Hostname: page-component-6766d58669-6mz5d Total loading time: 0 Render date: 2026-05-23T02:37:04.101Z Has data issue: false hasContentIssue false
  • English
  • Français

Immediate and longitudinal effects of maltreatment on systemic inflammation in young children

Published online by Cambridge University Press:  11 January 2021

Sonja Entringer ,
Karin de Punder ,
Judith Overfeld ,
Gergana Karaboycheva ,
Katja Dittrich ,
Claudia Buss ,
Sibylle Maria Winter ,
Elisabeth B. Binder  and
Christine Heim
Sonja Entringer
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany Development, Health, and Disease Research Program, University of California, Irvine, CA, USA
Karin de Punder
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany
Judith Overfeld
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany
Gergana Karaboycheva
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Child & Adolescent Psychiatry, Psychosomatic Medicine, and Psychotherapy, Berlin, Germany
Katja Dittrich
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Child & Adolescent Psychiatry, Psychosomatic Medicine, and Psychotherapy, Berlin, Germany
Claudia Buss
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany Development, Health, and Disease Research Program, University of California, Irvine, CA, USA
Sibylle Maria Winter
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Child & Adolescent Psychiatry, Psychosomatic Medicine, and Psychotherapy, Berlin, Germany
Elisabeth B. Binder
Affiliation:
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
Christine Heim*
Affiliation:
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Medical Psychology, Berlin, Germany Department of Biobehavioral Health, College of Health & Human Development, The Pennsylvania State University, University Park, PA, USA
*
Author for Correspondence: Christine Heim, PhD, Institute of Medical Psychology, Charité – Universitätsmedizin Berlin, Luisenstraβe 57, 10117 Berlin, Germany; E-mail: christine.heim@charite.de
Rights & Permissions [Opens in a new window]

Abstract

Exposure to child maltreatment increases the risk for psychiatric and physical diseases. Inflammation has been proposed as a mechanism through which early adverse experiences become biologically embedded. However, most studies providing evidence for the link between early adverse exposures and inflammation have been retrospective or cross-sectional in design, or did not assess inflammation immediately after maltreatment in young children. In the present study we investigated the association between childhood maltreatment and salivary C-reactive protein (CRP) concentrations in a population of N = 173 children, 3–5 years of age, who were recruited in the immediate aftermath of maltreatment and followed-up longitudinally every 6 months over a period of 2 years. We found that the association between maltreatment and CRP concentrations was significantly moderated by child sex, such that in girls, CRP concentrations were higher in the maltreated compared to the control group, and this difference was stable across the 2-year follow-up-period, while in boys, there was no association between maltreatment and CRP. Our findings suggest that the effect of maltreatment on inflammation may already emerge right after exposure at a very young age in girls and manifest over time. Our study provides important evidence for the development of personalized, early interventions strategies targeting the early-life period.

Keywords

CRPearly life stressinflammationmaltreatmentsex differences

Information

Type
Special Section 2: Early Adversity and Development: Contributions from the Field
Information
Development and Psychopathology , Volume 32 , Special Issue 5: Early Adversity, Stress, and Neurobehavioral Development: Honoring Megan R. Gunnar's Contributions to Developmental Science , December 2020 , pp. 1725 - 1731
Check for updates
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
Copyright © The Author(s), 2020. Published by Cambridge University Press

Introduction

Child maltreatment in the form of physical, emotional, and sexual abuse as well as physical and emotional neglect has an unfortunately high prevalence (Stoltenborgh, Bakermans-Kranenburg, Alink, & van IJzendoorn, Reference Stoltenborgh, Bakermans-Kranenburg, Alink and van IJzendoorn2015). Substantial evidence from epidemiological and clinical studies suggests that exposure to maltreatment strongly and robustly alters emotional and physiological stress regulation (Engel & Gunnar, Reference Engel and Gunnar2020; Herzberg & Gunnar, Reference Herzberg and Gunnar2020) and increases the risk for psychiatric diseases, including depression and anxiety disorders, impaired cognitive development, and for chronic physical disease outcomes, including cardiovascular disease, obesity, diabetes, lung cancer, chronic pain, headaches, and immune-related diseases, resulting in reduced longevity (Brown et al., Reference Brown, Anda, Tiemeier, Felitti, Edwards, Croft and Giles2009; Felitti et al., Reference Felitti, Anda, Nordenberg, Williamson, Spitz, Edwards and Marks1998; Heim & Binder, Reference Heim and Binder2012; Norman et al., Reference Norman, Byambaa, De, Butchart, Scott and Vos2012; Wegman & Stetler, Reference Wegman and Stetler2009). Based on the considerations that in the majority of these diseases inflammation plays a dominant pathological role, inflammation has been proposed as a mechanism through which early adverse experiences may become ‘biologically embedded’ (Danese & Baldwin, Reference Danese and Baldwin2017; Danese & McEwen, Reference Danese and McEwen2012; Miller, Chen, & Cole, Reference Miller, Chen and Cole2009).

