Adverse childhood experiences and lower urinary tract symptoms in adolescence: the mediating effect of inflammation
Authors: Burrows Kimberley , Heron Jon , Hammerton Gemma , Goncalves Soares Ana L. , Joinson Carol 
Published: May 2024

AbstractBackgroundThere is evidence that adverse childhood experiences (ACEs) are associated with lower urinary tract symptoms (LUTS) in adulthood, but few studies have explored these associations in adolescence. Little is known about the biological mechanisms that could explain these associations. We examine whether inflammatory biomarkers mediate the relationship between ACEs and LUTS in adolescence.MethodsWe used data from 4,745 participants from the Avon Longitudinal Study of Parents and Children on ACEs (10 ‘classical’ ACEs assessed from birth to age 8), LUTS at age 14 (any urinary incontinence (UI), daytime and bedwetting, urgency, nocturia, frequent urination, voiding postponement, and low voiding volume) and inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP) measured at age 9. We first examined associations between the (i) ACE score (summed score [scale of 0 to 10] of total ACEs) and LUTS and (ii) inflammation and LUTS using multivariable logistic regression. We evaluated the mediating effects of IL-6 and CRP on the association between the ACE score and LUTS using the parametric g-formula whilst adjusting for baseline and intermediate confounders.FindingsHigher ACE scores were associated with increased odds of LUTS, e.g. a one-unit increase in ACE score was associated with an increase in the odds of any UI (odds ratio [OR] 1·16, 95% confidence interval [CI] 1·03-1·30). Higher levels of IL-6 were associated with increased odds of LUTS, e.g. any UI (OR 1·24, 95%CI 1·05-1·47). There was weak evidence that the associations between ACE score and any UI, daytime wetting, bedwetting, urgency, and frequency were mediated by IL-6 (e.g. any UI ORnatural indirect effect1·03, 95%CI 1·00-1·06, proportion mediated 21%). There was no evidence that CRP was associated with LUTS, nor mediated the association between ACE score and LUTS.InterpretationThis study reports novel findings that could shed light on the biological mechanisms that underlie the link between ACEs and LUTS. Early intervention is needed in childhood to prevent LUTS persisting into adolescence.FundingMedical Research Council (grant ref: MR/V033581/1: Mental Health and Incontinence).Research in contextEvidence before this studyThere is growing evidence that adverse childhood experiences (ACEs) are associated with an increased risk of lower urinary tract symptoms (LUTS), but the mechanisms are unknown. One plausible biological mechanism is through ACEs leading to increased inflammation, which has been implicated as a contributing factor for LUTS. We searched PubMed and Google Scholar from March 2023 to January 2024 for studies published in English describing associations between ACEs (search terms: “adverse childhood experiences” OR “ACEs” OR “adversity” OR “adversities” OR “adverse experiences” OR “stressful life events”) and LUTS (search terms: “lower urinary tract symptoms” OR “incontinence” OR “overactive bladder” OR “enuresis” OR “bedwetting” OR “daytime wetting” OR “bladder symptoms” OR “urinary symptoms” OR “urgency”), ACEs and inflammation (search terms: “inflammation” OR “interleukin 6” OR “c reactive protein”), and inflammation and LUTS in populations of children, adolescents and adults (search terms: “child OR childhood”, “adolescent OR adolescence”, “adult”). We did not identify previous cohort studies that have explored the association between ACEs and LUTS during adolescence. Previous studies found that ACEs were associated with LUTS, but they focussed on relatively small samples of adult women, they relied on retrospective recall of ACEs, and one study lacked a control group without LUTS. No cohort studies have to our knowledge examined associations between inflammation and LUTS in adolescence.Added value of this studyTo our knowledge, this is the first cohort study to report that exposure to more ACEs between birth and 8 years is associated with an increased risk of subsequent LUTS in adolescence (age 14). We also found that inflammation increases the risk of subsequent LUTS. Finally, we show that the associations between ACEs and LUTS are partially mediated by the inflammation biomarker IL-6.Implication of all the available evidenceOur findings should raise awareness amongst clinicians of the importance of screening for ACEs in children presenting with LUTS. Evidence of biological mechanisms (such as inflammation) linking ACEs to LUTS could lead to the identification of novel translational targets for intervention and potential therapeutic advances in the treatment of LUTS.