Girls who are abused in early life have higher levels of inflammation than boys


New research by a University of Georgia scientist reveals that girls who are maltreated show higher levels of inflammation at an early age than boys who are maltreated or children who have not experienced abuse.

This finding may forecast chronic mental and physical health problems in midlife.

Led by psychologist Katherine Ehrlich, the study is the first to examine the link between abuse and low-grade inflammation during childhood.

Inflammation plays a role in many chronic diseases of aging–diabetes, cardiovascular disease, stroke, obesity–as well as mental health outcomes, and the findings suggest that maltreatment’s association with inflammation does not lie dormant before emerging in adulthood.

Instead, the study shows that traumatic experiences have a much more immediate impact.

“We and others have speculated that there’s something about the immune system that’s getting calibrated, particularly during childhood, that might be setting people up on long-term trajectories toward accelerated health problems,” said Ehrlich, assistant professor in the Franklin College of Arts and Sciences.

“What I’m struck by is just how early in development we can see these effects. What our study highlights is that, even as early as childhood, we can see that a substantial portion of the children have levels of inflammation that the American Heart Association considers ‘moderate risk’ for heart disease.

This is concerning from a public health perspective and suggests that these children may be at risk for significant health problems at an earlier age than their nonmaltreated peers.”

Participants in the study included 155 children aged 8-12 from low-income backgrounds who attended a weeklong day camp. The sample was racially diverse and included maltreated and nonmaltreated children.

Researchers captured detailed information on children’s exposure to abuse by utilizing Department of Human Services records about maltreatment experiences in families.

The children-documented experiences included neglect (55%), emotional maltreatment (67%), physical abuse (35%) and sexual abuse (8%). Many children experienced more than one type of abuse, and 35% of children experienced abuse across multiple developmental periods.

The team measured five biomarkers of low-grade inflammation using non-fasting blood samples from the children.

Results revealed that childhood maltreatment–for girls–was associated with higher levels of low-grade inflammation in late childhood. Girls who had been abused over multiple periods or had multiple kinds of exposures had the highest levels of inflammation. Girls’ greatest risk for elevated inflammation emerged when they were abused early in life, before the age of 5.

For boys in the study, exposure to maltreatment was not reflected in higher levels of inflammation, but Ehrlich cautioned against drawing conclusions without additional research targeted to boys.

“One question is, are these variations due to developmental timing differences?” she said. “We know that girls mature faster than boys in terms of their biological and physical development. If we tested these same boys two years later, would we find the same patterns of inflammation that we found for the girls?”

Co-authors include Dante Cicchetti, University of Minnesota and University of Rochester; Gregory E. Miller, Northwestern University; and Fred A. Rogosch, University of Rochester.

The relationship between adverse childhood experiences (ACEs), such as child maltreatment, parental divorce and parental mental illness, and a wide range of poorer health outcomes has been extensively studied, e.g.(Bellis et al., 2019).

The underlying biological mechanisms linking ACEs and poorer health are being increasingly unravelled thanks to the growing availability of high-quality longitudinal datasets with information on both ACEs and biomarkers. One particularly salient biological pathway of interest involves chronic inflammation.

Inflammation forms part of the innate immune response to physical trauma and infection. However, chronic activation of the inflammatory response can be harmful and is thought to be one of the key biological mechanisms linking ACEs to psychopathology (Danese and Baldwin, 2017) and cardiometabolic disease (Baldwin and Danese, 2019).

ACEs have been linked to chronic inflammation across the life course. For instance, recent studies have shown that early life adversities, such as parental mental illness (O’Connor et al., 2019) and the number of adversities experienced prior to age 9 (Flouri et al., 2020, Slopen et al., 2013) were associated with elevated Interleukin-6 (IL-6) and C-Reactive Protein (CRP) levels in childhood and adolescence.

Also children exposed to multiple ACEs or maltreatment in childhood had higher CRP levels in early adulthood (Baldwin et al., 2018, Danese et al., 2007) and beyond (Chen and Lacey, 2018). A systematic review by Baumeister et al (2015) included 25 studies, finding that overall childhood trauma was linked with higher levels of inflammation in adulthood.

Operationalising ACEs
ACE scores and single adversity approaches

There has been little consideration in the ACEs and inflammation literature thus far on how ACEs are operationalised and in comparing different methods. This is important to consider in order to elucidate the underlying mechanisms and planning of effective interventions.

It is recognised that ACEs tend to cluster so that people reporting one adversity are more likely to report others. In the Kaiser Permanente ACE study a high proportion of participants (between 81 and 98%) reporting an adversity reported at least one other (Dong et al., 2004).

Generally, studies into the health effects of ACEs have relied on a simple approach using cumulative adversity (i.e. ACE scores) whereby the number of adversities reported are summed to deal with this ACE clustering. For instance, Felitti’s study of adults in the Kaiser Permanente Adverse Childhood Experiences Study demonstrated a graded relationship between retrospectively reported ACE scores and multiple negative health outcomes, including risky health behaviours, heart disease, cancer and lung conditions (Felitti et al., 1998).

The ACE score approach has been widely applied in ACEs and health research, including to studies of inflammation (Chen and Lacey, 2018, Rasmussen et al., 2019, Slopen et al., 2015). However there are several limitations of this approach when investigating associations with health (Lacey and Minnis, 2019).

The most notable of these are the assumption that each adversity is equally important for a specific health outcome and the specific patterning of ACEs co-occurrence is ignored. For instance, the combination of parental mental illness and parental separation (ACE score of 2) is treated as the same as physical and sexual abuse (also an ACE score of 2) – which is unlikely to be the case. Moreover, as discussed elsewhere (Danese, 2019, Kelly-Irving and Delpierre, 2019), there are concerns regarding the potential misuse of ACE questionnaires and the resulting score.