A large number of retrospective studies have provided evidence for elevated concentrations of inflammation-related biomarkers in adults with a history of maltreatment (reviewed in Baumeister, Akhtar, Ciufolini, Pariante, & Mondelli, Reference Baumeister, Akhtar, Ciufolini, Pariante and Mondelli2016; Coelho, Viola, Walss-Bass, Brietzke, & Grassi-Oliveira, Reference Coelho, Viola, Walss-Bass, Brietzke and Grassi-Oliveira2014). However, most of these studies in adults have been cross-sectional in design and rely on retrospective self-reports of childhood maltreatment exposure, not allowing for causal inferences, nor do they inform about early embedding processes. A few longitudinal studies exist that report associations between childhood maltreatment and increased markers of inflammation assessed in early adulthood (Danese, Pariante, Caspi, Taylor, & Poulton, Reference Danese, Pariante, Caspi, Taylor and Poulton2007; Rasmussen et al., Reference Rasmussen, Moffitt, Eugen-Olsen, Belsky, Danese, Harrington and Caspi2019). However, these studies did not collect biological data in the immediate aftermath of exposure to maltreatment and across development. So far only very few studies have provided evidence that the association between childhood maltreatment and higher levels of inflammation can already be observed during childhood. Danese et al. (Reference Danese, Caspi, Williams, Ambler, Sugden, Mika and Arseneault2011) reported that inflammation levels in maltreated children who developed depression were already elevated by age 12 compared to controls. Furthermore, higher C-reactive protein (CRP) levels were found in 10-year old children with recent onset of maltreatment and a genotype predisposing to higher CRP levels (Cicchetti, Handley, & Rogosch, Reference Cicchetti, Handley and Rogosch2015). A prospective longitudinal study showed that exposure to adverse events before the age of 8 is associated with elevated CRP concentrations at the age of 10 and 15 years (Slopen, Kubzansky, McLaughlin, & Koenen, Reference Slopen, Kubzansky, McLaughlin and Koenen2013). To the best of our knowledge, only one study so far investigated the relationship between exposure to childhood adversity and inflammation in preschool-aged children (3–5 year old) and found higher concentrations of a pro-inflammatory cytokine (IL-1β) in relation to higher exposure to childhood adversity (Tyrka, Parade, Valentine, Eslinger, & Seifer, Reference Tyrka, Parade, Valentine, Eslinger and Seifer2015). Findings from the E-Risk study suggest that there may be sex differences in the vulnerability to develop a pro-inflammatory state after childhood maltreatment exposure (Baldwin et al., Reference Baldwin, Arseneault, Caspi, Fisher, Moffitt, Odgers and Danese2018): in females, CRP concentrations assessed at the age of 18 years were significantly associated with childhood victimization, while no significant association was observed in males. Evidence from experimental studies in animals supports the notion of sex-specific effects of early-life stress on inflammation (reviewed in Ganguly & Brenhouse, Reference Ganguly and Brenhouse2015), and findings in humans suggest that, in general, women may be more sensitive than men to the effects of stress in eliciting a pro-inflammatory response (Rampp et al., Reference Rampp, Eichelkraut, Best, Czamara, Rex-Haffner, Uhr and Menke2018; Rohleder, Schommer, Hellhammer, Engel, & Kirschbaum, Reference Rohleder, Schommer, Hellhammer, Engel and Kirschbaum2001).

Thus, given the limited number of studies on the effects of childhood maltreatment on inflammation in younger children and evidence that this association may be moderated by sex, in the present study we investigated the association between childhood maltreatment and inflammation and the role of child sex in this context in a population of 3–5 year-old children that were recruited in the immediate aftermath of maltreatment and were followed-up longitudinally every 6 months over a period of 2 years, and in a nonexposed control group. At each assessment time point, salivary concentrations of CRP were assessed. (CRP is produced in the liver in response to interleukin-6 secretion by macrophages and T cells and is therefore considered a biomarker of systemic inflammation.)

We hypothesized that (a) maltreated children show increased CRP concentrations compared to the control group; (b) the association between maltreatment and CRP is moderated by child sex; and (c) the observed differences between the maltreatment and comparison group remain stable over the course of the 2-year follow-up period.

Method

Recruitment, study sample, and design

This report is part of a larger research study entitled “Immediate Biological Embedding of Maltreatment in Children: The Berlin Longitudinal Children Study (BerlinLCS)” that was funded by Federal Ministry of Education and Research (01KR1301). The present report presents data on inflammatory markers obtained in this study.

Approval for the study was obtained from the ethics committee of Charité – Universitätsmedizin Berlin. All procedures are in accordance with the Ethical Principles for Medical Research as established by the Medical Association Declaration of Helsinki. Written informed consent was obtained from all participants after the procedures were fully explained. Children gave consent by painting or signing a form that was appropriate for the children's age range.

A total of 173 children aged 3 to 5 years and their caregivers were recruited at study entry (T0, see Table 1 for sample characteristics). The sample includes 86 children who had been exposed to maltreatment within 6 months before study entry and 87 nonmaltreated children. Maltreatment and control groups were frequency-matched for sex and age. General exclusion criteria for all children included parents under the age of 18 years, moderate or severe mental intellectual dysfunction or neurodevelopmental disorders, chronic medical illness as well as serious medical disease of the parents. The absence of fever or acute severe infection at the time the sample was taken for CRP analyses was confirmed during a medical exam.

Table 1.

Sample characteristics of children in the control and maltreatment group at baseline (T0)

Note. CRP, C-reactive protein; SD, standard deviation; SES, socioeconomic status.

Maltreated children were recruited from a broad range of local child welfare and protection services, pediatric offices, and through advertisements and letters sent to families with children aged 3–5 years mainly identified through public census records. Nonmaltreated children were recruited from the community using advertising as well as letters directed to families with children between 3–5 years of age using census records. For assignment to the control group, children were screened to exclude exposure to any severe critical or traumatic life event.

The study employed a prospective, longitudinal design with serial assessments of the children with follow-up visits scheduled after an initial baseline assessment (T0, maltreatment group: n = 86, control group n = 87) at 6 months (T1, maltreatment group: n = 65, control group: n = 80), 12 months (T2, maltreatment group: n = 60; control group: n = 70), 18 months (T3, maltreatment group: n = 47, control group n = 64), and 24 months (T4, maltreatment group n = 35, control group n = 52).

