disease risk in adulthood. For example, elevated CRP in childhood is associated with elevated CRP in adulthood (Juonala et al., 2006); and CRP in childhood is also associated with a variety of cardiovascular (Cook et al., 2000) and atherosclerotic risk factors among youth, such as disturbed endothelial function and intima media thickening, even after adjustment for body mass index (BMI) (Jarvisalo et al., 2002). Although a number of studies have examined the relationship between childhood adversity on inflammation in child or adolescent samples, results have been inconsistent. In a recent systematic review of studies that examined childhood adversity, as measured by either socioeconomic or interpersonal stressors, in relation to inflammation in healthy children and adolescents, the pattern of findings was not clear (Slopen et al., 2011). Some of these studies documented associations between adversity and elevated levels of inflammation (Murasko, 2008, Fuligni et al., 2009a, Howe et al., 2010), while others found no associations (Cook et al., 2000, Gimeno et al., 2008, Miller et al., 2009b), conditional associations (Marin et al., 2007, Danese et al., 2011), or inconsistent associations depending on the measure of adversity (McDade et al., 2005, Dowd et al., 2010).

Some of the inconsistencies across studies may be due to aspects of adversity that prior literature has not been able to consider in detail in relation to inflammation. For example, variation in the type or severity of stressors, or differences in the proximity of stress exposure to assessment of inflammation may account for differences in the impact of adversity on inflammatory biomarkers. Furthermore, existing studies have rarely examined childhood adversity and inflammation prospectively in child and adolescent samples, with repeated measures of either the exposures or outcomes. Accordingly, we have limited evidence about whether childhood adversity has persistent effects on inflammation in youth, and whether adversity during early childhood, in contrast to later developmental periods, has a differential impact on later inflammation.

The present study utilized longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We used severity-weighted reports of acute adverse events as a measure of childhood adversity. The primary aim was to examine the association between adverse events, measured at seven time points between 1.5 and 8 years of age, and two commonly assessed measures of inflammation, CRP and IL-6. CRP and IL-6 were selected as these inflammatory biomarkers are indicative of systemic inflammation. As it is unclear as to whether CRP per se is causally associated with cardiovascular or other diseases (Casas et al., 2006, Kaptoge et al., 2010), we do not assume that they are on the causal pathway between adversity and coronary heart disease (C Reactive Protein Coronary Heart Disease Genetics Collaboration, 2011) or metabolic syndrome (Timpson et al., 2005). Rather, we consider them as a potential early marker of disease risk, based on prior work demonstrating that elevated levels of CRP are consistently associated with greater atherosclerosis and incident coronary events (Pearson et al., 2003, Danesh et al., 2004). Both IL-6 and CRP were measured at age 10 and CRP was measured again in mid-adolescence (age 15). Repeated assessment of adverse events allowed us to examine the associations of adverse events occurring in specific developmental periods as well as cumulatively with inflammatory processes in childhood and the persistence of those processes into mid-adolescence.

We hypothesized that adverse events at any time point prior to age 8 would be associated with inflammation at both time points, and the association would be greatest for a cumulative measure that incorporated all assessments of adverse events between 1.5 and 8 years of age. We tested for possible interactions by sex because studies have found sex differences in the relationship between adversity and cardiovascular risk factors in youth (Howe et al., 2010). The second aim was to examine covariates that may explain associations between adverse events and inflammation, including BMI, depression, and cigarette smoking. We selected these potential mediators based on evidence that psychosocial stressors are associated with each of these characteristics and behaviors in youth (Wills et al., 2002, Grant et al., 2004, Gundersen et al., 2011), and that these characteristics are also associated with elevated inflammation (Howren et al., 2009, O’Connor et al., 2009, Dowd et al., 2010).

Section snippets

Sample

Participants in this study were drawn from ALSPAC, a population-based prospective longitudinal study of children born to mothers living in Avon county while pregnant (Golding and the ALSPAC Study Team, 2004). ALSPAC was designed to provide insight on how social, biological, and environmental factors interact to influence pregnancy outcomes and child physical and mental health. A total of 14,541 pregnant women with estimated delivery dates between April 1991 and December 1992 agreed to

Results

Table 1 describes characteristics of the sample, including means and proportions for the main predictors, outcomes, and covariates. The sample had a similar proportion of males and females, and was predominantly white (95%), consistent with the general population in Avon county. There was considerable heterogeneity in maternal education and family income. Exposure to each of the adverse events was relatively uncommon. Across the 7 time points, the number of children who experienced each adverse

Discussion

The present study used data from a population-based prospective cohort of healthy children to examine the associations between adverse events collected from age 1.5 to 8 years and inflammation at ages 10 and 15. Adverse events in middle childhood (occurring between ages 6 to 8), as well as adverse events cumulated from age 1.5 through age 8, were associated with higher levels of IL-6 and CRP at age 10. In contrast, adverse events experienced earlier in childhood (i.e., reports between 1.5 and 6 

Role of funding source

The study sponsors were not involved in analysis, interpretation of data, writing of this report, or decision to submit this paper for publication.

