Adverse childhood experiences and lower urinary tract symptoms in adolescence: the mediating effect of inflammation

Background There 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.Methods We 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.Findings Higher 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] 1textperiodcentered16, 95CI] 1textperiodcentered03-1textperiodcentered30). Higher levels of IL-6 were associated with increased odds of LUTS, e.g. any UI (OR 1textperiodcentered24, 95textperiodcentered05-1textperiodcentered47). 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 effect 1textperiodcentered03, 95textperiodcentered00-1textperiodcentered06, proportion mediated 21. There was no evidence that CRP was associated with LUTS, nor mediated the association between ACE score and LUTS.Interpretation This 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.Funding Medical Research Council (grant ref: MR/V033581/1: Mental Health and Incontinence).Evidence before this study There 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: textquotedblleftadverse childhood experiencestextquotedblright OR textquotedblleftACEstextquotedblright OR textquotedblleftadversitytextquotedblright OR textquotedblleftadversitiestextquotedblright OR textquotedblleftadverse experiencestextquotedblright OR textquotedblleftstressful life eventstextquotedblright) and LUTS (search terms: textquotedblleftlower urinary tract symptomstextquotedblright OR textquotedblleftincontinencetextquotedblright OR textquotedblleftoveractive bladdertextquotedblright OR textquotedblleftenuresistextquotedblright OR textquotedblleftbedwettingtextquotedblright OR textquotedblleftdaytime wettingtextquotedblright OR textquotedblleftbladder symptomstextquotedblright OR textquotedbllefturinary symptomstextquotedblright OR textquotedbllefturgencytextquotedblright), ACEs and inflammation (search terms: textquotedblleftinflammationtextquotedblright OR textquotedblleftinterleukin 6textquotedblright OR textquotedblleftc reactive proteintextquotedblright), and inflammation and LUTS in populations of children, adolescents and adults (search terms: textquotedblleftchild OR childhoodtextquotedblright, textquotedblleftadolescent OR adolescencetextquotedblright, textquotedblleftadulttextquotedblright). 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 study To 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 evidence Our 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.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work is supported by funding from the Medical Research Council (grant ref: MR/V033581/1: Mental Health and Incontinence). GH, AGS, and JH are members of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7). AGS’ salary is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 874739 (LongITools). The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Kimberley Burrows will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website: http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesALSPAC data are available by request from the ALSPAC Executive Committee for researchers who meet the criteria for access to confidential data (https://bristol.ac.uk/alspac/researchers/access/).