Measures

Childhood maltreatment

The occurrence and features of maltreatment were assessed at T0. At each follow-up visit, the assessment was repeated for the interim time for safety purposes. To assess features of maltreatment, we used the Maternal Interview for the Classification of Maltreatment (Cicchetti, Toth, & Manly, Reference Cicchetti, Toth and Manly2003). The interview was administered by trained clinicians and based on caregiver reports. Responses were coded according to the Maltreatment Classification System (Barnett, Manly, & Cicchetti, Reference Barnett, Manly, Cicchetti, Cicchetti and Toth1993), which provides specific criteria for classifying and quantifying the occurrence and features of subtypes of maltreatment. The interview covers a range of subtypes, including emotional maltreatment (i.e. emotional abuse and/or emotional neglect), physical neglect (i.e. failure to provide and/or lack of supervision), physical abuse, and moral, legal and/or educational maltreatment. In our sample, the latter subtype overlapped with lack of supervision due to excessive video gaming or keeping the child busy, which we therefore assigned to the physical neglect category. For each incidence, severity is rated on a 5-point scale ranging from mild (1) to severe or life-threatening maltreatment (5). Severity cutoff scores were used to include children in the maltreatment group (emotional maltreatment ≥2, physical abuse ≥1, physical neglect ≥2). We did not specifically recruit for sexual abuse, as sexual abuse usually leads to removal of the child from the home, which we considered would be a significant intervention; however, co-incident mild forms of sexual abuse were detected in 11 of 86 maltreated children.

Salivary C-reactive protein (CRP)

Due to the noninvasiveness of sampling, salivary CRP sampling constitutes a feasible measure to study peripheral inflammation in children (Cicchetti et al., Reference Cicchetti, Handley and Rogosch2015). Several studies (Ouellet-Morin, Danese, Williams, & Arseneault, Reference Ouellet-Morin, Danese, Williams and Arseneault2011; Out, Hall, Granger, Page, & Woods, Reference Out, Hall, Granger, Page and Woods2012) report moderate to strong associations between serum and salivary CRP levels. Saliva samples were collected during each clinical visit at 11 a.m. by oral swabs specially designed for small children (Salimetrics) and were immediately stored at −80 °C. Salivary CRP was determined using a commercial ELISA kit (Salimetrics) with a sensitivity of 10 pg/ml. Intra-assay and inter-assay coefficients of variability were 6% and 13%, respectively.

Insufficient amounts of saliva for CRP analyses were collected for some children. The final sample size with valid CRP measurements included in the analyses is as follows: T0, maltreatment group: n = 86; control group n = 82; T1, maltreatment group: n = 64, control group n = 80; T2, maltreatment group: n = 59, control group: n = 70; T3, maltreatment group: n = 43, control group n = 64; T4, maltreatment group: n = 35, control group: n = 52.

Covariates and potential confounders

Socioeconomic status (SES)

SES was estimated based on a modification of the Winkler and Stolzenberg Index (Lange et al., Reference Lange, Kamtsiuris, Lange, Schaffrath Rosario, Stolzenberg and Lampert2007). This multidimensional index score represents the sum of three metric components: education and occupational qualification, occupational status, and net income. The score reflects low (score 3 to 8), middle (9–14), or high (15–21) SES of the participating family.

Body mass index (BMI)

Child's body weight and length were measured by a physician during a physical examination at each clinical visit. BMI percentiles were calculated according to German clinical standards (Rosario, Kurth, Stolzenberg, Ellert, & Neuhauser, Reference Rosario, Kurth, Stolzenberg, Ellert and Neuhauser2010).

Data analysis

t tests and chi-square tests were used to compare the maltreatment and control group regarding demographics and clinical characteristics at baseline (T0, see Table 1). We observed significant differences in age (t = 2.07, p = .04) and SES (t = −10.91, p < .001) such that the maltreatment group was slightly older and of lower SES compared to the control group. The differences in age and SES remained constant over all clinical time points. At T1–T3, the maltreatment group had a higher BMI compared to controls (T1, t = 2.02, p = .046; T2, t = 2.44, p = .016; T3; t = 2.16, p = .015). In order to account for the possible confounding influence of age, SES, and BMI, these covariates were included in all statistical models.

CRP measures were first log transformed to bring outliers closer to the mean. Linear mixed effects models were employed to determine the associations between maltreatment exposure and CRP concentration across all visits. Restricted maximum likelihood estimation was performed. These models allow inclusion of all subjects with incomplete measurements in the repeated measures variables. This method does not impute any data, but rather uses each case available to compute maximum likelihood estimates, thereby minimizing biased estimates (Snijders & Bosker, Reference Snijders and Bosker2012). The final sample included in the mixed effects model consisted of N = 173 children. The models included a random intercept term as well as an autoregressive (AR(1)) heterogeneous covariance structure in order to account for the expected within-subject correlation of CRP across time (clinical visits).

To examine group differences between the maltreatment and comparison group across all time points, group status was entered as the predictor, along with the covariates age, SES and BMI, and child sex (main effect model, Model 1).

In a second step, to test effect modification by child sex, an interaction term between group status and child sex (Group×Child sex) was entered as an additional predictor (Model 2).

Third, to test whether the observed differences in CRP concentrations remained stable or were associated with different trajectories over time, an additional interaction term with time point (Group×Child sex×Time point) was entered (Model 3).

Results

In the main effect model (Model 1), CRP concentrations did not differ between the maltreatment and control group across all clinical visits (B = −0.030, F = −0.048, p = .827). Among the other predictors in the model, only SES was significantly and negatively associated with CRP levels (B = −0.026, F = −4.644, p = .032).

Model 2 revealed that the association between maltreatment and CRP concentrations was significantly moderated by child sex (interaction term Group×Maltreatment B = .538, F = 5.648, p = .019), such that in girls, CRP concentrations were higher across all clinical visits in the maltreatment compared to the control group, whereas in boys, there was no association between maltreatment status and CRP levels (see Table 2 and Figure 1).