Conflict of interest

None declared.

Acknowledgments

We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council (Grant ref.: 74882) the Wellcome Trust (Grant ref.: 076467) and the University of Bristol provide core support for ALSPAC. This publication is the work of the

References (70)

  • J.E. Murasko

    Male-female differences in the association between socioeconomic status and atherosclerotic risk in adolescents

    Soc. Sci. Med.

    (2008)
  • A. Nazmi et al.

    Lifecourse socioeconomic trajectories and C-reactive protein levels in young adults: Findings from a Brazilian birth cohort

    Soc. Sci. Med.

    (2010)
  • M.F. O’Connor et al.

    To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers

    Brain Behav. Immun.

    (2009)
  • G.C. Patton et al.

    Predicting female depression across puberty: a two-nation longitudinal study

    J. Am. Acad. Child Adolesc. Psychiatr.

    (2008)
  • E.S. Paykel

    Methodological aspects of life events research

    J. Psychosom. Res.

    (1983)
  • A. Steptoe et al.

    The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis

    Brain Behav. Immun.

    (2007)
  • S.E. Taylor et al.

    Relationship of early life stress and psychological functioning to adult C-reactive protein in the coronary artery risk development in young adults study

    Biol. Psychiatr.

    (2006)
  • N.J. Timpson et al.

    C-reactive protein and its role in metabolic syndrome: mendelian randomisation study

    Lancet

    (2005)
  • M. Von Korff et al.

    Childhood psychosocial stressors and adult onset arthritis: Broad spectrum risk factors and allostatic load

    Pain

    (2009)
  • J.M. Wolf et al.

    Parent psychological states predict changes in inflammatory markers in children with asthma and healthy children

    Brain Behav. Immun.

    (2008)
  • J. Allen et al.

    Assessment of maternally reported life events in children and adolescents: a comparison of interview and checklist methods

    J. Psychopathol. Behav.

    (2011)
  • A. Angold et al.

    Development of a short questionnaire for use in epidemiological studies of depression in children and adolescents

    Int. J. Methods Psychiatr. Res.

    (1995)
  • A. Angold et al.

    Depression scale scores in 8-17-year-olds: effects of age and gender

    J. Child Psychol. Psyc.

    (2002)
  • C Reactive Protein Coronary Heart Disease Genetics Collaboration

    Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

    BMJ

    (2011)
  • J.P. Casas et al.

    Insight into the nature of the CRP-coronary event association using Mendelian randomization

    Int. J. Epidemiol.

    (2006)
  • J.L. Cox et al.

    Detection of postnatal depression development of the 10-item Edinburgh Postnatal Depression Scale

    Br. J. Psychiatr.

    (1987)
  • A. Danese et al.

    Biological embedding of stress through inflammation processes in childhood

    Mol. Psychiatr.

    (2011)
  • A. Danese et al.

    Adverse Childhood Experiences and Adult Risk Factors for Age-Related Disease Depression Inflammation, and Clustering of Metabolic Risk Markers

    Arch. Pediat. Adol. Med.

    (2009)
  • A. Danese et al.

    Elevated inflammation levels in depressed adults with a history of childhood maltreatment

    Arch. Gen. Psychiatry

    (2008)
  • A. Danese et al.

    Childhood maltreatment predicts adult inflammation in a life-course study

    Proc. Natl. Acad. Sci. U.S.A.

    (2007)
  • J. Danesh et al.

    C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease

    N. Engl. J. Med.

    (2004)
  • M. Dong et al.

    Insights into causal pathways for ischemic heart disease: adverse childhood experiences study

    Circulation

    (2004)
  • S.R. Dube et al.

    Cumulative childhood stress and autoimmune diseases in adults

    Psychosom. Med.

    (2009)
  • M.A. Enoch et al.

    Early life stress, MAOA, and gene-environment interactions predict behavioral disinhibition in children

    Genes Brain Behav.

    (2010)
  • A.J. Fuligni et al.

    A preliminary study of daily interpersonal stress and C-reactive protein levels among adolescents from Latin American and European backgrounds

    Psychosom. Med.

    (2009)
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    1

    Present address: Department of Society, Human Development, and Health, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, United States.

    2

    Present address: Division of General Pediatrics, Children's Hospital Boston, 21 Autumn Street, Boston, MA 02115, United States.

    3

    Present address: Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, United States.

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