One alternative to the ACE score approach is to explore the effect of each adversity separately. There are numerous studies which examine the association of single adversities on inflammation, e.g.(Pinto Pereira et al., 2019). It is likely that different adversities show different associations with inflammation. In a meta-analysis of childhood maltreatment and adult inflammation, sexual and physical abuse were associated with higher Tumour Necrosis Factor-α (TNF-α) and IL-6 but psychological abuse was not (Baumeister et al., 2015).

Also parental absence was associated with raised CRP but abuse experiences were not. Whilst looking at single adversities might be informative in teasing out the life course mechanisms involved e.g. (Lacey et al., 2013), the effects of that adversity might be confounded by the experience of other adversities which have not been accounted for in the analyses.

Person-centred approaches

Given the increasing recognition of the limitations of ACE score and single adversity approaches in ACEs research, there has been an emergence of alternative methods of operationalising ACEs which respect their clustering and are more informative when looking at associations with health. These alternative analytic approaches have included the person-centred methods (e.g. Latent Class Analysis, LCA). LCA is a data-driven approach which aims to identify distinct groups or classes of individuals who have similar patterns of reported adversities (Masyn, 2013). The use of LCA with ACEs data has increased in the past few years and allows the researcher to explore whether the specific patterning of ACEs is important for health outcomes.

Several studies have explored whether ACE classes obtained using LCA show differing associations with health outcomes. In a sample of German children aged 4–17 years, Witt et al. (2016) identified three maltreatment classes using LCA – ‘Multiple types of maltreatment excluding sexual abuse’ (63.1%), ‘Multiple types of maltreatment including sexual abuse’ (26.5%) and ‘Predominately sexual abuse (10.3%)’.

The second class showed the poorest health outcomes in terms of mental disorders and health-related quality of life suggesting that the combination of sexual abuse with other maltreatments (physical and psychological abuse, witnessing domestic violence and neglect) was particularly detrimental to health. Ho et al (2019) also identified three ACE classes among university students in Hong Kong – ‘Low ACEs’ (76.0%), ‘Household violence’ (20.6%) and ‘Household dysfunction’ (3.4%).

Students in the ‘Household violence’ class – characterised by high probability of reporting physical and psychological abuse and domestic violence – were more likely to report depression and maladjustment symptoms than those in the ‘Low ACEs’ class.

Whilst LCA is showing promise as an emerging approach to operationalising ACEs data, few studies have applied LCA to adversities beyond child maltreatment and there have been no studies to the authors’ knowledge that have explored whether different LCA-derived clusters show different associations with inflammation.

Comparing methods of ACEs operationalisation

There are few studies comparing the main approaches – ACE scores, single adversities and LCA – to ACEs operationalisation. Lanier et al. (2018) compared LCA to ACE scores using the 2011/12 US National Survey of Children’s Health. The ACE score showed a graded relationship with poor child health, the presence of chronic health conditions and special healthcare need – the three child health outcomes in the study.

The LCA identified seven classes ‘0–1 ACEs’ (76%), ‘1–2 ACEs’ (11%), ‘Domestic violence, no mental illness’ (3%), ‘Mental illness and poverty’ (1%), ‘Substance use and incarceration’ (2%), and ‘High ACEs’ (2%). The ‘Mental illness and poverty’ class was most strongly associated with poorer child health outcomes, suggesting that this specific ACE combination might be more important for the child health.

Similarly, Merians et al (2018) compared ACE scores to LCA of retrospectively-reported ACE measures from a sample of US college students. The differences between students with an ACE score of 5+ and those with no ACEs were comparable to the difference between the ‘High ACEs’ and ‘Low ACEs’ classes identified from the LCA, in terms of the magnitude of association and also the variance explained in the three outcomes (physical health, alcohol use consequences and academic performance).

Whilst these two studies compared two approaches to ACE operationalisation – typically ACE scores and LCA – there have been no studies as yet which have compared ACE scores, LCA and single adversities. Further there have been no studies which have investigated how different ACE operationalisations are linked to inflammation in adulthood.

Prospective vs retrospective ACEs measures

Another key methodological consideration in ACEs research is whether the information on adversities is reported prospectively or retrospectively. There has been a large reliance thus far on retrospective reports of adversities experienced in childhood. Recent work has demonstrated poor agreement between prospective and retrospective ACE reports, with the exception of separation from a parent (Baldwin et al., 2019).

Retrospective ACEs reports are influenced by various factors such as personality, current mental wellbeing and life stress (Colman et al., 2015, Jaffee, 2017, Reuben et al., 2016). Given these findings it is important that prospective and retrospective information is not used interchangeably.

Gaps in the literature and aim of the present study
Several gaps have been identified in the current literature.

There have been no studies as yet which have compared LCA, ACE scores and single adversity approaches to ACEs with adult inflammation. This is essential to investigate because it is likely that specific ACEs or ACE combinations are important for inflammatory responses to adversity. Furthermore, prospective and retrospective reports of ACEs show poor agreement.

Therefore, it is important to directly compare findings based on prospective and retrospective measures in the same individuals. Given these gaps, the aim of the present study was to examine the strength of associations between three approaches to ACEs operationalisation – ACE scores, single adversities and LCA – and two types of ACEs measures – prospective and retrospective – for adult inflammation in a large, longitudinal dataset in Great Britain (the 1958 British birth cohort).

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Source: University of Georgia


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