Figure 1.

Mean (+ SE) CRP concentration in girls and boys of the maltreatment and comparison group at each clinical visit (T0-4). CRP, C-reactive protein.

Table 2.

Effect estimates of the linear mixed effects model with C-reactive protein (CRP) (Ln) as the outcome and maltreatment status, sex, Maltreatment×Sex and potentially confounding covariates as predictors

Note. Test of fixed effects, Type III; SE, standard error; CI, confidence interval; CRP, C-reactive protein; SES, socioeconomic status.

The differences in CRP concentrations between girls in the maltreatment and the comparison group were stable across all visits, as suggested by the nonsignificant coefficient of the three-way interaction Group×Sex×Time point (Model 3: B = .028, F = .316, p = .814).

Discussion

We here prospectively examined the association between childhood maltreatment and inflammation in the immediate aftermath of the exposure and over a 2-year follow-up period in very young children (3–5 years age). Our results suggest a sex-specific effect of childhood maltreatment exposure on CRP concentrations, such that after accounting for potential confounders like SES, BMI, and age, maltreated girls exhibited higher CRP concentrations at study entry and over a 2-year follow-up period compared to nonexposed girls, whereas there was no association between maltreatment and CRP in boys.

Our findings are in line with those of earlier studies that show associations between childhood adversity and a pro-inflammatory states in adults, adolescence, and children (Baumeister et al., Reference Baumeister, Akhtar, Ciufolini, Pariante and Mondelli2016; Cicchetti et al., Reference Cicchetti, Handley and Rogosch2015; Coelho et al., Reference Coelho, Viola, Walss-Bass, Brietzke and Grassi-Oliveira2014; Danese et al., Reference Danese, Pariante, Caspi, Taylor and Poulton2007; Danese et al., Reference Danese, Caspi, Williams, Ambler, Sugden, Mika and Arseneault2011;Rasmussen et al., Reference Rasmussen, Moffitt, Eugen-Olsen, Belsky, Danese, Harrington and Caspi2019; Slopen et al., Reference Slopen, Kubzansky, McLaughlin and Koenen2013; Tyrka et al., Reference Tyrka, Parade, Valentine, Eslinger and Seifer2015). We here find that this effect emerges right after exposure in very young children. We replicate findings from previous studies that suggest that lower SES is associated with increased inflammation (see Milaniak & Jaffee [Reference Milaniak and Jaffee2019] for a recent meta-analysis). Our study tested for sex-specific effects of early-life stress on inflammation at this very early age, and our observation of a sex-specific effect of childhood maltreatment on CRP concentrations replicates findings from a recent study in young adults (Baldwin et al., Reference Baldwin, Arseneault, Caspi, Fisher, Moffitt, Odgers and Danese2018).

There are several potential pathways and mechanisms through which exposure to childhood maltreatment can induce a pro-inflammatory state (Danese & Lewis, Reference Danese and Lewis2017): acute stress through stimulation of the sympathetic nervous system can prompt an acute inflammatory response (Prather et al., Reference Prather, Carroll, Fury, McDade, Ross and Marsland2009; Steptoe, Hamer, & Chida, Reference Steptoe, Hamer and Chida2007) and induces the up-regulation of the transcription factor NF-κB, a key regulator of inflammation, in circulating immune cells (Bierhaus et al., Reference Bierhaus, Wolf, Andrassy, Rohleder, Humpert, Petrov and Nawroth2003). Short-term activation of the inflammatory response during sensitive periods in early development may affect brain development and later microglia and neuroendocrine reactivity. Furthermore, early-life stress may be indirectly linked to inflammation through neuroendocrine dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Childhood trauma is associated with hyperactivity of the HPA axis (Danese & McEwen, Reference Danese and McEwen2012; Gunnar & Quevedo, Reference Gunnar and Quevedo2007; Heim, Newport, Bonsall, Miller, & Nemeroff, Reference Heim, Newport, Bonsall, Miller and Nemeroff2001), presumably because of reduced sensitivity of the glucocorticoid receptor (GR), which mediates the HPA axis negative feedback. Owing to the increased resistance of the GR that expands to immune cells, the anti-inflammatory properties of cortisol are also reduced, resulting in higher inflammation levels particularly after acute stress exposure (Heim et al., Reference Heim, Newport, Heit, Graham, Wilcox, Bonsall and Nemeroff2000; Miller, Cohen, & Ritchey, Reference Miller, Cohen and Ritchey2002; Pace et al., Reference Pace, Mletzko, Alagbe, Musselman, Nemeroff, Miller and Heim2006). In addition, as proposed and reviewed by Danese and Lewis (Reference Danese and Lewis2017) psychological trauma may cooccur with physical trauma which can facilitate pathogen infection that in turn can induce inflammation. Furthermore, early-life stress has been associated with disruption of sleep, the composition of the microbiome, and self-harming behavior, all of which can contribute to a pro-inflammatory state.

Sex differences in the effects of maltreatment on inflammation may be explained by sex-related differences in HPA axis regulation and immune system function. The sexual differentiation of the brain induces neuroanatomical and physiological changes that impact the neuroendocrine stress response (McCarthy, Reference McCarthy2016), and a substantial amount of literature has reported sex differences in HPA axis activity and reactivity in adults and children (Hollanders, van der Voorn, Rotteveel, & Finken, Reference Hollanders, van der Voorn, Rotteveel and Finken2017; van der Voorn, Hollanders, Ket, Rotteveel, & Finken, Reference van der Voorn, Hollanders, Ket, Rotteveel and Finken2017). Stress-related immune activation is also affected by sex (Rampp et al., Reference Rampp, Eichelkraut, Best, Czamara, Rex-Haffner, Uhr and Menke2018; Rohleder et al., Reference Rohleder, Schommer, Hellhammer, Engel and Kirschbaum2001), inflammation-related genes exhibit unique expression profiles in males and females based on interactions between estrogen and glucocorticoid receptors (Deak et al., Reference Deak, Quinn, Cidlowski, Victoria, Murphy and Sheridan2015), and glucocorticoids do not work as potently as anti-inflammatory molecules in females versus males in response to a global inflammatory challenge (Duma, Collins, Chou, & Cidlowski, Reference Duma, Collins, Chou and Cidlowski2010). As speculated by Baldwin et al. (Reference Baldwin, Arseneault, Caspi, Fisher, Moffitt, Odgers and Danese2018), in their study in adolescence, sex hormones may partly contribute to the observed sex-specific effects because testosterone levels in male adolescents negatively correlate with CRP levels (Shanahan et al., Reference Shanahan, Copeland, Worthman, Erkanli, Angold and Costello2013). However, in our very young cohort it is unlikely that differences in sex hormones at the time of exposure may have directly contributed to the observed sex-specific effect. Developmentally programmed sex differences at this early age in brain development and immune function rather emerge through contributions of differential expression of X and Y chromosome genes in cells (Marrocco & McEwen, Reference Marrocco and McEwen2016). Furthermore, androgen exposure during earlier developmental windows (testosterone is elevated in male compared to female fetuses between about 8 and 24 weeks of gestation [Reyes, Boroditsky, Winter, & Faiman, Reference Reyes, Boroditsky, Winter and Faiman1974] and peaks again at 1–3 months of age [Winter, Hughes, Reyes, & Faiman, Reference Winter, Hughes, Reyes and Faiman1976]) may differentially imprint or prime the male and female brain and the immune system for effects of stress exposure during later developmental stages (Marrocco & McEwen, Reference Marrocco and McEwen2016). In addition, sexually dimorphic trajectories of brain development have been observed, with in general more rapid maturation in females, potentially rendering them more vulnerable to adverse exposures at this early age (Lenroot et al., Reference Lenroot, Gogtay, Greenstein, Wells, Wallace, Clasen and Giedd2007). The association between childhood maltreatment and inflammation in males as observed in other studies with older individuals may emerge later in life when males exposed to early-life stress engage in more unhealthy behaviors that are associated with inflammation (Danese & Baldwin, Reference Danese and Baldwin2017).

A key strength of the present study was the prospective, longitudinal study design, which enabled us to test for associations between maltreatment and inflammation right after exposure and over a 2-year period. Another strength involves the thorough assessment of maltreatment and the absence of it in the comparison group. Limitations are the relatively small sample size and the attrition rate over the 2-year follow-up, and that CRP concentrations were assessed in saliva and not in serum. However, moderate to strong associations between serum and salivary CRP levels have been reported (Ouellet-Morin et al., Reference Ouellet-Morin, Danese, Williams and Arseneault2011; Out et al., Reference Out, Hall, Granger, Page and Woods2012), and CRP levels and other inflammatory makers have been assessed in saliva in several other studies investigating the relationship between childhood maltreatment and inflammation (Cicchetti et al., Reference Cicchetti, Handley and Rogosch2015; Tyrka et al., Reference Tyrka, Parade, Valentine, Eslinger and Seifer2015). How these CRP trajectories in children relate to alterations in other biological system as well as clinical and developmental trajectories over time will be the aim of future, forthcoming analyses in this cohort.

Our finding of increased inflammation in young girls exposed to maltreatment has important clinical implications, because it may predispose them for a range of diseases in later life in which inflammation plays a dominant pathological role, including cardiovascular disease, cardiovascular disease, cancer, diabetes mellitus, autoimmune and neurodegenerative disorders, and psychopathology including depression (Furman et al., Reference Furman, Campisi, Verdin, Carrera-Bastos, Targ, Franceschi and Slavich2019). Moreover, the observed sex-specific association may have consequences for treatment success of depression, since depressed patients with elevated inflammation are less likely to respond to conventional antidepressants (Cattaneo et al., Reference Cattaneo, Gennarelli, Uher, Breen, Farmer, Aitchison and Pariante2013; Chamberlain et al., Reference Chamberlain, Cavanagh, de Boer, Mondelli, Jones, Drevets and Bullmore2018). We argued previously that novel intervention strategies that are mechanism driven and sensitive to developmental timing should be developed, which we can offer to victims of early adversity in order to efficiently prevent or reverse adverse health outcomes (Heim, Entringer, & Buss, Reference Heim, Entringer and Buss2019). Based on the findings of the current study, girls exposed to maltreatment might benefit from early interventions targeting inflammatory pathways, for example through anti-inflammatory agents (Rook, Raison, & Lowry, Reference Rook, Raison and Lowry2012) and interventions such as exercise (Gleeson et al., Reference Gleeson, Bishop, Stensel, Lindley, Mastana and Nimmo2011), healthy diet (Minihane et al., Reference Minihane, Vinoy, Russell, Baka, Roche, Tuohy and Calder2015), and cognitive- and meditation-based therapies (Creswell et al., Reference Creswell, Irwin, Burklund, Lieberman, Arevalo, Ma and Cole2012) to prevent or treat pathological outcomes following maltreatment exposure in early childhood.

To conclude, our findings contribute to the existing literature on the association between childhood maltreatment and inflammation, and suggest that the effect may already emerge right after exposure at a very young age in girls and manifest over time. Our study provides important evidence for the development of personalized, early intervention strategies targeting the early-life period in order to mitigate the adverse consequences of childhood maltreatment and to program lifelong health in children.

Funding Statement

This work was funded by BMBF grant 01K13101-A (to CH) and 01K13101-B (to EB).

Conflict of Interest

None

Footnotes

*

Both authors contributed equally to this work.

References

Baldwin, J. R., Arseneault, L., Caspi, A., Fisher, H. L., Moffitt, T. E., Odgers, C. L., … Danese, A. (2018). Childhood victimization and inflammation in young adulthood: A genetically sensitive cohort study. Brain, Behavior and Immunity, 67, 211–217. doi:10.1016/j.bbi.2017.08.025CrossRefGoogle ScholarPubMed
Barnett, D., Manly, J. T., & Cicchetti, D. (1993). Defining child maltreatment: The interface between policy and research. In Cicchetti, D. & Toth, S. L. (Eds.), Child abuse, child development, and social policy (pp. 7–73). Norwood, NJ: Ablex.Google Scholar
Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C. M., & Mondelli, V. (2016). Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Molecular Psychiatry, 21, 642–649. doi:10.1038/mp.2015.67CrossRefGoogle ScholarPubMed
Bierhaus, A., Wolf, J., Andrassy, M., Rohleder, N., Humpert, P. M., Petrov, D., … Nawroth, P. P. (2003). A mechanism converting psychosocial stress into mononuclear cell activation. Proceedings of the National Academy of Sciences USA, 100, 1920–1925. doi:10.1073/pnas.0438019100CrossRefGoogle ScholarPubMed
Brown, D. W., Anda, R. F., Tiemeier, H., Felitti, V. J., Edwards, V. J., Croft, J. B., & Giles, W. H. (2009). Adverse childhood experiences and the risk of premature mortality. American Journal of Preventive Medicine, 37, 389–396.CrossRefGoogle ScholarPubMed
Cattaneo, A., Gennarelli, M., Uher, R., Breen, G., Farmer, A., Aitchison, K. J., … Pariante, C. M. (2013). Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology, 38, 377–385. doi:10.1038/npp.2012.191CrossRefGoogle Scholar
Chamberlain, S. R., Cavanagh, J., de Boer, P., Mondelli, V., Jones, D. N. C., Drevets, W. C., … Bullmore, E. T. (2018). Treatment-resistant depression and peripheral C-reactive protein. British Journal of Psychiatry, 214, 1–9. doi:10.1192/bjp.2018.66.Google ScholarPubMed
Cicchetti, D., Handley, E. D., & Rogosch, F. A. (2015). Child maltreatment, inflammation, and internalizing symptoms: Investigating the roles of C-reactive protein, gene variation, and neuroendocrine regulation. Development and Psychopathology, 27, 553–566. doi:10.1017/S0954579415000152CrossRefGoogle ScholarPubMed
Cicchetti, D., Toth, S. L., & Manly, J. T. (2003). Maternal Child Maltreatment Interview (MDMI).Google Scholar
Coelho, R., Viola, T. W., Walss-Bass, C., Brietzke, E., & Grassi-Oliveira, R. (2014). Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatrica Scandinavica, 129, 180–192. doi:10.1111/acps.12217CrossRefGoogle ScholarPubMed
Creswell, J. D., Irwin, M. R., Burklund, L. J., Lieberman, M. D., Arevalo, J. M., Ma, J., … Cole, S. W. (2012). Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain Behaviour and Immunity, 26, 1095–1101. doi:10.1016/j.bbi.2012.07.006CrossRefGoogle ScholarPubMed
Danese, A., & Baldwin, J. R. (2017). Hidden wounds? Inflammatory links between childhood trauma and psychopathology. Annual Review of Psychology, 68, 517–544. doi:10.1146/annurev-psych-010416-044208CrossRefGoogle ScholarPubMed
Danese, A., Caspi, A., Williams, B., Ambler, A., Sugden, K., Mika, J., … Arseneault, L. (2011). Biological embedding of stress through inflammation processes in childhood. Molecular Psychiatry, 16, 244–246. doi:10.1038/mp.2010.5CrossRefGoogle ScholarPubMed
Danese, A., & Lewis, J. S. (2017). Psychoneuroimmunology of early-life stress: The hidden wounds of childhood trauma? Neuropsychopharmacology, 42, 99–114. doi:10.1038/npp.2016.198CrossRefGoogle ScholarPubMed
Danese, A., & McEwen, B. S. (2012). Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiology & Behaviour, 106, 29–39. doi:10.1016/j.physbeh.2011.08.019CrossRefGoogle ScholarPubMed
Danese, A., Pariante, C. M., Caspi, A., Taylor, A., & Poulton, R. (2007). Childhood maltreatment predicts adult inflammation in a life-course study. Proceedings of the National Academy of Sciences USA, 104, 1319–1324. doi:10.1073/pnas.0610362104CrossRefGoogle Scholar
Deak, T., Quinn, M., Cidlowski, J. A., Victoria, N. C., Murphy, A. Z., & Sheridan, J. F. (2015). Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease. Stress, 18, 367–380. doi:10.3109/10253890.2015.1053451CrossRefGoogle ScholarPubMed
Duma, D., Collins, J. B., Chou, J. W., & Cidlowski, J. A. (2010). Sexually dimorphic actions of glucocorticoids provide a link to inflammatory diseases with gender differences in prevalence. Science Signaling, 3, ra74. doi:10.1126/scisignal.2001077CrossRefGoogle ScholarPubMed
Engel, M. L., & Gunnar, M. R. (2020). The development of stress reactivity and regulation during human development. International Review of Neurobiology, 150, 41–76. doi:10.1016/bs.irn.2019.11.003CrossRefGoogle ScholarPubMed
Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., … Marks, J. S. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The adverse childhood experiences (ACE) study. American Journal of Preventive Medicine, 14, 245–258.CrossRefGoogle ScholarPubMed
Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., … Slavich, G. M. (2019). Chronic inflammation in the etiology of disease across the life span. Nature Medicine, 25, 1822–1832. doi:10.1038/s41591-019-0675-0CrossRefGoogle ScholarPubMed
Ganguly, P., & Brenhouse, H. C. (2015). Broken or maladaptive? Altered trajectories in neuroinflammation and behavior after early life adversity. Developmental Cognitive Neuroscience, 11, 18–30. doi:10.1016/j.dcn.2014.07.001CrossRefGoogle ScholarPubMed
Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R., Mastana, S. S., & Nimmo, M. A. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nature Reviews Immunology, 11, 607–615. doi:10.1038/nri3041CrossRefGoogle ScholarPubMed
Gunnar, M., & Quevedo, K. (2007). The neurobiology of stress and development. Annual Reviews of Psychology, 58, 145–173. doi:10.1146/annurev.psych.58.110405.085605CrossRefGoogle ScholarPubMed
Heim, C., & Binder, E. B. (2012). Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Experiments in Neurology, 233, 102–111. doi:10.1016/j.expneurol.2011.10.032CrossRefGoogle ScholarPubMed
Heim, C. M., Entringer, S., & Buss, C. (2019). Translating basic research knowledge on the biological embedding of early-life stress into novel approache. Psychoneuroendocrinology, 105, 123–137. doi: 10.1016/j.psyneuen.2018.12.011.CrossRefGoogle Scholar
Heim, C., Newport, D. J., Bonsall, R., Miller, A. H., & Nemeroff, C. B. (2001). Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. American Journal of Psychiatry, 158, 575–581.CrossRefGoogle ScholarPubMed
Heim, C., Newport, D. J., Heit, S., Graham, Y. P., Wilcox, M., Bonsall, R., … Nemeroff, C. B. (2000). Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. Journal of the American Medical Association, 284, 592–597.CrossRefGoogle ScholarPubMed
Herzberg, M. P., & Gunnar, M. R. (2020). Early life stress and brain function: Activity and connectivity associated with processing emotion and reward. Neuroimage, 209, 116493. doi:10.1016/j.neuroimage.2019.116493CrossRefGoogle ScholarPubMed
Hollanders, J. J., van der Voorn, B., Rotteveel, J., & Finken, M. J. J. (2017). Is HPA axis reactivity in childhood gender-specific? A Systematic Review. Biology of Sex Differences, 8, 23. doi:10.1186/s13293-017-0144-8CrossRefGoogle ScholarPubMed
Lange, M., Kamtsiuris, P., Lange, C., Schaffrath Rosario, A., Stolzenberg, H., & Lampert, T. (2007). Sociodemographic characteristics in the German health interview and examination survey for children and adolescents (KiGGS) – operationalisation and public health significance, taking as an example the assessment of general state of health. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 50, 578–589. doi:10.1007/s00103-007-0219-5CrossRefGoogle ScholarPubMed
Lenroot, R. K., Gogtay, N., Greenstein, D. K., Wells, E. M., Wallace, G. L., Clasen, L. S., … Giedd, J. N. (2007). Sexual dimorphism of brain developmental trajectories during childhood and adolescence. Neuroimage, 36, 1065–1073. doi:10.1016/j.neuroimage.2007.03.053CrossRefGoogle ScholarPubMed
Marrocco, J., & McEwen, B. S. (2016). Sex in the brain: hormones and sex differences. Dialogues in Clinical Neuroscience, 18, 373–383.CrossRefGoogle ScholarPubMed
McCarthy, M. M. (2016). Sex differences in the developing brain as a source of inherent risk. Dialogues in Clinical Neuroscience, 18, 361–372.CrossRefGoogle ScholarPubMed
Milaniak, I., & Jaffee, S. R. (2019). Childhood Socioeconomic Status and Inflammation: A systematic review and meta-analysis. Brain, Behaviour and Immunity, 78, 161–176. doi:10.1016/j.bbi.2019.01.018.CrossRefGoogle ScholarPubMed
Miller, G., Chen, E., & Cole, S. W. (2009). Health psychology: developing biologically plausible models linking the social world and physical health. Annual Reviews of Psychology, 60, 501–524. doi:10.1146/annurev.psych.60.110707.163551CrossRefGoogle ScholarPubMed
Miller, G. E., Cohen, S., & Ritchey, A. K. (2002). Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychology, 21, 531–541. doi:10.1037//0278-6133.21.6.531CrossRefGoogle ScholarPubMed
Minihane, A. M., Vinoy, S., Russell, W. R., Baka, A., Roche, H. M., Tuohy, K. M., … Calder, P. C. (2015). Low-grade inflammation, diet composition and health: current research evidence and its translation. British Journal of Nutrition, 114, 999–1012. doi:10.1017/S0007114515002093CrossRefGoogle ScholarPubMed
Norman, R. E., Byambaa, M., De, R., Butchart, A., Scott, J., & Vos, T. (2012). The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis. PLoS Medicine, 9, e1001349. doi:10.1371/journal.pmed.1001349.CrossRefGoogle ScholarPubMed
Ouellet-Morin, I., Danese, A., Williams, B., & Arseneault, L. (2011). Validation of a high-sensitivity assay for C-reactive protein in human saliva. Brain, Behaviour and Immunity, 25, 640–646. doi:10.1016/j.bbi.2010.12.020CrossRefGoogle ScholarPubMed
Out, D., Hall, R. J., Granger, D. A., Page, G. G., & Woods, S. J. (2012). Assessing salivary C-reactive protein: longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence. Brain, Behaviour and Immunity, 26, 543–551. doi:10.1016/j.bbi.2012.01.019CrossRefGoogle ScholarPubMed
Pace, T. W., Mletzko, T. C., Alagbe, O., Musselman, D. L., Nemeroff, C. B., Miller, A. H., & Heim, C. M. (2006). Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. American Journal of Psychiatry, 163, 1630–1633. doi:10.1176/appi.ajp.163.9.1630CrossRefGoogle ScholarPubMed
Prather, A. A., Carroll, J. E., Fury, J. M., McDade, K. K., Ross, D., & Marsland, A. L. (2009). Gender differences in stimulated cytokine production following acute psychological stress. Brain, Behaviour and Immunity, 23, 622–628. doi:10.1016/j.bbi.2008.11.004CrossRefGoogle ScholarPubMed
Rampp, C., Eichelkraut, A., Best, J., Czamara, D., Rex-Haffner, M., Uhr, M., … Menke, A. (2018). Sex-related differential response to dexamethasone in endocrine and immune measures in depressed in-patients and healthy controls. Journal of Psychiatric Research, 98, 107–115. doi:10.1016/j.jpsychires.2017.12.020CrossRefGoogle ScholarPubMed
Rasmussen, L. J. H., Moffitt, T. E., Eugen-Olsen, J., Belsky, D. W., Danese, A., Harrington, H., … Caspi, A. (2019). Cumulative childhood risk is associated with a new measure of chronic inflammation in adulthood. Journal of Child Psychology and Psychiatry, 60, 199–208. doi:10.1111/jcpp.12928CrossRefGoogle ScholarPubMed
Reyes, F. I., Boroditsky, R. S., Winter, J. S., & Faiman, C. (1974). Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. Journal of Clinical Endocrinology and Metabolism, 38, 612–617. doi:10.1210/jcem-38-4-612CrossRefGoogle ScholarPubMed
Rohleder, N., Schommer, N. C., Hellhammer, D. H., Engel, R., & Kirschbaum, C. (2001). Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosomatic Medicine, 63, 966–972. doi:10.1097/00006842-200111000-00016CrossRefGoogle ScholarPubMed
Rook, G. A., Raison, C. L., & Lowry, C. A. (2012). Can we vaccinate against depression? Drug Discovery Today, 17, 451–458. doi:10.1016/j.drudis.2012.03.018CrossRefGoogle ScholarPubMed
Rosario, A. S., Kurth, B. M., Stolzenberg, H., Ellert, U., & Neuhauser, H. (2010). Body mass index percentiles for children and adolescents in Germany based on a nationally representative sample (KiGGS 2003-2006). European Journal of Clinical Nutrition, 64, 341–349. doi:10.1038/ejcn.2010.8CrossRefGoogle Scholar
Shanahan, L., Copeland, W. E., Worthman, C. M., Erkanli, A., Angold, A., & Costello, E. J. (2013). Sex-differentiated changes in C-reactive protein from ages 9 to 21: the contributions of BMI and physical/sexual maturation. Psychoneuroendocrinology, 38, 2209–2217. doi:10.1016/j.psyneuen.2013.04.010CrossRefGoogle ScholarPubMed
Slopen, N., Kubzansky, L. D., McLaughlin, K. A., & Koenen, K. C. (2013). Childhood adversity and inflammatory processes in youth: a prospective study. Psychoneuroendocrinology, 38, 188–200. doi:10.1016/j.psyneuen.2012.05.013CrossRefGoogle ScholarPubMed
Snijders, T. A. B., & Bosker, R. J. (2012). Multilevel analysis: An introduction to basic and advanced multilevel modeling (2nd ed.). London: Sage Publishers.Google Scholar
Steptoe, A., Hamer, M., & Chida, Y. (2007). The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain, Behaviour and Immunity, 21, 901–912. doi:10.1016/j.bbi.2007.03.011CrossRefGoogle ScholarPubMed
Stoltenborgh, M., Bakermans-Kranenburg, M. J., Alink, L. R. A., & van IJzendoorn, M. H. (2015). The prevalence of child maltreatment across the globe: Review of a series of meta-analyses. Child Abuse Review, 24, 37–50. doi:10.1002/car.2353CrossRefGoogle Scholar
Tyrka, A. R., Parade, S. H., Valentine, T. R., Eslinger, N. M., & Seifer, R. (2015). Adversity in preschool-aged children: Effects on salivary interleukin-1beta. Development and Psychopathology, 27, 567–576. doi:10.1017/S0954579415000164CrossRefGoogle ScholarPubMed
van der Voorn, B., Hollanders, J. J., Ket, J. C. F., Rotteveel, J., & Finken, M. J. J. (2017). Gender-specific differences in hypothalamus-pituitary-adrenal axis activity during childhood: a systematic review and meta-analysis. Biology of Sex Differences, 8, 3. doi:10.1186/s13293-016-0123-5CrossRefGoogle ScholarPubMed
Wegman, H. L., & Stetler, C. (2009). A meta-analytic review of the effects of childhood abuse on medical outcomes in adulthood. Psychosomatic Medicine, 71, 805–812. doi:10.1097/PSY.0b013e3181bb2b46CrossRefGoogle ScholarPubMed
Winter, J. S., Hughes, I. A., Reyes, F. I., & Faiman, C. (1976). Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. Journal of Clinical Endocrinology and Metabolism, 42, 679–686. doi:10.1210/jcem-42-4-679CrossRefGoogle Scholar
Figure 0

Table 1. Sample characteristics of children in the control and maltreatment group at baseline (T0)

Figure 1

Figure 1. Mean (+ SE) CRP concentration in girls and boys of the maltreatment and comparison group at each clinical visit (T0-4). CRP, C-reactive protein.

Figure 2

Table 2. Effect estimates of the linear mixed effects model with C-reactive protein (CRP) (Ln) as the outcome and maltreatment status, sex, Maltreatment×Sex and potentially confounding covariates as predictors